Nanotechnology for Multimodal Synergistic Cancer Therapy

Review Cite This: Chem. Rev. 2017, 117, 13566-13638

pubs.acs.org/CR

Nanotechnology for Multimodal Synergistic Cancer Therapy Wenpei Fan,†,‡,§ Bryant Yung,§ Peng Huang,*,† and Xiaoyuan Chen*,§ †

Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen 518060, China ‡ Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong Province, College of Optoelectronic Engineering, Shenzhen University, Shenzhen 518060, China § Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland 20892, United States ABSTRACT: The complexity, diversity, and heterogeneity of tumors seriously undermine the therapeutic potential of treatment. Therefore, the current trend in clinical research has gradually shifted from a focus on monotherapy to combination therapy for enhanced treatment efficacy. More importantly, the cooperative enhancement interactions between several types of monotherapy contribute to the naissance of multimodal synergistic therapy, which results in remarkable superadditive (namely “1 + 1 > 2”) effects, stronger than any single therapy or their theoretical combination. In this review, state-ofthe-art studies concerning recent advances in nanotechnology-mediated multimodal synergistic therapy will be systematically discussed, with an emphasis on the construction of multifunctional nanomaterials for realizing bimodal and trimodal synergistic therapy as well as the intensive exploration of the underlying synergistic mechanisms for explaining the significant improvements in synergistic therapeutic outcome. Furthermore, the featured applications of multimodal synergistic therapy in overcoming tumor multidrug resistance, hypoxia, and metastasis will also be discussed in detail, which may provide new ways for the efficient regression and even elimination of drug resistant, hypoxic solid, or distant metastatic tumors. Finally, some design tips for multifunctional nanomaterials and an outlook on the future development of multimodal synergistic therapy will be provided, highlighting key scientific issues and technical challenges and requiring remediation to accelerate clinical translation.

CONTENTS 1. Introduction 1.1. Status Quo of Cancer Monotherapy 1.2. Definition of “Multimodal Synergistic Therapy” 1.3. Advantages of Nanotechnology for Multimodal Synergistic Therapy 1.4. Scope of This Review 2. Classification and Characteristics of Major Cancer Monotherapies 2.1. Chemotherapy 2.2. Gene Therapy (GT) 2.3. Immunotherapy 2.4. Photodynamic Therapy (PDT) 2.5. Photothermal Therapy (PTT) 2.6. Radiotherapy (RT) 2.7. Magnetic Hyperthermia (MHT) 2.8. High Intensity Focused Ultrasound (HIFU) 3. Nanotechnology for Bimodal Synergistic Therapy 3.1. Chemotherapy-Based Bimodal Synergistic Therapy 3.1.1. Chemotherapy-Enhanced Immunotherapy 3.1.2. Chemotherapy-Enhanced RT 3.2. GT-Based Bimodal Synergistic Therapy

© 2017 American Chemical Society

3.2.1. GT-Enhanced Chemotherapy 3.2.2. GT-Enhanced PDT 3.2.3. GT-Enhanced PTT 3.3. PDT-Based Bimodal Synergistic Therapy 3.3.1. PDT-Enhanced Chemotherapy 3.3.2. PDT-Enhanced Immunotherapy 3.3.3. PDT-Enhanced RT 3.4. PTT-Based Bimodal Synergistic Therapy 3.4.1. PTT-Enhanced Chemotherapy 3.4.2. PTT-Enhanced GT 3.4.3. PTT-Enhanced Immunotherapy 3.4.4. PTT-Enhanced PDT 3.4.5. PTT-Enhanced RT 3.5. MHT/HIFU-Enhanced Chemotherapy 3.6. Other Potential Forms of Bimodal Synergistic Therapy 3.7. Featured Applications of Bimodal Synergistic Therapy 4. Nanotechnology for Trimodal Synergistic Therapy 4.1. Chemotherapy/PDT/PTT 4.2. Chemotherapy/GT/PTT 4.3. Chemotherapy/PDT/RT 4.4. Chemotherapy/Immunotherapy/PDT

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Received: May 8, 2017 Published: October 19, 2017 13566

DOI: 10.1021/acs.chemrev.7b00258 Chem. Rev. 2017, 117, 13566−13638

Chemical Reviews 4.5. GT/Immunotherapy/PDT 4.6. Other Potential Forms of Trimodal Synergistic Therapy 5. Design Tips for Multifunctional Nanomaterials for Multimodal Synergistic Therapy 6. Conclusions and Prospects Author Information Corresponding Authors ORCID Notes Biographies Acknowledgments References

Review

resistant to monotherapy. For example, long-term use of anticancer drugs usually induces multidrug resistance (MDR) of tumors, which is responsible for the ineffectiveness of chemotherapy.67−69 RT also loses its potency in low-oxygen environments because of the insensitivity of hypoxic cancer cells to ionizing radiation.70−73 Therefore, to overcome these impediments of monotherapy, combined therapy, which employs the integration of two or more forms of treatment,74−76 has been proposed as an alternative approach. Beneficially, with the help of advanced nanotechnology in the smart design of multifunctional nanomaterials for the codelivery/coassembly of two or more therapeutic agents,77 combined therapy has been made possible based on the integration of multiple therapeutic modalities within a single system.78

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1.2. Definition of “Multimodal Synergistic Therapy”

1. INTRODUCTION Cancer, as one of the deadliest diseases worldwide, remains a serious health concern. Despite enormous investments in manpower, materials, and financial resources to develop new cancer therapies, only limited success has been achieved with current clinical treatment options due to the complexity, diversity, and heterogeneity of tumors.1 To this end, in 2016 the United States announced the “Cancer Moonshot” initiative as part of the 21st Century Cures Act to provide financial support for cancer research with the intent of enhancing accessibility of therapies to patients and augmenting efforts for the early detection and prevention of cancer.2,3 Scores of material scientists, chemists, biologists, pharmacologists, and clinicians have joined forces to discover innovative ways to detect, treat, and cure cancer in its early stages. The rapid development of medical imaging techniques,4 such as fluorescence imaging,5−7 magnetic resonance imaging (MRI),8−11 ultrasound (US) imaging,12−14 photoacoustic (PA) imaging,15−18 computed tomography (CT) imaging,19−21 positron emission tomography (PET) imaging,22−25 and single-photon emission computed tomography (SPECT) imaging,26,27 have made early cancer diagnosis possible by the sensitive and accurate detection of previously undetectable tumors. However, while imaging has bolstered our understanding of cancer and its progression, the ultimate goal is the curing of cancer. Numerous efforts are underway to construct high-performance theranostic platforms for complete elimination of tumors with efficient prevention of tumor invasion and metastasis in the early stages, which will realize the advent of a cancer free world.

Recent advances in cancer therapy have gradually shifted from a focus on monotherapy to combined therapy, based on the cooperative enhancement interactions between two or more treatments, which may result in ostentatious superadditive (namely “1 + 1 > 2”) therapeutic effects.79−81 For instance, some radiosensitizing anticancer drugs not only kill cancer cells by chemotherapy but also greatly increase the tumor cells’ sensitivity toward ionizing radiation for enhanced RT,82−84 so as to produce bimodal synergistic effects based on chemotherapy-enhanced RT.85 Herein, multimodal synergistic therapy is defined as the cooperation among different treatments with integration into a single nanoplatform, which yields much stronger therapeutic effects than the theoretical combination of the corresponding individual treatments. In contrast to the limited treatment efficacy and possible side effects arising from monotherapy, the development of multimodal synergistic therapy may harbor the collective merits of respective individual treatments and give rise to much higher anticancer efficacy at lower dosage of therapeutic agents administered,86 thus avoiding high-dose-induced side effects. Disparagingly, the potential synergistic therapeutic effects have been largely ignored in much of the previous literature due to the complexity of synergism among different therapeutic modalities. On the basis of our research experiences86−88 and other groups’ studies,89−93 a synergistic effect arises from the combined use of several therapeutic modalities through the participation of a variety of nanostructures and yields high treatment efficacy with few side effects.

1.1. Status Quo of Cancer Monotherapy

1.3. Advantages of Nanotechnology for Multimodal Synergistic Therapy

Currently, chemotherapy,28−32 radiotherapy (RT),33−36 and high intensity focused ultrasound (HIFU) therapy37−39 have been widely used in the clinic with great success in suppressing tumor proliferation and prolonging patient survival. Photodynamic therapy (PDT)40−44 has also proved to be very effective in treating nonsmall cell lung cancer and esophageal cancer. Other treatments, such as photothermal therapy (PTT),45−50 immunotherapy,51−55 gene therapy (GT),56−60 and magnetic hyperthermia (MHT),61−64 although still in preliminary clinical studies, have demonstrated high anticancer efficacy in a lot of laboratory and preclinical research with substantial promise for future clinical translation. However, in both clinical practice and exploratory studies, it has been found that a single treatment modality is incapable of eliminating the whole tumor, and further it is ineffective in preventing cancer metastasis,65,66 which is primarily attributed to the reason that the heterogeneous tumor tissue may contain subpopulations of cancer cells that are

The realization of multimodal synergistic therapy relies heavily on the integration of multiple therapeutic modalities in a single nanoplatform rather than simple mixing to reinforce their synergistic effects. The rapid development of nanotechnology has allowed for the possibility of assembling several types of therapeutic agents into one nanostructure through physical adsorption and chemical binding forces,94 so as to bring about multifunctional nanomaterials for achieving the “mission” of multimodal synergistic therapy. Importantly, nanomaterials exhibit several prominent advantages over small molecule probes in biomedical applications.95 First, nanomaterials are able to passively accumulate and preferentially remain at the tumor site via the so-called enhanced permeability and retention (EPR) effect.96−99 Second, owing to the presence of diverse functional groups, the surface of nanomaterials can be easily engineered with proteins, peptides, and other biomolecules to reduce nonspecific uptake by the reticuloendothelial system (RES) and 13567


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Figure 1. Outline of this review.

tional nanomaterials are expected to arouse collaborative research among diverse scientific communities to advance synergistic therapy technology and promote its clinical translation applications.

further specifically bind to overexpressed tumor cell receptors for enhanced accumulation.100−102 Third, the large surface-area-tovolume ratio of nanomaterials efficiently entraps high payloads of drugs, genes, and other therapeutic molecules and protects them from enzymatic degradation in the complex physiological microenvironment.103 Moreover, the functionalized nanomaterials are able to control the release of the loaded drug molecules via diverse internal and external stimuli (e.g., pH, GSH, light, etc.),104,105 which help prevent premature drug leakage in healthy tissues and mitigate the potential side effects. In this regard, ever-increasing research studies have turned to utilizing nanotechnology to design high-performance nanomaterials through selective physical/chemical coloading of two or more kinds of therapeutic agents for multimodal synergistic therapy, which may substantially improve the therapeutic effectiveness and efficaciously treat those malignant tumors that harbor resistance to monotherapy.

2. CLASSIFICATION AND CHARACTERISTICS OF MAJOR CANCER MONOTHERAPIES Chemotherapy, GT, immunotherapy, PDT, PTT, RT, MHT, and HIFU therapy are the eight major types of monotherapies reported and studied extensively. Nanotechnology is making significant contributions to these therapeutic modalities through both treatment efficacy enhancement and side effect reduction. In this section, the characteristics of the eight types of monotherapies are described in detail, which lays the foundation for further discussion of their cooperative interactions mediated by nanotechnology toward applications for bimodal and trimodal synergistic therapies.

1.4. Scope of This Review

2.1. Chemotherapy

In view of the increasingly important clinical value of multimodal synergistic therapy, this review aims to explain the synergistic mechanisms behind the diverse combinations of therapeutic modalities. This review focuses on nanotechnology-mediated multimodal synergistic therapy and interprets the underlying synergistic mechanisms in detail based on the survey of a large body of state-of-the-art studies. More importantly, representative studies of multimodal synergistic therapies based on multifunctional nanostructures are included, which will open tremendous prospects in the elaborate design of inorganic/organic nanomaterials for highly efficient cancer therapy in the future. In this comprehensive review (Figure 1), we will begin with the introduction of the characteristics, advantages, and disadvantages of the eight kinds of major monotherapies. Subsequently, emphasis will be focused on the cooperative enhancement interactions between two or more individual treatments. In particular, to facilitate the understanding of complex synergistic mechanisms, the representative nanostructures for achieving various kinds of multimodal synergistic therapies will be extrapolated and discussed in detail. Moreover, the featured applications of multimodal synergistic therapy in overcoming tumor MDR/hypoxia/metastasis will be highlighted to reveal new insights into the efficient treatment of malignant MDR/ hypoxic/metastatic tumors. Finally, the challenges and future developments in this research direction are envisaged. The proposed multimodal synergetic therapy, the underlying synergistic mechanisms, and the instructive design of multifunc-

As a modality known for the utilization of drugs to destroy cancer cells, chemotherapy has achieved great success in prolonging the lives of millions of patients.106 These frequently used chemotherapeutics, such as doxorubicin (DOX), 107 paclitaxel (PTX),108 docetaxel (Dtxl),109 and cisplatin (CDDP),110 are able to kill cancer cells rapidly upon uptake. However, the rapid clearance and nonspecific distribution of these chemotherapeutics severely diminish the chemotherapeutic effectiveness and inevitably cause systemic toxicity.111 Additionally, prolonged drug use often induces the strong resistance pathways of cancer cells against chemotherapeutics, known as MDR.112−114 To tackle these problems, custom-designed drug delivery systems (DDSs) have been implemented for tumor-targeted drug delivery,115−118 promising efficient tumor accumulation through both passive and active targeting approaches. First, the enhanced permeability of the tumor vasculature and the suppressed lymphatic drainage allow DDSs to enter the tumor interstitial space and then be retained, which lays the foundation of the wellknown EPR phenomenon, facilitating drug delivery to tumors via DDSs.97 However, the EPR effect has not been fully understood yet. In general, the EPR effect is dependent on the cancer type due to the varied pore dimensions of the vasculature and is further influenced by many factors, including tumor biology, extent of macrophage tumor infiltration, nature of the vascular bed, and activity of the mononuclear phagocytic system (MPS). Therefore, sometimes there is no significant improvement in the chemotherapeutic efficacy of DDSs based on the EPR effect 13568


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Table 1. Classification and Characteristics of DDSs types

advantages

disadvantages

organic DDSs

high biocompatibility good biodegradability controlled drug release

low stability immunogenicity tedious purification

inorganic DDSs

high dispersity/stability

rapid RES clearance poor tumor accumulation short blood circulation

low immunogenicity large drug loading capacity easy multifunctionalization

poor biodegradability long-term toxicity

representative

ref

liposomes micelles dendrimers polymer NPs carbon nanomaterials

121 122 123 124 125

magnetic NPs

126

gold nanomaterials MSNs QDs

127 128 129

Figure 2. (a) Schematic of preparation of the RBC-membrane-coated polymeric NPs. (b) Blood retentions of bare polymeric NPs, PEGylated NPs and RBC membrane-camouflaged NPs. Reproduced with permission from ref 144. Copyright 2011 National Academy of Sciences. (c) Blood retentions of PVP-AuNCs and RBC-AuNCs over 24 h. (d) Biodistribution of PVP-AuNCs and RBC-AuNCs at 24 h after injection. Reproduced with permission from ref 145. Copyright 2014 American Chemical Society.

compared to free drugs,119 which requires further mechanistic research into the EPR effect for optimizing the passive targeting approach. Second, the therapeutic index of EPR-driven DDSs can be further improved with the involvement of tumor-specific targeting ligands, which results in the remarkable enhanced tumor accumulation of DDSs through the active targeting approach. Over the past decades, a large variety of organic and inorganic DDSs have been designed and synthesized for tumor-specific drug delivery.120 Organic DDSs (Table 1), including liposomes,121 micelles,122 dendrimers,123 and polymer nanoparticles (NPs),124 have a long history of research and development. Some of these organic drug formulas have even

been put into clinical trial/use owing to their high biocompatibility and biodegradability. However, their extensive applications are restricted by poor stability and immunogenicity. In contrast, inorganic DDSs (Table 1), such as carbon nanomaterials,125 magnetic NPs,126 gold nanomaterials,127 mesoporous silica nanoparticles (MSNs),128 and quantum dots (QDs),129 are featured with high dispersity/stability, large drug loading capacity, and low immunogenicity,130−134 which may overcome the disadvantages of organic DDSs. However, inorganic DDSs experience short blood circulation, rapid RES clearance, longterm toxicity, and poor biodegradability. In this regard, the design of organic/inorganic hybrid DDSs may be a good choice for drug delivery. 13569


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Figure 3. (a) Illustration of ERP loaded with TRAIL plasmid for cancer gene therapy. Reproduced with permission from ref 165. Copyright 2016 WileyVCH. (b) Fabrication of the ultrasensitive pH-triggered and charge/size-responsive gene delivery system. (c) Transfection efficiency of P[(GP)D] with various PEG mass ratios at pH values of 7.4 and 6.8 in CT26 cells for 2 h. (d) Tumor volume changes of mice after intravenous injection of PBS, D, PD, G(PD), (GP)D, or P[(GP)D]. Reproduced with permission from ref 150. Copyright 2016 American Chemical Society.

tumor-specific targeting ligands, such as arginine-glycine-aspartic acid (RGD),146 hyaluronic acid (HA),147 and folic acid (FA)148 with high affinity toward integrin αvβ3, CD44, and folate receptors expressed in cancer cells, respectively, was found to further enhance the preferential accumulation of DDSs within U87MG and HeLa tumors.148 By aid of surface modification and targeting ligand conjugation, DDSs can achieve “three-step” hierarchical targeting drug delivery (first by EPR, second by ligand-mediated tumor targeting, and third by cell pathwaydirected cellular uptake), which may promise high accumulation of drugs at the target site and simultaneously minimize the side effects on normal tissues.149 However, despite substantial endeavors into the surface modification of DDSs, only a limited amount of drugs can be delivered to tumors as most of the drugs accumulate in the liver or spleen, which causes considerable drug wastage and serious organ toxicity. Therefore, the next stage of research on chemotherapy must focus on the enhanced tumortargeted delivery of DDSs and reduced RES uptake.

In order to improve the biocompatibility and avoid the RES uptake, the synthesized DDSs must undergo surface modification to afford high biocompatibility and prolonged blood circulation.135 Polyethylene glycol (PEG) is recognized as a preferential candidate for surface modification of DDSs with the following advantages, such as reduced nonspecific protein adsorption, depressed opsonization, and improved blood compatibility.136 This “stealth” effect of PEG increases the circulatory residence time of DDSs.137−139 However, PEG may induce blood clotting of cells and the production of anti-PEG immunoglobulin M antibody.140 Alternatively, by taking advantage of biocompatible, biodegradable, and nonimmunogenic red blood cells (RBCs),141−143 Zhang et al. designed RBC membrane-camouflaged polymeric NPs featuring a long period of blood circulation (Figure 2a).144 As shown in Figure 2b, the in vivo elimination half-life of RBC-membrane-coated NPs was 39.6 h, over 2-fold longer than the 15.8 h half-life of PEG-coated NPs, which indicated the significant contribution of the RBC membrane to retard clearance and prolong retention. Later, Yang et al. also found that RBC membrane-coated gold nanocages (RBC-AuNCs) exhibited a significantly extended blood retention period of over 24 h, and their blood retention at 24 h postinjection was 9.7%ID/g, over 5-fold greater than that of polyvinylpyrrolidone (PVP)-coated gold nanocages (PVPAuNCs; Figure 2c).145 The longer blood retention of RBCAuNCs encouraged richer tumor accumulation according to a typical passive targeting mechanism, as shown by the greater tumor uptake of RBC-AuNCs relative to PVP-AuNCs (Figure 2d). Besides superior surface camouflage, the conjugation of

2.2. Gene Therapy (GT)

GT involves the use of therapeutic genes to treat cancer or other diseases. GT is designed to introduce genetic material into patients’ cells to compensate for abnormal genes and to express specific proteins, thus avoiding the systemic toxicity arising from chemotherapy.150,151 Since the first demonstration of gene transfer and insertion of human DNA into the nuclear genome by Anderson in 1990, several techniques have been explored to carry out GT: (1) gene augmentation therapy, which inserts a healthy copy of the gene into the cells to replace a mutated variant;152 (2) gene inhibition therapy, which introduces a new gene to inhibit 13570


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efficacy.172−175 Besides, three-dimensional oligonucleotide NPs composed of complementary DNA fragments also benefit the siRNA delivery owing to their unique advantage of producing a series of molecularly identical NPs with defined characteristics and providing valuable structure−function information.176−178 In addition to other organic polymeric nanocarriers (e.g., PEI, PAMAM, etc.),179−181 some inorganic NPs have been also exploited for siRNA delivery.182 The most representative is large pore-size MSN,183 which can not only allow for efficient storage and sustained release of siRNA but also protect siRNA away from RNAase degradation. Moreover, the construction of nucleustargeted large pore-sized mesoporous organosilica nanoparticles can facilitate intranuclear siRNA delivery,184 which is expected to further enhance the gene transfection and therapy efficacy. In general, the above nanocarriers should be designed with a positive charge to interact with the negatively charged cell membrane for enhanced cellular uptake and benefit the complex formation with the polyanionic phosphate backbone of siRNA. Furthermore, in order to successfully pass through a series of physiological barriers to deliver siRNA to the interior of target tumor cells in vivo,185,186 current efforts have focused on engineering the nanocarriers by surface modification of shielding agents like PEG and conjugation of endogenous/exogenous targeting ligands, which can lead to evasion of the immune system, avoidance of renal clearance, and resistance against serum nucleases. In a word, regardless of the type of therapeutic gene, both tumor-specific gene delivery and controlled gene release are of fundamental importance to GT. Despite potential advantages, there is a safety concern which may cause adverse effects on the body’s immune system, so the long-term biosafety of GT must be critically evaluated before clinical implementation.

the expression of a target diseased gene or inactivate an improperly functioning gene;153 (3) gene-mediated cell-killing therapy, which delivers therapeutic genes into diseased cells to trigger apoptosis.154 GT is also playing diverse roles in cancer therapy. For instance, GT is able to activate pro-drugs to kill cancer cells or to block the self-inhibition of apoptosis to speed up programmed cancer cell death.155 More importantly, GT can sensitize cancer cells toward chemotherapeutics or ionizing radiation to improve the effectiveness of treatments,156−159 which paves the way for GT-based synergistic cancer therapy. The development of GT depends heavily on nanotechnology, which has been demonstrated by the fabrication of powerful nanocarriers for the efficient intracellular delivery of therapeutic DNA/RNA molecules to prevent nucleases-induced degradation and improve pharmacokinetics.160,161 Controlled intracellular DNA/RNA release without extracellular leakage is an additional prerequisite for effective GT.162−164 Recently, Shen et al. synthesized an esterase-responsive charge-reversal polymer (ERP) for DNA delivery.165 The selective gene expression in esterase-rich cancer cells promises greatly improved tumorspecific GT effects. Thanks to the high esterase activity in HeLa cancer cells relative to the surrounding cancer associated fibroblasts, the ERP/DNA polyplexes could be selectively uptaken by cancer cells to quickly dissociate and release DNA molecules for efficient gene expression (Figure 3a). The selective delivery of a cancer suicide gene (tumor necrosis factor related apoptosis-inducing ligand gene, TRAIL) via the polyplexes induced high TRAIL expression to induce cancer cell apoptosis without damaging the fibroblasts, thus demonstrating GTmediated anticancer activity with mitigated off-target cytotoxicity. Chen et al. combined a negatively charged DNA with polyethylenimine (PEI) and poly-L-glutamate (PLG) to form a charge/size-responsive and pH-activated gene delivery system (Figure 3b).150 In this system, PEG cross-linking shielded the surface from the positive charges of PEI and thus improved its biocompatibility/stability. Use of an acid sensitive cleavable PEG resulted in higher positive potential following removal of the PEG layer, and the resulting bigger particle size further enhanced the tumor cell uptake efficiency. The PEG[(PLG/PEI)/DNA] (P[(GP)D]) formulation demonstrated much higher transfection efficiency at pH 6.8 than 7.4 (Figure 3c). Accordingly, the tumor growth was completely suppressed by intravenous injection of PEG-coated P[(GP)D] (Figure 3d), indicating the enhanced GT efficacy in vivo. Small interfering RNA (siRNA) belongs to a typical kind of double-stranded RNA molecules which serves as a commonly used RNA interference (RNAi) tool for silencing the expression of cancer-related genes, such as polo-like kinase-1 (Plk-1) and Bcell lymphoma-2 (Bcl-2), which can lead to the impairment of mitosis machinery, activation of cancer cell apoptosis, as well as the inhibition of antiapoptotic cellular defense pathways.166 However, naked siRNA molecules are too hydrophilic to penetrate the cell membrane through passive diffusion.167 Therefore, smart nanocarriers are developed to realize efficient intracellular siRNA delivery through endocytosis and protect siRNA from degradation by serum nuclease. For example, cyclodextrin polymer-based NPs composed of oligomers with amidine functional groups exhibit low toxicity and efficient condensation with nucleic acids,168,169 which was the first nanocarrier for siRNA delivery in clinical trials.170,171 Liposomal NPs have also entered clinical trials because liposomes are able to avoid renal clearance and promote endosomal escape following cellular uptake for improving the intracellular siRNA delivery

2.3. Immunotherapy

Immunotherapy involves a broad category of anticancer therapies through the activation of the body’s immune system.187 The immune system always serves as a “policeman” to rid the body of foreign invaders like cancer cells. Immunotherapy works in the following three ways:188−190 (1) design of monoclonal antibodies to boost immune responses to destroy cancer cells;191 (2) use of immune checkpoint inhibitors to help the immune system recognize and attack cancer cells;192 and (3) synthesis of cancer vaccines to evoke immune responses to treat and prevent cancer.193−195 Different from chemotherapy that uses drugs to directly kill cancer cells, immunotherapy mainly empowers the human body via activation of the immune system to attack tumor cells, the process of which may persist long after the initial treatment owing to the memory function of the body’s immune system.196 Another important function of the immune system is its ability to distinguish cancer cells from normal ones and meanwhile generate immune responses via the activation of “checkpoints” (molecules on certain immunological cells) to selectively attack cancer cells and avoid damaging normal cells.197 However, due to the strong binding interaction between programmed cell death protein 1 (PD-1) on immune T cells and its ligand 1 (PD-L1) on cancer cells, the immune responses are usually suppressed, thus decreasing the effectiveness of immunotherapy. Fortunately, with the emergence of monoclonal antibodies like anti-PD-1 (aPD1), the binding interaction between PD-1 and PD-L1 is blocked, restoring immune response,198 of which has shown advanced antitumor activity in treating melanoma.199 Similar to chemotherapy, which is dependent on drug delivery, the 13571


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Figure 4. (a) Schematic of the delivery of aPD1 by an MN patch. (b) Schematic of the blockade of PD-1 by using aPD1 to activate immune-mediated destruction of cancer cells. Reproduced with permission from ref 53. Copyright 2016 American Chemical Society. (c) Schematic of the preparation of HES-D-IL-2 nanocapsules. (d) Schematic of HES-D-IL-2 nanocapsules for specific T cell targeting. Reproduced with permission from ref 205. Copyright 2016 American Chemical Society.

simultaneously mitigate adverse immune effects,207 which will be introduced in section 3.

controlled delivery and sustained release of aPD1 antibodies via nanocarriers is also essential to effective immunotherapy.200−202 To accomplish this, Gu et al. developed a self-degradable microneedle (MN) patch composed of HA integrated with dextran NPs for the controlled delivery and release of aPD1 toward melanoma.53 Assisted by the glucose oxidase (GOx)triggered conversion of glucose to gluconic acid, the acidsensitive dextran NPs were dissociated to release aPD1 (Figure 4a), which consequently blocked the PD-1 pathway to activate the immune system to destroy cancer cells (Figure 4b). In addition, targeting T cells also contributes to efficacious immunotherapy as T cells play a pivotal role in attacking cancer cells.203,204 By linking cytokine interleukin-2 (IL-2) to the surface of dibenzylcyclooctyne (DBCO)-functionalized hydroxyethyl starch (HES) nanocapsules via copper-free click reactions (denoted as HES-D-IL-2, Figure 4c), Steinbrink et al. observed that the engineered IL-2-functionalized nanocapsules could achieve specific T cell targeting both in vitro and in vivo through IL-2 receptor-mediated internalization (Figure 4d), which strikingly mediated T cell responses for enhanced immunotherapy.205 Besides stimulating immune responses to destroy cancer cells,206 immunotherapy may also trigger a litany of side effects, including high blood pressure, nausea, diarrhea, and fatigue. As drugs, reactive oxygen species (ROS), or heat can also trigger immune responses, immunotherapy may be combined with other treatments to produce synergistic therapeutic effects and

2.4. Photodynamic Therapy (PDT)

As a typical noninvasive light-excited treatment paradigm, PDT has been approved in the clinic and has been successfully used for treating esophageal cancer, skin cancer, and nonsmall cell lung cancer.208−210 Three major elements are involved in PDT: light, photosensitizer (PS), and oxygen.41 Upon excitation by a designated wavelength of light, PSs can be selectively activated to generate cytotoxic ROS to induce cancer cell death.211−215 Thanks to the spatiotemporal regulation of light delivery, ROS can be generated with precise control in tumor rather than normal tissue, so as to realize tumor-specific PDT with minimized side effects.216 Upon certain light irradiation, a PS at the ground singlet state can be activated to its triplet state, which then goes through two different photochemical reaction pathways. Accordingly, PDT can be classified into type I PDT and type II PDT.217 For type I PDT, the triplet state of PS reacts with a biological substrate to form radical anions or cations. These radicals may further react with triplet oxygen (3O2) or water to generate superoxide anions (O2•‑) or hydroxyl radicals (•OH). Alternatively, the triplet state of PS can transfer its energy to 3O2 to generate singlet oxygen (1O2) for type II PDT. Most organic PSs (e.g., porphyrin,218 phthalocyanine,219 chlorine,220 etc.) are involved in the type II photochemical reaction process with reliance on oxygen for 1O2 generation, which only takes 13572


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Figure 5. (a) Schematic of ZnPc/MC540 coloaded UCNs for PDT. (b) Fluorescence emission spectrum of UCN under 980 nm NIR laser excitation and absorption spectra of ZnPc and MC540. (c) Comparison of 1O2 production among MC540/ZnPc coloaded, MC540-loaded, ZnPc-loaded, and void UCNs under 980 nm NIR irradiation as determined by the decay of 9,10-anthracenediyl-bis(methylene)dimalonic acid (ABDA) fluorescence. Reproduced with permission from ref 247. Copyright 2012 Nature Publishing Group. (d) Schematic of MC540-loaded SAO for X-ray-activated PDT. (e) Spectral overlap between the X-ray excited optical luminescence of SAO (red) and the absorbance of MC540 (black). (f) Evaluation of 1O2 production from X-ray-excited PDT using singlet oxygen sensor green (SOSG) as an indicator. Reproduced with permission from ref 248. Copyright 2015 American Chemical Society. (g) Schematic of the luminal-OPV system for self-illuminating PDT. (h) Normalized absorption spectrum of OPV and luminescence emission spectrum of luminal. (i) Luminescence emission spectra of luminol in the presence of different concentrations of OPV. Reproduced with permission from ref 250. Copyright 2012 American Chemical Society.

penetration,235−237 PDT based on direct light excitation of PSs can only reach tumors on or immediately below the skin or on the lining of internal organs accessible by endoscopy, thus it fails to effectively treat deep-seated tumors. Although a large number of two-photon absorption (TPA) PSs (e.g., tetraphenylporphycenes, difuranonaphthalenes, porphyrazins, gold nanorods, etc.) have been exploited for NIR two-photon-excited PDT,238−240 the short-pulsed femtosecond NIR laser irradiation still bears limited tissue penetration and may even cause severe heat damage, both of which impede its clinical application. Assisted by the Förster resonance energy transfer (FRET) of some kinds of photoconversion NPs to PSs, PDT based on indirect light excitation of PSs comes into fruition, which may overcome the tissue penetration limitation of conventional PDT and provide new avenues for efficient treatment of deep-seated tumors. The most representative photoconversion NPs are upconversion nanoparticles (UCNPs)241 and scintillating nanoparticles (SCNPs),242 which are able to convert long-wavelength NIR

effect in well-oxygenated environments and thus fails to treat oxygen-deficient tumors. However, some inorganic PSs, such as semiconductors (e.g., CdSe,221 ZnO,222 etc.) and photocatalysts (e.g., TiO2,223 W18O49,224 etc.), can be photoactivated to produce • OH through the type I photochemical reaction process, without requiring oxygen participation, which remains effective in lowoxygen environments. Thanks to the unique feature of oxygen independence for type I PDT, researchers are exploring new inorganic PSs for effective hypoxic cancer therapy. With the help of nanotechnology, PDT systems evolve from direct light excitation to indirect light excitation of PSs.225 The excitation wavelength of most PSs falls within the ultraviolet (UV) and visible (vis) region (λ ≈ 400−700 nm),226−229 while only a few PSs (e.g., indocyanine green (ICG), cypate, naphthalocyanines, etc.) can be directly activated by nearinfrared (NIR) light (λ ≈ 800 nm).230−234 However, few can be excited by light with a wavelength longer than 1000 nm. As light with a wavelength below 800 nm encounters poor tissue 13573


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light (λ ≈ 800 or 980 nm) and high-energy X-ray radiation into UV−vis light, respectively. Based on the spectral overlap between the fluorescence emission of UCNPs/SCNPs and the UV−vis absorption of PSs, PDT can be initiated by NIR light243 or by highly penetrating X-rays.244 Accordingly the tissue penetration depth may be increased from 1 cm to virtually any depth.245,246 For example, Zhang et al. synthesized mesoporous silica-coated UCNPs for coencapsulation of merocyanine 540 (MC540) and zinc phthalocyanine (ZnPc; Figure 5a),247 whose absorption matched well with the green and red luminescence emissions of UCNPs, respectively (Figure 5b), allowing for high FRET efficiency from UCNPs to both MC540 and ZnPc. Therefore, upon a single NIR laser irradiation, a greater amount of 1O2 was generated by MC540/ZnPc coloaded UCNPs than single MC540 or ZnPc loaded UCNPs (Figure 5c). In another case, Xie et al. synthesized SrAl2O4:Eu2+ (SAO, Figure 5d) for the conversion of X-ray radiation into luminescence peaking around 520 nm (Figure 5e),248 which could trigger MC540 to generate 1 O2 for X-ray-induced PDT (Figure 5f) without tissue penetration depth limitation. Besides, there is another type of depth-independent internal PDT achieved by self-illuminating NPs, instead of photoconversion NPs, to trigger PSs for ROS generation without the need for external light excitation.249 Thus, the PDT process can spontaneously last for a long time to yield a satisfactory therapeutic effect in spite of weak selfluminescence. For instance, Wang et al. designed a selfilluminating luminol with persistent bioluminescence emission in the presence of H2O2 and horseradish peroxidease (HRP) (Figure 5g).250 Thanks to the optimal spectral overlap between oligo(p-phenylenevinylene) (OPV) and luminol (Figure 5h), the bioluminescence of luminol could be absorbed by OPV to generate ROS (Figure 5i), which efficiently caused cancer cell death through long-lasting self-illuminating PDT. Featuring the extremely high body-permeability of X-ray radiation and depth independence of a built-in self-luminescence source, the X-rayexcited PDT and self-illuminating PDT systems will usher in new development opportunities in the future and play an increasingly important role in treating deep-seated tumors by breaking through the depth dependency of conventional PDT.

Table 2. List of Inorganic and Organic NIR-Absorbing PTCAs PTCAs inorganic PTCAs

types

representatives

refs

Au-based nanomaterials

Au NPs, Au nanorods, Au nanoshells, Au nanocages, Au nanostars, Au cubics, Au nanoflowers, Au vesicles carbon nanotubes, carbon dots, graphene, Fe5C2 Pd nanosheets, Pd NPs

48, 252, 253, 272−277

carbon-based nanomaterials Pd-based nanomaterials metal sulfide

organic PTCAs

CuS, WS2, MoS2, FeS2, Bi2S3

metal oxide metal selenide

MoOx, W18O49 FeSe2, Co9Se8, CuSe, Bi2Se3

others NIR dye polymeric NPs

BP, PB ICG, IR825 polypyrrole, polyaniline, polydopamine porphysome, melanin

others

254, 255, 278, 279 256, 257 258, 259, 280−282 260, 261 262, 263, 283, 284 266, 267 264, 265 268, 269, 285 47, 286

etc.). These PTCAs have shown great success in photothermal killing of cancer cells in vitro and ablation of malignant tumors in vivo. However, PTT usually upregulates the expression of heat shock protein (HSP),270 which increases the cancer cells’ heat stress tolerance and decreases the thermal effect. Therefore, in order to achieve high PTT efficacy upon low power NIR laser irradiation to minimize the side effects, it is paramount to design other NIR-absorbing PTCAs with high light-to-heat conversion efficiency and to explore strategies for increasing the cancer cells’ sensitivity to heat via the downregulation of HSP expression.271 In some cases, PTCAs also serve as PSs,287 which makes the combination of PTT and PDT possible to obtain synchronous photokilling effects. More interestingly, there exists a nanostructure-driven conversion between PTT and PDT, which means that some PS-included/assembled NPs are endowed with photothermal properties, while these nanostructured PTCAs recover to their photodynamic form through multiple pathways (e.g., cancer cell targeting, particle disassembly, etc.). For example, Tan et al. designed a typical kind of PS-included PTCAs by linking Ce6 to aptamer switch probe (ASP)-modified AuNRs.288 Owing to the spectral overlap between Ce6 emission and AuNR absorption, the photosensitization of Ce6 (with proximity to the AuNR surface) was suppressed, so that the ASPCe6-AuNRs system yielded a photothermal rather than photodynamic effect upon laser irradiation. However, ASP underwent structural transformation upon targeting cancer cells so that Ce6 would be driven away from the AuNR surface to recover the photodynamic activity (Figure 6a). Zheng et al. designed porphysomes (porphyrin NPs) based on the self-assembly of porphyrin monomers.286 They found that porphysomes can only be used as PTCAs because of the self-quenching excited states arising from compactly packed porphyrin (Figure 6b). Once disassembled, these photothermally active porphyrin NPs were converted into photodynamically active monomers, thus inducing cancer cell death from a thermal to ROS generating mechanism. The above nanostructure-driven PTT-to-PDT conversion may play an important role in closing the loop between these two phototherapies and lay the technical foundation for their synergistic integration into a single nanosystem. Zheng et al. even systemically compared PDT and PTT effects using porphyrin monomer (Photofrin) and porphyrin NPs (porphysome) under hyperoxic and hypoxic conditions,

2.5. Photothermal Therapy (PTT)

In contrast to PDT for ROS-induced cancer cell death via light activation of PSs, PTT is another phototherapy paradigm that applies photothermal conversion agents (PTCAs) to generate heat for thermal ablation of cancer cells.251 The strong in vivo PTT effect primarily hinges on the exploitation of highperformance PTCAs. In addition to nontoxic and tumor targeting properties, these PTCAs should have strong NIR absorption for the conversion of NIR light into heat because the transparency window of biological tissues is located within the NIR region.48 Importantly, the NIR-absorbing PTCAs can be used for PTT of deep-seated tumors due to the relatively high tissue penetration ability of NIR light. So far, a large number of organic/inorganic NIR-absorbing PTCAs have been applied for PTT (Table 2), including but not limited to gold-based nanomaterials (e.g., Au nanorods,252 Au nanocages,253 etc.), carbon-based nanomaterials (e.g., carbon nanotubes,254 carbon dots,255 etc.), Pd-based nanomaterials (e.g., Pd nanosheets,256 Pd NPs,257 etc.), metal sulfide (e.g., CuS,258 WS2,259 etc.), metal oxide (e.g., MoOx,260 W18O49,261 etc.), metal selenide (e.g., FeSe2,262 Co9Se8,263 etc.), NIR-absorbing organic dyes (e.g., ICG,264 IR825,265 etc.), black phosphorus (BP),266 Prussian blue (PB),267 and polymeric NPs (e.g., polypyrrole,268 polyaniline,269 13574


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Figure 6. (a) Schematic of ASP-PS-AuNRs for PTT-to-PDT conversion via cancer cell targeting. Reproduced with permission from ref 288. Copyright 2012 American Chemical Society. (b) Schematic of the design of porphyrin monomers and NPs for PDT and PTT. (c) Final tumor temperatures under different conditions: Photofrin PDT, porphysome PDT, and porphysome PTT. (d) Tumor growth curves subjected to PDT by Photofrin or porphysomes and PTT by porphysomes. Reproduced with permission from ref 286. Copyright 2013 American Chemical Society.

Table 3. List of Strategies for Hypoxic Radiosensitization radiosensitizers oxygen

drugs

representatives catalase MnO2 PFC TPZ, mitomycin C (MMC) PTX, Dtxl

high-Z elements

Au, Bi, Pt, Yb, W, Ba

gasotransmitters

NO, H2S

mechanisms catalyze the decomposition of H2O2 into O2 oxidization of H2O2 into O2 oxygen absorption, delivery, and release selective killing of hypoxic cells

refs 314, 315 316, 317 311−313 318, 327−329

trap the cell cycle within the G2/M phase where hypoxic cells exhibit the most sensitivity to 83, 85 X-ray radiation absorb and scatter X-ray radiation for amplifying ionizing radiation dose based on the 34, 303, 304, 319−322, Compton scattering effect 330−332 increase all the hypoxic cells’ radio-sensitivity via the “bystander effect” 323−326

administration in a minimally invasive manner,290−292 which is able to treat both local and metastatic tumors spread throughout the body.293 Importantly, tumor-targeted delivery of radioisotopes is essential to avoiding systemic radio-toxicity to normal organs.294−296 EBRT, as the most common form of RT, is excited by three types of external ionizing radiation sources for precise localized treatment of deep-seated solid tumors, such as breast, lung, colorectal, and brain tumors. Tailored to the diverse ionizing radiation sources, such as protons, heavy ion (carbon ion) beams, and X/γ-ray radiation, EBRT can be divided into proton therapy, heavy ion therapy, and X/γ-ray therapy.297−300 In the clinic, the most widely used form of RT is X-ray therapy, which applies high-energy X-ray radiation to inhibit cancer cell proliferation by damaging the DNA of rapid proliferating tumor tissues while minimizing the effect in comparatively slower growing normal tissues.301 Therefore, this review will mainly focus on X-ray-excited RT. Different from CT imaging that uses low energy (∼keV) Xrays to provide three-dimensional (3D) structural details of

respectively. The 1O2 arising from light-excited Photofrin was inhibited under hypoxia while the heat generation via light irradiation of porphysome could take place irrespective of the oxygen condition, which largely increased the temperature of both hyperoxic and hypoxic tumors (Figure 6c). Therefore, it was observed that PDT was unable to suppress the tumor growth under hypoxia while PTT could efficiently eradicate tumors without oxygen dependence (Figure 6d). Therefore, distinct from PDT with reliance on oxygen for ROS production, PTT causes a steep temperature rise to kill all cancer cells, including hypoxic ones. 2.6. Radiotherapy (RT)

Radiation therapy, alternatively termed radiotherapy or RT, is one of the most commonly used treatments to suppress tumor growth.33 According to different radiation sources, RT can be classified into internal radioisotope therapy (IRT) and externalbeam radiation therapy (EBRT).289 IRT is excited by the intrinsic radiation from therapeutic radioisotopes (e.g., 131I, 177 Lu, 90Y, 188Re, etc.) injected in vivo through systemic 13575


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Figure 7. (a) Schematic of TaOx@PFC−PEG as an oxygen carrier for radiosensitization. (b) Quantification of tumor hypoxia areas after treatment with TaOx@PFC−PEG@O2. Reproduced with permission from ref 313. Copyright 2017 Elsevier. (c) The mechanism of TPZ for selectively killing hypoxic cells. (d) Viabilities of HeLa cells treated with varied concentrations of free TPZ or TPZ-loaded UCMHs (TPZ@UCHMs), in pO2: 21% or pO2: 2%. Reproduced with permission from ref 318. Copyright 2015 Elsevier. (e) Fluorescent DNA stain images of HeLa cells treated with only radiation (3 Gy), Bi2Se3 NPs, and Bi2Se3 NPs + radiation (3 Gy). (f) Viabilities of HeLa cells treated with only radiation [control, black line], Bi2Se3 NPs (100 μg/mL) + radiation [red line], and Bi2Se3 NPs (200 μg/mL) + radiation [blue line]. Reproduced with permission from ref 35. Copyright 2014 Wiley-VCH. (g) Schematic of the design of PEG-USMSs-SNO for X-ray-controlled NO release. (h) Cumulative NO release from PEG-USMSs-SNO in 24 h after subjected to different doses of X-ray irradiation. (i) Relative growth curve of 4T1 tumors in half a month after subjected to different treatments. Reproduced with permission from ref 326. Copyright 2015 Wiley-VCH.

radiation enhancement.313 After treatment with TaOx@PFC− PEG@O2, the intratumoral hypoxic areas were remarkably reduced (Figure 7b), suggesting a mitigation of tumor hypoxia for improved tumor oxygenation. By making full use of the H2O2rich tumor microenvironment, O2 could be generated in situ via catalase-catalyzed H2O2 decomposition for tumor oxygenation.314,315 Alternatively, the redox reaction between MnO2 and H2O2 could also produce O2 in addition to yielding Mn2+ for MRI.316,317 Some drugs like tirapazamine (TPZ)318 can selectively kill hypoxic cells (Figure 7c,d) and simultaneously promote hypoxic radiosensitization. Other drugs like PTX83 and Dtxl85 are able to trap the cell within the G2/M phase where the hypoxic cells exhibit the most sensitivity to X-ray radiation, which remarkably improves the RT effect toward hypoxic cancer cells. Besides, heavy metal atoms (e.g., Au,34 Bi,319 W,320 Ba,303 etc.) can also serve as radiation sensitizers (abbreviated as radiosensitizers) to amplify X-ray radiation doses based on the well-known Compton scattering effect.319,321 These high-Z atoms absorb more X-rays and deposit more radiation locally on tumors for an improved dose-amplification effect.322 Moreover, they selectively scatter Xrays for augmentation of radiation damage. Both of these mechanisms decrease the original radiation dose to minimize the side effects.301 For example, Jeong et al. investigated the role of PVP-modified Bi2Se3 nanoplates in radiation enhancement.35

tissues based on the varied X-ray absorptions of differential tissues, RT focuses high energy (∼MeV) ionizing radiation to treat tumors.302 Thanks to the precise positioning via CT imaging, ionizing radiation can be directly targeted to tumor regions, thus minimizing the radiation damage to surrounding tissues.303,304 However, a dilemma in the application of RT is the resistance of solid tumors to X-ray radiation.305 A principal signature of solid tumors is tumor hypoxia, arising from the inadequate supply of oxygen in blood vessels,306−308 which may exhibit about 2−3 times more resistance to ionizing radiation damage than the normoxic tumor.309 To overcome hypoxia-induced ionizing radiation resistance, some effective strategies have been explored to enhance the RT efficacy in treating hypoxic solid tumors (Table 3). Perhaps the most direct yet effective strategy is to pump high-pressure oxygen gas into the tumor for improved oxygenation. However, it is difficult to be put into practice because most tumors are located deep inside the body where external oxygen has poor penetration. Nanotechnology promises to construct oxygenloaded nanocarriers for oxygen delivery.310 For example, perfluorocarbon (PFC), a temperature-sensitive carbon−fluorine compound with high affinity for oxygen,311,312 has been used for oxygen adsorption and delivery. As an example, Liu et al. fabricated PEG modified TaOx@PFC nanodroplets (Figure 7a) as an oxygen reservoir for efficient oxygen delivery and X-ray 13576


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Figure 8. (a) Schematic of the preparation of phase-transformation material (liquid Fe/PLGA and solid Fe/PLGA) for MHT-induced tumor ablation. (b) Photograph images of the phase-transformation of injectable Fe/PLGA in progress and after contact with water. (c) Quantitative temperature rise curve of tumor tissues after exposure to an AC magnetic field. (d) Tumor volume change curve in 6 days after thermal ablation. Reproduced with permission from ref 340. Copyright 2014 Wiley-VCH.

2.7. Magnetic Hyperthermia (MHT)

Compared with single RT, the combination of Bi2Se3 and X-ray caused more significant DNA damage (as shown by the longer tail of stain in Figure 7e), which resulted in much lower cell viability (Figure 7f), mainly attributed to the contribution of Bi to radiosensitization. Considering the potential toxicity of chemotherapeutics and heavy metals, it is highly desirable to explore “green” radiosensitizers with high biocompatibility. Some gasotransmitters (NO323 and H2S324) can not only serve as “star” signaling molecules to regulate a number of physiological and pathophysiological activities (e.g., neuronal communication, blood vessel modulation, wound healing, etc.) but also play a role as radiosensitizers to increase all of the hypoxic cells’ radiosensitivity via the “bystander effect”, which attempts to explain the phenomenon of gas radiosensitizers penetrating and diffusing among all of the cancer cells though only reaching a small number of cells.325 A radiation-controlled NO release system was designed by incorporating an X-ray-responsive S-nitrosothiol (RSNO) group into mesoporous silica coated on UCNPs (denoted as PEG-USMSs-SNO, Figure 7g).326 The S-NO bond in PEGUSMSs-SNO was broken down to generate NO upon X-ray radiation. Meanwhile, the released NO concentrations could be controlled by X-ray doses (Figure 7h), which produced ondemand radiation enhancement effects for efficient suppression of hypoxic tumor growth (Figure 7i). These “green” gas radiosensitizers are expected to largely improve the radiotherapeutic effectiveness of low-dose X-ray radiation and thus avoid high-dose X-ray-induced radiation damage.

As a distinct magnet-thermal treatment paradigm based on the transformation of electromagnetic energy (generated from a high-frequency alternating magnetic field (AMF)) into heat,333 MHT can cause protein denaturation, DNA damage, signaling interruption, cell growth inhibition, and apoptosis.62,63,334,335 The main difference between MHT and PTT is the attainable tissue penetration. PTT is only able to treat tumors seated at the surface or a few millimeters below the tissue level because of limited tissue penetration of light, while MHT can treat tumors seated at any depth thanks to the large tissue penetration ability of the magnetic field. Moreover, the contactless use of AMF enables MHT to be a controllable remote treatment to eliminate nonaccessible tumors that are unavailable to PTT.61,64,336,337 The most widely used magnetic nanomaterials for MHT are superparamagnetic Fe3O4 NPs.338 Featuring strong magnetic properties and low biotoxicity, Fe3O4 NPs can efficiently accumulate in tumors based on the magnetic attraction force and quickly increase the temperature to thermally eradicate tumors with the assistance of an AMF,339 which is helpful to diminish the thermal damage against the surrounding tissues. In order to further improve the effectiveness of MHT, Zheng et al. constructed a phase-transformation material to trap Fe implants within the tumor for repeated MHT treatment (Figure 8a).340 The designed liquid Fe/polylactic-co-glycolic acid (PLGA)/Nmethylpyrrolidone (NMP) gel (denoted as L-Fe/PLGA) quickly turned into solid Fe implants (denoted as S−Fe/PLGA) after contact with body fluids or water (Figure 8b). Upon exposure to 13577


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Figure 9. (a) Schematic of the fabrication of MSNC-PFH for HIFU therapy. (b) Schematic 3D illustration of HIFU-triggered ablation of bovine livers in vitro. (c) Necrotic volumes of bovine livers after injection of PBS, MSNCs, and MSNC-PFH upon exposure to HIFU. Reproduced with permission from ref 38. Copyright 2012 Wiley-VCH. (d) Schematic of MRI-guided HIFU for the surgery of hepatic neoplasm in rabbits. (e) Coagulated necrotic volumes of VX2 liver tumor by MRI-guided HIFU exposure in rabbit liver tumors after ear vein injection of different agents (inset: digital pictures of tumor tissue after HIFU exposure). Reproduced with permission from ref 39. Copyright 2011 Wiley-VCH.

AMF, the firmly fixed Fe implants generated sufficient heat to cause a rapid increase in tumor temperature (Figure 8c). The high temperature of over 70 °C completely ablated the tumor within 3 days (Figure 8d). Meanwhile, thanks to the long-term intratumoral retention of Fe implants, the MHT treatment could be easily repeated by making periodic use of an AMF to prevent tumor regrowth, promising significant clinical value. Future efforts are being made to improve the magnetic-to-heat conversion efficiency of magnetic nanomaterials for achieving the optimized MHT efficacy upon exposure to low-frequency AMF, which is beneficial to further minimize the potential heat damage to normal tissues.

blood-brain barrier for efficient drug delivery to the brain tissue.357 On the other hand, the focused US beams cause acoustic cavitation, which makes microbubbles appear, grow, and eventually implode.358 Due to the very high temperature inside, the collapse of the whole microbubble is associated with a shockwave, resulting in considerable mechanical damage to tumors.359,360 Therefore, HIFU may give rise to both thermal and mechanical effects on tumor ablation upon exposure to highpower US radiation. Despite the superior advantage in inducing tumor necrosis, the rapid US wave attenuation with increased penetration depth remains a major concern for the HIFU ablation of deep-seated tumors, so HIFU enhancement agents (EAs) are strongly recommended to enlarge the lesion site and to enhance the deep treatment efficacy. Some commercial US imaging agents like organic microbubbles, can be also used as HIFU EAs361−363 because the generated echogenic gas bubbles are able to improve the thermal and acoustic effects. However, the limited blood circulation time and poor tumor accumulation arising from the large micrometer size of microbubbles severely impede the in vivo applications of these commercial HIFU EAs.364 Alternatively, hollow-structured inorganic nanocarriers loaded with thermosensitive PFC may serve as superior HIFU EAs owing to their easy nanometer size control, high thermal stability, and bubble-enhanced acoustic effects.365 For instance, Shi et al. used mesoporous silica nanocapsules (MSNCs) to encapsulate perfluorohexane (PFH) for simultaneous enhanced US imaging and HIFU therapy (Figure 9a).38 The PFH-loaded MSNCs (denoted as MSNC-PFH) were well-dispersed in PBS with high stability. Upon exposure to HIFU (Figure 9b), the rapid temperature rise above 56 °C triggered the phase transformation of PFH from liquid to gas bubbles, which were found to remarkably enhance the HIFU efficacy. MSNC-PFH resulted in a 2-fold increase of tumor necrosis volume compared with only MSNCs or PBS (Figure 9c). Furthermore, by loading PFH into

2.8. High Intensity Focused Ultrasound (HIFU)

HIFU therapy, known as the “bloodless surgical knife”, is a noninvasive US treatment paradigm, which focuses numerous US waves on target tumors through fast US energy deposition to cause irreversible cell death and destroy tumor vasculatures.341−345 Although the effect of an individual US beam is negligible, several US beams converging at one focused point can yield considerable thermal and mechanical effects.346−348 As US beams easily penetrate through soft tissue, HIFU may be applied to treat virtually any deep-seated tumor without depth limitation. Moreover, real-time US and MRI imaging monitoring/guidance may be provided before, during, and after the HIFU process, allowing for timely feedback of treatment efficacy.349−352 Following the deposition of numerous US beams, HIFU works under two major mechanisms: heat generation and acoustic cavitation.353 On the one hand, the US beams can be absorbed by tissue and converted into heat to “cook” cancer cells and ablate a focused volume of tumor.354,355 The heat generation depends on the deposited US energy. The high-power US radiation induces a fast temperature increase to instantaneously generate sufficient heat for thermal eradication of tumors,356 while mild hyperthermia arising from a slow temperature rise upon exposure to low-power US radiation can be used to temporarily disrupt the 13578


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Table 4. Summary of the Characteristics of the Eight Major Types of Cancer Monotherapies types

advantages

chemotherapy

systemic treatment

GT

systemic treatment low toxicity activation of systemic immune responses; longtime memory function; low toxicity local treatment minimal damage to normal tissues

immunotherapy

PDT

PTT

RT MHT

local treatment oxygen independence thermal ablation local treatment high body-permeability high body-permeability thermal ablation

HIFU

high body-permeability thermal ablation; mechanical cavitation

disadvantages

enhancement strategies

systemic toxicity nonspecific drug delivery premature gene leakage enzymatic degradation lost effectiveness of antibody

design of tumor-specific/targeted nanocarriers controlled drug release design of powerful gene-loaded nanocarriers

induction of diarrhea, fatigue, nausea, and high blood pressure

combined use with other treatments

oxygen dependence tissue penetration limitation tissue penetration limitation;

improved tumor oxygenation type I photochemical reaction NIR light/X-ray/self-luminescence excitation NIR light excitation downregulation of HSP expression

design of advanced antibody-loaded nanocarriers

heat resistance oxygen dependence radiation resistance limited tumor accumulation of magnetic nanomaterials heat resistance rapid US wave attenuation unfocused US beams

improved tumor oxygenation drug/high-Z element/gasotransmitter as radiosensitizers enhanced magnetic-to-heat conversion efficiency of magnetic nanomaterials construction of injectable magnetic implants downregulation of HSP expression exploration of HIFU EAs multimodal imaging guidance

section, the underlying synergistic mechanisms behind various types of nanotechnology-mediated bimodal therapies will be explored and discussed in detail. Some representative studies will be illustrated to interpret the synergistic mechanisms as well as shed light on the construction of multifunctional nanostructures to realize bimodal synergistic therapy.

Mn-doped mesoporous composite nanocapsules (denoted as PFH-MCNCs), MRI-guided HIFU cancer surgery could be achieved for precisely focusing US beams on the targeted VX2 liver tumor (Figure 9d).39 The PFH-MCNCs caused drastically enlarged coagulated necrotic tumor volumes upon HIFU exposure (Figure 9e), facilitating the HIFU ablation of tumors. Besides PFH, n-perfluoropentane (PFP), another kind of PFC with a phase transformation temperature of 29 °C,366 is more easily transformed into bubbles upon low-power HIFU exposure,367 which may enhance the low-power HIFU treatment efficacy and simultaneously diminish the thermal/mechanical damage to normal tissues. It should be noted that the storage of PFP remains a big issue owing to its low boiling point. Therefore, the PFP-loaded nanocarriers are usually stored at 4 °C rather than at room temperature. The advantages and disadvantages of the above eight major types of cancer monotherapy are summarized in Table 4. In addition to the nanotechnology-mediated enhancement strategies listed in this table, the disadvantage of one monotherapy may be offset by the advantage of another monotherapy, which inspires cooperative use of two or more types of interrelated monotherapy to promote the advantages and diminish the disadvantages. Therefore, a growing trend in cancer research has shifted from monotherapy to multimodal synergistic therapy, which may overcome the intrinsic drawbacks of individual monotherapies and improve the overall therapeutic effectiveness.

3.1. Chemotherapy-Based Bimodal Synergistic Therapy

As shown in Figure 10, chemotherapy can cooperatively enhance the efficacy of immunotherapy and radiotherapy to achieve

Figure 10. Schematic of the mechanisms behind chemotherapy-based bimodal synergistic therapy.

3. NANOTECHNOLOGY FOR BIMODAL SYNERGISTIC THERAPY Regarding bimodal synergistic therapy, cooperative enhancement interactions have been observed between two types of monotherapies through the integration of two kinds of therapeutic agents within a single nanostructure, which results in striking superadditive therapeutic effects that are stronger than the theoretical combination of each component therapy. The recent years have witnessed an explosive increase in the number of studies on the topic of bimodal synergistic therapy. In this

synergistic chemo-/immunotherapy and chemo-/radiotherapy, respectively. The synergistic mechanisms as well as the related representative studies will be introduced in this subsection. 3.1.1. Chemotherapy-Enhanced Immunotherapy. It is now widely accepted that chemotherapy not only directly causes cancer cell death but also augments tumor sensitivity for enhanced immunotherapy by taking advantage of the tumor antigens released from dead/dying cells.368 Therefore, the combination of chemotherapy and immunotherapy may produce superadditive synergistic therapeutic effects.369−371 Chemo13579


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upregulating costimulatory molecules, and downregulating checkpoint molecules like PD-L1 (Figure 11).376−378 The above two strategies lay the theoretical basis for synergistic chemo-/immunotherapy via chemotherapeutics-promoted tumor immunity. Apoptotic tumor cells may trigger specific immune responses via the emission of danger-associated molecules (e.g., high mobility binding box 1 (HMGB1), adenosine triphosphate (ATP), etc.), which will activate immunotherapy through induction of ICD. Moreover, the delivery of ICD-inducing chemotherapeutics via nanocarriers is helpful to realize chemotherapy-induced immunotherapy. Nie et al. compared the impact of two kinds of nanomedicine on ICD, oxaliplatin (OXA, an ICD inducer) and gemcitabine (GEM, a non-ICD inducer), both of which were encapsulated into the amphiphilic diblock copolymer NPs (Figure 12a).379 The ICD inducers (OXA and NP-OXA) remarkably accelerated the release of HMGB1 and secretion of ATP from cancer cells into cell supernatant when compared with the non-ICD inducers (GEM and NP-GEM; Figure 12b−d). Especially, NP-OXA resulted in 70% and 48% enhancement in HMGB1 release and ATP secretion, respectively, and even a 100% increase in CRT exposure as compared to OXA, which showed the superiority of nanocarriers in improving ICD inducer-triggered danger-associated molecule exposure. Compared with OXA, NP-OXA induced stronger immune responses of dendritic cells and T lymphocytes in vitro as well as exhibited much higher treatment efficacy in vivo (Figure 12e), allowing for synergistic chemo-/immunotherapy of refractory tumors in immunocompetent C57BL/6 mice. Other than the use of a single ICD-inducing chemotherapeutic, codelivery of an immunomodulating chemotherapeutic and an immunoactivator via nanocarriers may further enhance synergistic chemo-/immunotherapy efficacy. For

therapy promotes tumor sensitivity toward immunotherapy via the following two strategies. First, some anticancer drugs (e.g., anthracyclines, cyclophosphamide, oxaliplatin, etc.) induce immunogenic cell death (ICD) to promote immunotherapy through diverse pathways, including the concomitant release of tumor antigens, the translocation of calreticulin (CRT) to the dendritic cell surface, and the secretion of danger-associated molecules (Figure 11).372−375 Second, other drugs (e.g., 5-

Figure 11. Schematic of the mechanisms behind chemotherapytriggered immunogenic tumor cell death. Certain chemotherapeutics cause ICD through diverse pathways.

fluorouracil (5-FU), PTX, DOX, etc.) are able to modulate the tumor immunity (the activity of immune cell subsets or immune phenotype of tumor cells) by enhancing antigen presentation,

Figure 12. (a) Schematic of the impact of NP-OXA and NP-GEM on ICD. (b) Release of HMGB1, (c) amount of released ATP, and (d) percentage of CRT-positive cells rates after different treatments. (e) The tumor mass in C57BL/6 mice and Nu/Nu mice subjected to different treatments. Reproduced with permission from ref 379. Copyright 2016 Elsevier. 13580


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Figure 13. (a) Schematic diagram of DOX@HIMSN for in vivo synergistic chemo-/immunotherapy. (b) In vivo blood retention of free DOX and DOX@HIMSN. (c) Relative tumor volume after different treatments. (d and e) Representative images of the (d) lungs and (e) livers on the 25th day post-treatment. 1, PBS; 2, DOX; 3, DOX@MSN; 4, DOX@IMSN; 5, DOX@HIMSN. Reproduced with permission from ref 386. Copyright 2016 American Chemical Society.

Figure 14. (a) Synthetic scheme for SeC@MSNs-Tf/TAT NPs. (b) Viabilities of HeLa cells treated by SeC@MSNs-Tf/TAT or free SeC, with or without X-ray irradiation. Reproduced with permission from ref 387. Copyright 2015 Elsevier. (c) Scheme of H-TaOx-PEG@SN38 for enhanced radiotherapy. (d) Scheme of the cell cycle and the radio-sensitivity of different cell phases. (e) Quantitative analysis of the G1, G2/M, S phases of 4T1 cells treated with PBS, H-TaOx-PEG, or H-TaOx-PEG@SN-38. (f) Viabilities of 4T1 cells treated with H-TaOx-PEG or H-TaOx-PEG@SN-38 with exposure to X-ray radiation. Reproduced with permission from ref 392. Copyright 2016 Wiley-VCH.

example, Yin et al. designed a hydrophilic cationic polymer NP for coloading DOX and interleukin-2 (rhIL-2).380 They found that a low dose of DOX could also serve as an immunomodulator to augment tumor sensitivity in addition with rhIL-2 (an effective immunoactivator), which increased both the serum immunoglobulin G (IgG) level and tumor infiltrated cytotoxic T lymphocyte amount, thus leading to great synergistic chemo-/ immunotherapeutic effects for remarkably delaying tumor growth. By making cooperative use of the dual-role of low dose of drugs in inducing ICD and modulating immune

responses, synergistic chemo-/immunotherapy is expected to yield much better antitumor efficacy, which may also alleviate dose limiting toxicity. Cancer is comparatively easier to eliminate at the early stage but is significantly more difficult to treat in the terminal stage, mainly due to tumor metastasis.381−383 Therefore, the complete suppression of tumor metastasis is the premise for successful cancer therapy.384,385 Herein, one featured application of synergistic chemo-/immunotherapy is to treat metastatic tumors, which has been reported by Zhang et al.386 Focusing on highly 13581


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Figure 15. (a) Schematic of radiosensitization by UCSNs-CDDP. (b) Plots of surviving fractions of HeLa cells after treatment with free CDDP or UCSNs-CDDP in combination with 4 Gy of X-ray radiation on the indicated days postradiation. Reproduced with permission from ref 87. Copyright 2013 American Chemical Society. (c) Schematic of RUMSNs-TAT-MMC for intranuclear radiosensitization. (d) The relative ATP level, (e) P-gp expression, and (f) ROS generation of MCF-7/ADR cells after different treatments. (g) Viabilities of MCF-7/ADR cells subjected to different treatments. (h) MCF-7/ADR tumor growth curves after treatment with RUMSNs-TAT-MMC + RT. Reproduced with permission from ref 329. Copyright 2015 Royal Society of Chemistry.

3.1.2. Chemotherapy-Enhanced RT. The mechanism for chemotherapy-enhanced RT is associated with the action of radiosensitizing drugs, which work through radiosensitization via diverse pathways. Some drugs (e.g., PTX, Dtxl, etc.) may increase the tumor cells’ sensitivity to X-ray radiation for radiosensitization via selective cell cycle arrest in the radiosensitive G2/M phases, which achieves synergistic chemo-/radiotherapy by chemotherapeutic-sensitized RT. Moreover, tumor-specific delivery of these radiosensitizing drugs via nanocarriers can enhance bimodal synergistic therapy efficacy. As an example, Wang et al. synthesized folate-targeted Dtxl-loaded lipid-polymer NPs (denoted as FT-NP Dtxl),85 which exhibited much higher anticancer efficacy upon exposure to X-ray radiation than free Dtxl. Chen et al. designed transferrin (Tf) and TAT modified MSNs to load radiosensitizing selenoamino acid (SeC) for synergistic chemo-/radiotherapy (Figure 14a).387 Due to the Tf/ TAT-promoted cell internalization and endocytosis, the designed SeC@MSNs-Tf/TAT not only sensitized cancer cells toward X-ray radiation but also promoted X-ray-induced ROS

metastatic triple negative breast cancer (TNBC), they prepared DOX-loaded highly integrated MSNs (DOX@HIMSNs), which exhibited pH/GSH dual-stimuli responsive DOX release and avoided premature DOX leakage (Figure 13a). Meanwhile, the plasma half-life of DOX@HIMSNs in vivo was 20.9 times higher than that of free DOX (Figure 13b), which allowed for more tumor accumulation of DOX@HIMSNs than DOX. Collectively, DOX@HIMSNs not only released sufficient DOX to thoroughly suppress TNBC tumor growth (Figure 13c) but also triggered strong anticancer immune responses (e.g., dendritic cell maturation, antitumor cytokine release, etc.) to prevent the metastasis of TNBC cells to the liver and lungs (Figure 13d,e), a feature lacking free DOX. Therefore, the encapsulation of chemotherapeutics in custom-designed nanocarriers will surpass conventional chemotherapy to achieve synergistic chemo/ immunotherapy for protecting normal organs from the metastasis of primary cancer cells in addition to improving the tumorspecific drug delivery, which may provide a promising comprehensive strategy to fight recalcitrant metastatic tumors. 13582


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Figure 16. (a) Clonogenic survival fractions of HeLa cells cultured under 2% and 21% oxygen pressures (pO2) after varied doses (ranging from 0 to 6 Gy) of X-ray irradiation. (b) Clonogenic survival fractions of hypoxic HeLa cells coincubated with UCHMs, TPZ, or TPZ-loaded UCHMs (TPZ@ UCHMs) with or without 3 Gy of X-ray irradiation. Reproduced with permission from ref 318. Copyright 2015 Elsevier. (c) Representative immunofluorescence images of tumor slices after treatment with BM@NCP(DSP)-PEG and BP@NCP(DSP)-PEG. The blue, red, and green fluorescence indicate the cell nuclei, blood vessels, and hypoxic areas, respectively. (d) Quantitative analysis of the relative hypoxia positive area of each group in panel c. (e) 4T1 Tumor volume growth curves of balb/c mice subjected to various treatments. Reproduced with permission from ref 411. Copyright 2017 Wiley-VCH.

generation and cell apoptosis.388−391 While the cell viabilities treated by X-ray (2 Gy) and SeC@MSNs-Tf/TAT were 91.3% and 49.6%, respectively, SeC@MSNs-Tf/TAT plus X-ray remarkably decreased the cell viability to 18.6%, much less than that by free SeC plus X-ray (Figure 14b), which confirmed the much larger contribution of SeC@MSNs-Tf/TAT to radiosensitization than free SeC for enhanced synergistic chemo-/radiotherapy. Liu et al. synthesized PEG-modified hollow tantalum oxide (H-TaOx-PEG) to load 7-ethyl-10hydroxycamptothecin (SN-38) for radiosensitization (Figure 14c).392 Apart from the ability of SN-38 to facilitate cell cycle arrest in the G2/M phase to promote X-ray-induced cell apoptosis (Figure 14d,e),393,394 the high-Z element Ta could further amplify X-ray doses via the Compton scattering effect for enhanced X-ray-mediated DNA damage.395,396 Therefore, the designed H-TaOx-PEG@SN-38 served as an effective radiation enhancement agent based on the dual radiosensitization of SN38 and Ta, as confirmed by the diminished cancer cell viability induced by H-TaOx-PEG@SN-38 + RT over the projected addition of H-TaOx-PEG + RT and H-TaOx-PEG@SN-38 (Figure 14f). Consequently, by encapsulation of radiosensitizing drugs into high-Z element-doped nanocarriers for tumor-specific delivery and receptor-mediated cell endocytosis, both radiosensitization and radioenhancement can be achieved for maximizing synergistic chemo-/radiotherapy efficacy. According to the Compton scattering effect, some heavy metal atom-containing chemotherapeutics like cisplatin (CDDP) can scatter one X-ray beam into several more beams for enhanced RT. High-energy X-ray radiation is able to enhance the tumor cell

uptake of Pt in CDDP, which in turn amplifies the intracellular Xray dose for multiplied DNA damage.397 To validate the Ptinduced radiosensitization, a rattle-structured Gd-doped UCNP core/porous silica shell nanotheranostic (denoted as UCSN) was constructed to load CDDP for MR/UCL imaging as well as synergistic chemo-/radiotherapy (Figure 15a).87 The combination of CDDP and X-ray radiation led to a lower survival fraction than CDDP alone, indicating the stronger anticancer effect of bimodal chemo-/radiotherapy over single chemotherapy (Figure 15b). Moreover, CDDP-loaded UCSNs (UCSNs-CDDP) demonstrated obviously higher cancer cell toxicity relative to free CDDP upon X-ray irradiation, which confirmed the contribution of the nanocarrier-UCSNs to enhance CDDPmediated radiosensitization. Tumor MDR has been a major cause for the failure of chemotherapy.398 Due to the overexpression of drug efflux pumps (P-glycoprotein (P-gp)) in the membrane of MDR cells, free drugs are not retained in cancer cells and thus lose effectiveness. Although the emerging nanosized DDSs can bypass the efflux of P-gp to some extent and transport a certain amount of drugs into the MDR cells for increased intracellular drug accumulation,399−403 limited success is achieved in overcoming MDR by single chemotherapy, which highlights the combination of chemotherapy and RT to produce synergistic therapeutic effects for the treatment of MDR tumors. By reducing the size of the above UCSNs below 50 nm and conjugating a nuclear localization signal (NLS) peptide-TAT on the surface, the designed RUMSNs-TAT could efficiently deliver MMC (a radiosensitizing drug) into the nucleus for intranuclear 13583


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resulted in thorough suppression of hypoxic tumor growth (Figure 16e). Therefore, both forms of synergistic chemotherapy/RT (radiosensitizing bioreductive chemotherapeutics and RT, oxygen-elevated radiosensitizing chemotherapeutics and RT) do well in overcoming tumor hypoxia, which particularly applies to deep-seated hypoxic cancer therapy by taking advantage of targeted drug delivery and highly penetrating Xray radiation.

radiosensitization (Figure 15c), which was especially useful for treating MDR cancer.329 As the target of MMC, DNA resides in the cell nucleus rather than cytoplasm, so the intracellular MMC delivery via nucleus-targeting nanocarriers can greatly increase the cytotoxicity of MMC for enhanced chemotherapy efficacy.404,405 This rule also applies to MDR cancer therapy.406 As RT could directly damage the double chains of MDR cells’ DNA as well as decrease the P-gp expression (Figure 15e), the cooperative enhancement interactions of MMC and X-ray within the MDR nucleus could substantially enhance synergistic chemotherapy/RT efficacy for overcoming MDR via intranuclear radiosensitization. The combination of RUMSNs-TATMMC and RT resulted in a remarkable decrease in P-gp protein expression and ATP level, much lower than MMC + RT or RUMSNs-MMC + RT (Figure 15d,e), which indicated the superior anti-MDR efficacy of intranuclear radiosensitization over extracellular or intracytoplasmic radiosensitization. Assisted by the highest intracellular ROS generation among the indicated treatments (Figure 15f), RUMSNs-TAT-MMC + RT also killed the largest number of MCF-7/ADR cells (Figure 15g). Importantly, RUMSNs-TAT-MMC + RT led to remarkable MCF-7/ADR tumor regression (Figure 15h), which successfully overcame MDR in vivo. More importantly, the developed technique of intranuclear synergistic chemotherapy/RT can be used for treating deep-seated MDR tumors thanks to intranuclear drug delivery plus high body permeability of X-ray radiation. Tumor hypoxia is another major cause for the failure of chemotherapy and RT due to the strong resistance of hypoxic cancer cells to chemotherapy and X-ray radiation. Despite a series of means explored for tumor oxygenation,407−410 singular use of chemotherapy or RT is still insufficient to completely suppress the hypoxic tumor growth. Fortunately, the combined use of chemotherapy and RT may yield much stronger synergistic therapeutic effects for efficiently overcoming hypoxia. TPZ, as a typical bioreductive drug, not only exhibits specific toxicity toward hypoxic tumor cells but also increases the cancer cells’ sensitivity to X-ray radiation for hypoxic radiosensitization, which compensates the reduced effectiveness of RT under low oxygen atmosphere (Figure 16a). By loading TPZ in a rattlestructured UCNP/MSN system (UCHMs), the combination of TPZ@UCHMs and X-ray radiation resulted in a much lower clonogenic survival fraction of hypoxic HeLa cells than the projected additive value (Figure 16b),318 which demonstrated the synergistic interactions between bioreductive chemotherapy and RT in overcoming tumor hypoxia. Moreover, the combination of heavy metal atom-containing chemotherapeutics and X-ray radiation together with tumor oxygenation can also efficiently overcome tumor oxygenation via oxygen-elevated synergistic chemotherapy/RT. As an example, Liu et al. synthesized PEG-modified nanoscale coordination polymers (NCPs), composed of Hf ions, c,c,t-(diamminedichlorodisuccinato) Pt(IV) (DSP, a prodrug of CDDP), and bovine serum albumin (BSA)-stabilized MnO2 NP (denoted as BM@NCP(DSP)-PEG) for in situ O2 generation and Pt-mediated radiation enhancement.411 After intravenous injection of BM@NCP(DSP)-PEG, the tumor hypoxia was remarkably alleviated compared to that treated with BP@NCP(DSP)-PEG without MnO2 (Figure 16c,d), which confirmed the key role of MnO2 in decomposing the endogenous H2O2 into O2 for tumor oxygenation. The elevated vascular O2 level greatly increased the hypoxic cells’ sensitivity to DSP and X-ray radiation for substantially enhanced synergistic chemotherapy/RT, which

3.2. GT-Based Bimodal Synergistic Therapy

As there are a large variety of genes involved in GT, the selection of an appropriate gene to promote or suppress certain protein expression is conducive to strengthen the corresponding therapeutic modality. So far, GT has been reported to cooperatively improve the effects of chemotherapy, PDT, and PTT, all of which result in remarkable synergistic anticancer efficacy. The corresponding synergistic mechanisms are illuminated in Figure 17 and are clarified in detail in this subsection.

Figure 17. Schematic of the mechanisms behind GT-based bimodal synergistic therapy.

3.2.1. GT-Enhanced Chemotherapy. Cancer cells develop MDR after frequent administration of high doses of drugs, which usually causes the ineffectiveness of chemotherapeutics. Some types of siRNA can specifically target and suppress the expression of multidrug resistance-related proteins (e.g., multidrug resistance protein 1 (MRP1),412 polo-like kinase-1 (Plk-1),413 B-cell lymphoma-2 (Bcl-2),414 etc.) for significant improvement of the chemotherapeutic effects. Therefore, the codelivery of siRNA and drugs via nanocarriers can achieve synergistic GTenhanced chemotherapy.415−419 For instance, Hammond et al. designed layer-by-layer (LbL) NPs for codelivery of DOX and MRP1 siRNA, which were fabricated by coating poly-L-arginine (PLA)/siRNA/PLA/HA films on DOX-loaded phospholipid liposomes (Figure 18a).420 The synthesized LbL liposomal formulation ensured a high coloading efficiency of 5.5% w/w DOX/liposome and 3500 siRNA molecules per liposome, and exhibited a faster release of siRNA than DOX over 72 h (Figure 18b). MRP1 is a cell-surface efflux pump that regulates MDR through decreasing intracellular drug concentrations. The inhibition of MRP1 expression via MRP1 siRNA promoted DOX delivery into tumor cells and enhanced the DOX-killing efficacy by 4-fold in vitro (Figure 18c). Moreover, the combination of MRP1 siRNA and DOX was even able to decrease the average tumor volume by 8-fold in vivo compared to 13584


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Figure 18. (a) Design scheme of the siRNA-DOX LbL liposomes. (b) Release profile of siRNA and DOX from the LbL liposomal NPs in DMEM culture medium over 72 h. (c) Examination of the cytotoxicity of the combination therapy (DOX + MRP1/scramble siRNA) against MDA-MB-468 cells. (d) Quantitative RT-PCR analysis of the MRP1 mRNA level in tumor tissue isolated from mice treated with the combined therapies, compared with the DOX + scramble siRNA control. (e) Tumor volume growth curves of nude mice bearing subcutaneous MDAMB-468 xenografts after treatment with MRP1 siRNA and DOX coloaded LbL liposomes, compared to untreated controls. Reproduced with permission from ref 420. Copyright 2013 American Chemical Society.

hydrazone linkages and electrostatic interaction, respectively.426 Due to the acidic/redox tumor microenvironment, the accelerated release of DOX and P-gp siRNA from copolymers inhibited the P-gp protein expression and increased the intracellular DOX concentration, leading to greatly elevated cytotoxicity against MDR cells based on a gene/drug-mediated synergistic effect. In another case, Shi et al. developed large poresized hollow mesoporous organosilica nanoparticles with surface modifications of poly(β-amino esters) (PAE) and disulfide bonds (denoted as HMONs-ss-PAE) for codelivery of DOX and P-gp siRNA (Figure 19a),427 which prevented the premature degradation of siRNA in the extracellular microenvironment. The encapsulated P-gp siRNA downregulated about 90% P-gp expression (Figure 19b), and meanwhile HMONs-ss-PAE remarkably decreased the ATP level to cut off the energy supply for P-gp drug efflux (Figure 19c), both of which contributed to enhanced MDR cell uptake of DOX (Figure 19d). As a result, siRNA/DOX@HMONs-ss-PAE produced much stronger MDR cell-killing effects than DOX@HMONs-ss-PAE (Figure 19e), mainly attributed to the siRNA-mediated downregulation of Pgp expression. The complete MDR tumor growth suppression (Figure 19f) further confirmed the synergy of GT/chemotherapy (via siRNA/DOX@HMONs-ss-PAE) in overcoming MDR in vivo over monotherapy (via DOX@HMONs-ss-PAE or siRNA@HMONs-ss-PAE). Bcl-2 protein is a key regulator of antiapoptotic cellular defense to prevent cell apoptosis by blocking the release of cytochrome

the control group (Figure 18e), which may be attributed to the significantly decreased MRP1 mRNA level in the tumor (Figure 18d) via MRP1 siRNA and substantially increased DOX cytotoxicity. Similarly, tumor-targeted HA NPs engineered with an artificial RNA receptor, Zn(II)-dipicolylamine (DPA), and CaP coating were designed for the codelivery of MRP1 siRNA and DOX.421 This nanoformulation could strongly secure siRNA molecules and efficiently target the tumor cells in vivo through passive targeting and CD44-mediated endocytosis after intravenous administration. Thanks to the remarkable downregulation of MDR1 mRNA expression via MRP1 siRNA, the sensitivity of OVCAR8/ADR cells to DOX was recovered and even increased, which led to significant OVCAR8/ADR cell death in vitro and OVCAR8/ADR tumor growth suppression in vivo, also demonstrating the strong antitumor effect of synergistic GT/chemotherapy. P-gp overexpression is primarily responsible for drug efflux, so the downregulation and inhibition of P-gp expression would appear to be an effective strategy to reverse MDR and promote intracellular drug delivery for enhanced chemotherapy.422,423 Pgp siRNA can specifically knock down and disrupt the function of P-gp, so the codelivery of P-gp siRNA and anticancer drugs via nanocarriers is able to produce a synergistic chemo-/gene therapeutic effect for the efficient treatment of MDR tumors.424,425 For example, Qian et al. designed multifunctional triblock copolymers (FA/m-PEG-b-P(LG-Hyd)-b-PDMAPMA) for conjugating DOX and encapsulating P-gp siRNA through 13585


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Figure 19. (a) Schematic of the construction of P-gp siRNA and DOX coloaded HMONs-ss-PAE system for overcoming MDR. (b) P-gp expression in MCF-7/ADR cells treated with siRNA@HMONs-ss-PAE with different mass ratios of HMONs-ss-PAE to siRNA. (c) The relative ATP activity of MCF-7/ADR cells after treatment with HMONs-ss-PAE with different concentrations. (d) Quantitative analysis of DOX uptake in MCF-7/ADR cancer cells incubated for 4, 8, and 24 h. (e) Viabilities of MCF-7/ADR cells after treatment with free DOX, DOX@HMONs-ss-PAE, and siRNA/DOX@ HMONs-ss-PAE at varied DOX concentrations over 48 h. (f) Relative MCF-7/ADR tumor volume change curves subjected to different treatments. Reproduced with permission from ref 427. Copyright 2016 Wiley-VCH.

Figure 20. (a) Schematic of PTX, QDs, and Bcl-2 siRNA coloaded PQSLNs for synergistic PTX-siRNA therapy. (b) Bcl-2 gene expression levels of A549 cells after treatment with QSLNs, PQSLNs, and their siRNA complexes. (c) Viability of A549 cells after treatment with QSLNs, PQSLNs, siRNAcomplexed PQSLNs, Bcl-2 siRNA-complexed QSLNs, and Taxol formulation at varied PTX concentrations. (d) Combination index plot for the combined effects of PTX and Bcl-2 siRNA on the viability of A549 cells. Reproduced with permission from ref 430. Copyright 2013 Wiley-VCH.

C.428,429 Therefore, the suppression of antiapoptotic Bcl-2 protein expression via siRNA can both increase the cell sensitivity to chemotherapeutics and promote chemotherapeutics-induced

cell apoptosis for enhanced chemotherapy. To this end, Nam et al. synthesized QD-incorporated solid lipid NPs (QSLNs) via codelivery of Bcl-2 siRNA and PTX (denoted as PQSLN/Bcl-2 13586


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Figure 21. (a) Schematic of targeted delivery of Pc (PPI-Pc) and DJ-1 siRNA (PPI-siRNA) for synergistic GT/PDT. (b) Expression of DJ-1 mRNA in ES2 cells after treatment with media and PPI-siRNA. (Inset) Representative Western blot images of DJ-1 and β-actin expression in ES2 cells after treatment with media and PPI-siRNA. (c) Viability of ES2 cells after treatment with only PDT and combinatorial therapy (DJ-1 siRNA + PDT) at varied Pc concentrations. Reproduced with permission from ref 443. Copyright 2015 Elsevier.

siRNA) for synergistic GT/chemotherapy (Figure 20a).430 The QSLN could efficiently enter cancer cells to release Bcl-2 siRNA in the cytoplasm for considerable downregulation of Bcl-2 protein expression (Figure 20b), which greatly increased the sensitivity of A549 cells to PTX. Thanks to the Bcl-2 siRNAelevated cytotoxicity of PTX, PQSLN/Bcl-2 siRNA produced considerable cytotoxic effect by killing 70% of A549 cells, while single PQSLN only caused 30% cell death (Figure 20c). Significantly, the IC50 value of PQSLN/Bcl-2 siRNA against A549 cells was 225 ng/mL, approximately 20 times lower than 4.6 μg/mL of the Taxol formulation, which was attributed to the strong synergism between PTX and Bcl-2 siRNA, as confirmed by the combination indexes (CI) below 0.5 (Figure 20d). Therefore, a much lower dose of PTX in combination with Bcl-2 siRNA could achieve a similar therapeutic effect as a high dose of PTX, which would largely reduce the side effects on healthy tissues and simultaneously improve the synergistic gene-/ chemo-therapeutic index.431−434 3.2.2. GT-Enhanced PDT. PDT is mainly dependent on the ROS generation to damage the DNA and destroy cancer cells, but antioxidant defense proteins (e.g., superoxide dismutase,435 glutathione peroxidase 3,436 DJ-1,437 etc.) overexpressed in cancer cells usually scavenge ROS to diminish the PDT effect. Especially, DJ-1 protein plays a major role in preventing ROStriggered cell apoptosis through downregulation of the proapoptotic protein expression and inhibition of the caspase activation.438 Therefore, the suppression of DJ-1 protein expression via a certain type of siRNA (i.e., DJ-1 siRNA) can increase the sensitivity of cancer cells to ROS, which will improve the cell-killing effect of ROS for synergistic GT-enhanced

PDT.439−442 Taratula et al. prepared PPI dendrimer-based nanoplatforms for separate loading and sequential delivery of phthalocyanine (Pc, a PS) and DJ-1 siRNA into cancer cells (Figure 21a).443 The efficient intracellular delivery of DJ-1 siRNA molecules via PPI-siRNA suppressed DJ-1 protein expression and weakened the ROS defense system (Figure 21b), eliciting a synergistic therapeutic response. Sequentially, the Pc molecules delivered by PPI-Pc upon NIR light irradiation resulted in remarkable cell apoptosis for enhanced PDT efficacy. Therefore, the combined use of PDT with DJ-1 siRNA yielded a synergistic therapeutic effect with a much lower cell viability than PDT alone (Figure 21c), indicating the strong synergism between GT and PDT. Besides DJ-1, superoxide dismutase 1 (SOD1) is another key protein responsible for destroying free radicals/ROS and preventing cell apoptosis.444 As such, silencing of the SOD1 gene is helpful to accelerate ROS-induced cell apoptosis and cause cell death more efficiently.445 Unlike the above-mentioned separate delivery of DJ-1 siRNA and PS, the codelivery of SOD1 siRNA and PS via a single nanocarrier facilitates simultaneous uptake by cancer cells, which can further enhance synergistic GT/PDT efficacy. To this end, Hwang et al. designed SOD1 siRNA-loaded Au NEs for SOD1 silencing and NIR laser-excited PDT (Figure 22a).446 Compared to only 40% SOD1 gene silencing efficiency by free siRNA, siRNA-loaded Au NEs achieved as high as 86% silencing (Figure 22b), suggesting that nanocarrier-facilitated intracellular delivery of siRNA could increase SOD1 gene silencing efficiency. Au NEs could be excited to generate 1O2 for PDT upon 915 nm (NIR I) and 1064 nm (NIR II) laser irradiation, respectively. Interestingly, siRNA13587


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Figure 22. (a) Schematic representation of SOD1 siRNA-loaded Au NEs for combination of PDT and gene silencing of deep seated tumors. (b) Evaluation of SOD1 gene silencing efficiencies at varied SOD1 siRNA concentrations measured using RT-qPCR. (c) ROS generation in lipid-coated Au NEs and siRNA-lipid-coated Au NEs internalized HeLa cells followed by photoirradiation, monitored by the mean fluorescence intensities of DCF using flow cytometry. (d) Tumor growth curves of B16F0 tumor-bearing mice subjected to varied treatments. (Inset) Representative mice images showing the scar formation at day 15 and the formation of new skin at day 25 for siRNA-lipid-coated Au NE injected mice upon 1064 nm laser irradiation. Reproduced with permission from ref 446. Copyright 2015 Elsevier.

cooperatively enhance the PTT efficacy. The encapsulation of siRNA into a photothermal nanocarrier realizes the synergistic combination of GT and PTT. Zhao et al. designed PEI-modified WS2 NPs (denoted as WS2@PEI) as a combination of PTCA and siRNA carrier for synergistic GT/PTT (Figure 23a).452 WS2@ PEI caused a rapid temperature rise upon increased duration of NIR laser irradiation to produce considerable PTT effect (Figure 23b). Moreover, the surface coating of positively charged PEI made WS2 an effective nanocarrier of survivin siRNA by protecting siRNA from RNase-induced degradation. Although the upregulated HSP70 protein expression in the PTT group could enhance the heat stress tolerance of cancer cells by suppressing heat-induced apoptosis, the sharp downregulation of HSP70 protein expression in the GT group could reduce the cancer cells’ heat resistance to improve the photothermal effect (Figure 23d). Accordingly, the synergistic enhancement of GT for PTT gave rise to a much lower cancer cell viability than the corresponding monotherapy (Figure 23c). The combination of WS2@PEI-induced mild-hyperthermia (∼43 °C, Figure 23e) in vivo and the loaded siRNA was sufficient to eliminate the tumors and simultaneously suppress tumor recurrence (Figure 23f), which demonstrated the effective outcome of synergistic GT/ PTT. More importantly, the mild-hyperthermia involved in

Au NEs caused a higher ROS level in HeLa cells than the Au NEs-treated group under the same laser exposure (Figure 22c). As higher intracellular ROS level triggered more significant cell apoptosis/necrosis and thus caused a higher cell death rate, siRNA-Au NEs yielded a much stronger PDT effect than Au NEs in vitro and in vivo. While Au NEs plus 915 or 1064 nm laser irradiation only partially suppressed the tumor growth, siRNAAu NEs could completely eradicate tumors with the formation of new skin (Figure 22d), thus confirming the higher antitumor efficacy of synergistic GT/PDT than PDT alone. Consequently, via selective knockdown of anti-ROS protein expression using specific types of siRNA, the ROS-mediated PDT effects can be greatly improved by GT, which lays the foundation for the combined use of GT and PDT based on PS/siRNA coloaded nanocarriers. 3.2.3. GT-Enhanced PTT. While PTT does well in thermally ablating all kinds of tumors, heat shock proteins (such as HSP70) overexpressed in cancer cells confer thermoresistance and impair hyperthermia-induced cell death,447,448 which undermines the PTT efficacy through cytoprotective and antiapoptotic mechanisms.449 Certain types of siRNA can silence the expression of HSP70 proteins to inhibit the heat shock response and increase cancer cells’ susceptibility to PTT,186,450,451 which marks one of the significant instances that siRNA-mediated GT can 13588


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Figure 23. (a) Schematic of WS2@PEI-siRNA. (b) Temperature rise profiles of ultrapure water and different concentrations of WS2@PEI upon 808 nm laser irradiation. Inset: Photothermal images of water and WS2@PEI (300 μg/mL, 1 mL) upon 808 nm laser irradiation. (c) Viabilities of BEL-7402 cells subjected to different treatments. (d) Western blot analysis for the protein expression of survivin and HSP70 in BEL-7402 cells after different treatments. (e) Temperature rise profile and (inset) the corresponding photothermal images of balb/c nude mice bearing BEL-7402 tumors after intratumoral injection of WS2@PEI and subjected to 808 nm laser irradiation. (f) BEL-7402 tumor volume growth curves of mice after different treatments. Reproduced with permission from ref 452. Copyright 2016 Wiley-VCH.

Figure 24. (a) Schematic of GNRs-siRNA for synergistic GT/PTT. (b) BAG3 protein expression after indicated treatments (“+” indicates with and “−” indicates without). (c) Temperature change curves of pure water, CTAB-GNRs, and GNRs-siRNA upon 810 nm laser irradiation for 20 min. (d) The protein expression of the cleaved PARP in Cal-27 cells after indicated treatments (“+” indicates with and “−” indicates without). (e) Quantitative analysis of tumor uptake of siRNA. (f) Average tumor growth percent subjected to different treatments. Reproduced with permission from ref 456. Copyright 2016 Elsevier.

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Figure 25. (a) Schematic of albumin biomimetic nanocorona (DRI-S@HSA) loading Twist siRNA and IR-780. (b) Temperature rise profiles of DRI, DRI-S, and DRI-S@HSA upon 808 nm laser irradiation. (c) Western blot analysis for the Twist protein expression in 4T1 cells subjected to different treatments. (d) Quantified inhibitory effects of DRI, DRI-S, and DRI-S@HSA, with and without 808 nm laser combination on 4T1 cell migration. (e) 4T1 Tumor growth profiles after various treatments. (f) Numbers of visually detected metastatic nodules per lung subjected to different treatments. (g) Inhibitory effects of different treatments on lung metastasis in comparison to the negative control. Reproduced with permission from ref 457. Copyright 2017 Wiley-VCH.

completely eliminated without recurrence (Figure 24f), which soundly demonstrated the much higher in vivo anticancer efficacy of synergistic GT/PTT over PTT alone. While PTT can only eradicate local tumors, GT is a systemic treatment paradigm applicable for preventing distant tumor metastasis via downregulation of metastasis-driving protein expression. Therefore, the combined use of PTT and GT is able to produce a synergistic effect for simultaneous eradication of primary tumors and suppression of distant tumor metastasis. Li et al. reported an albumin biomimetic nanocorona coloading IR-780 and Twist siRNA (denoted as DRI-S@HSA, Figure 25a) for synergistic GT/PTT.457 In the structure of DRI-S@HSA, IR780 could be excited by NIR light to generate heat for PTT (Figure 25b) while Twist siRNA could specifically silence Twist protein expression (Figure 25c) for suppression of 4T1 cell migration (Figure 25d). After systemic administration, DRI-S@ HSA exhibited relatively long blood circulation, high tumor accumulation, and deep tumor penetration thanks to the albumin camouflage. Upon 808 nm laser irradiation of DRI-S@HSA, the resultant GT/PTT produced a synergistic effect for simultaneous inhibition of both primary tumor growth (Figure 25e) and lung metastasis (Figure 25f,g).

synergistic GT/PTT causes negligible heat damage to normal tissues, thus promoting its biosafety. BAG3 (Bcl-2 associated athanogene domain 3) is another typical family of heat shock proteins that yield cytoprotective effects to protect cancer cells from thermal death.453 Specific silencing of BAG3 protein expression can also attenuate the PTT-induced heat shock protective response and render cancer cells more sensitive to heat-induced apoptosis.454,455 For instance, Li et al. constructed a GNRs-siRNA nanoplatform against BAG3 protein for enhanced thermal damage (Figure 24a).456 After sequential surface modification of negatively charged poly(sodium 4-styrenesulfonate) (PSS) and positively charged poly(-diallyldimethylammonium chloride) (PDDAC), GNRs showed an unambiguous advantage in transporting siRNA into cancer cells with much greater BAG3 gene silencing efficiency than commercial Lipofectamine-siRNA (Figure 24b). Figure 24c showas that GNRs could rise about 38 °C after 20 min of NIR laser irradiation, and the bound siRNA hardly affected the prominent photothermal performance of GNRs. Interestingly, GNRs-siRNA induced much higher cleaved PARP protein expression (corresponding to much higher apoptosis) than GNRs upon NIR laser irradiation (Figure 24d), which could be ascribed to the siRNA-suppressed BAG3 protein expression for improving the photothermal effect of GNRs, suggesting the synergistic interaction based on GT-enhanced PTT. The in vivo BAG3 siRNA delivery efficiency of GNRs was evaluated by observing the green fluorescence (siRNAFAM) within frozen tumor sections (Figure 24e), demonstrating that tumor accumulation of GNRs-siRNA was much higher than that of siRNA alone. The tumor growth in the GNRs + laser group showed initial regression followed by a resurgence of tumor growth while the tumors treated by GNRs-siRNA + laser were

3.3. PDT-Based Bimodal Synergistic Therapy

The ROS generated in PDT plays diverse roles, not limited to causing nuclear DNA damage and triggering cancer cell death. ROS can also promote intracellular drug delivery/release, boost immune responses, and inhibit the DNA repair following exposure to ionizing radiation to enhance the treatment efficacy of chemotherapy, immunotherapy, and RT, respectively (Figure 26). 3.3.1. PDT-Enhanced Chemotherapy. By coloading anticancer drugs and PSs into a single nanostructure, chemo13590


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as well as increase the drug cytotoxicity, thus leading to remarkably enhanced synergistic PDT/chemotherapy efficacy. For MDR cells, ROS can even destroy the P-gp protein to boost intracellular drug accumulation for enhanced chemotherapy efficacy against MDR cells,465 which establishes a superior synergistic paradigm of PDT/chemotherapy over GT/ chemotherapy for overcoming MDR by avoiding the premature siRNA degradation. Hwang et al. performed a series of in vitro cellular experiments to demonstrate whether the synergistic use of PDT and chemotherapy could destroy DOX-resistant human breast cancer (MCF-7/MDR) cells.458 In their study, lanthanidedoped mesoporous silica frameworks (EuGdOx@MSF) were fabricated to load DOX for synergistic PDT/chemotherapy (Figure 27a). Upon NIR light (λ = 980 nm) irradiation, the 1O2 generated from EuGdOx@MSF was found to remarkably downregulate the P-gp expression (Figure 27b), indicating the ability of ROS to reverse MDR via oxidative damage of intracellular P-gp. As expected, accompanying the downregulated P-gp expression, strong DOX signal in MCF-7/ADR cells was observed (Figure 27c), mainly attributed to the enhanced cell uptake of EuGdOx@MSF. Thus, over 80% MCF7/ADR cells were killed by EuGdOx@MSF-DOX plus NIR irradiation (Figure 27d) owing to the ROS-elevated cytotoxicity of DOX, which was more effective than either monotherapy, thus demonstrating the superior advantage of synergistic PDT/ chemotherapy in overcoming MDR. Similarly, Zhu et al. constructed layered double hydroxide (LDH) NPs to codeliver chlorin e6 (Ce6, a PS) and DSCP (a Pt(IV) prodrug) for overcoming cisplatin resistance via synergistic PDT/chemotherapy.466 The generated ROS was also very effective in

Figure 26. Schematic of the mechanisms behind PDT-based bimodal synergistic therapy.

therapy and light-activated PDT can be combined to obtain a higher therapeutic effect.458−463 It has been found that the ROS generation from PDT is able to promote intracellular drug delivery and accelerate drug release for increased cytotoxicity, so PDT has the potential to enhance the chemotherapy efficacy, which leads to the naissance of synergistic chemotherapy/PDT. For instance, Liu et al. reported that PDT could facilitate the endosomal escape of drugs via the disruption of endosomes/ lyosomes for effective intracellular drug delivery.464 Meanwhile, light-triggered preferential distribution of PS and drug within cytoplasm/nucleus could greatly improve the ROS-killing effect

Figure 27. (a) Schematic representation of EuGdOx@MSF-DOX for NIR light-triggered synergistic PDT/chemotherapy. (b) Relative P-gp expression levels of MCF-7/MDR cells treated with DOX, EuGdOx@MSF, and EuGdOx@MSF-DOX under dark and photoirradiation conditions. (c) Confocal images of EuGdOx@MSF-DOX internalized MCF-7/MDR cells under dark and photoirradiation conditions. (d) Viabilities of EuGdOx@MSF and EuGdOx@MSF-DOX-internalized MCF-7/MDR cells at 48 h incubation time under dark and 980 nm light irradiation conditions. Reproduced with permission from ref 458. Copyright 2016 Wiley-VCH. 13591


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Figure 28. (a) Schematic of the light-controlled ROS-activated on-demand drug release for synergistic PDT/chemotherapy. (b) Cumulative DOX release profiles for TCP-DOX NPs with and without white light irradiation. (c) Viability of MDA-MB-231 cells incubated with free DOX, TCP NPs, and TCP-DOX NPs with (5 or 15 min) or without light irradiation. Reproduced with permission from ref 469. Copyright 2014 Wiley-VCH.

Figure 29. (a) Scheme of P-RFRT-mediated PDT for enhanced delivery of NPs to tumors. (b) Immunofluorescence staining images of tumors treated with P-RFRTs before and after light irradiation. “c” and “p” refer to the central and peripheral regions of the tumor, respectively. (c) Fluorescent images of bilateral 4T1 tumors with (right) and without (left) light irradiation. (d) 4T1 tumor growth curves subjected to different treatments. Reproduced with permission from ref 474. Copyright 2014 American Chemical Society.

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Figure 30. (a) Schematic of the multifunctional TPZ@MCMSN-Gd3+ nanoplatform for synergistic combination of supraPSs-based PDT and bioreductive chemotherapy. (b) Evaluation of tumor hypoxia after treatment with TPZ@MCMSN-Gd3+ plus laser irradiation using immunofluorescence assay. Nuclei and hypoxic tissues were stained with DAPI (blue) and antipimonidazole antibody (green), respectively. Reproduced with permission from ref 478. Copyright 2017 Elsevier. (c) Schematic of TPZ/AI-NV-mediated tumor hypoxia upon light irradiation. (d) HepS xenograft tumor growth curves after exposure to different treatments. Reproduced with permission from ref 479. Copyright 2017 Wiley-VCH.

decreasing the P-gp expression, which remarkably increased the DSCP concentration in cisplatin-resistant (A2780cisR) cancer cells for elevated cytotoxicity. Therefore, the combined use of PDT and chemotherapy may provide a versatile synergistic strategy for treating various kinds of drug-resistant cancers based on the ROS-suppressed P-gp expression and enhanced tumor cell uptake. If a PS and drug are connected through a ROS cleavable linker, the light-triggered ROS generation can break down the linker to release the drug for killing cancer cells. The sequential release of ROS and drugs upon light irradiation can realize on-demand synergistic PDT/chemotherapy.467 For example, Liu et al. developed a PS-drug conjugate system by using the ROScleavable thioketal linker468 to conjugate polyelectrolyte and DOX, which could self-assemble into NPs in aqueous media (Figure 28a).469 By the surface modification of PEG and cyclic RGD (cRGD) peptide, the designed TCP-DOX NPs could efficiently target αvβ3 integrin-overexpressed cancer cells for synergistic PDT/chemotherapy. Under white light irradiation, a considerable amount of ROS generation was observed by using a ROS-sensitive probe. Moreover, TCP-DOX NPs exhibited ROSresponsive DOX release, because the increased amount of ROS generation upon elevated power of white light irradiation could remarkably accelerate the DOX release (Figure 28b). However, negligible ROS generation and DOX release were found without white light irradiation, which indicated the light-controlled sequential release of ROS and DOX with minimized side effects under dark conditions. Due to the specific targeting of cRGD to αvβ3 integrin receptor, more TCP-DOX NPs were taken up by αvβ3 integrin overexpressing MDA-MB-231 cells than αvβ3

integrin poorly expressing MCF-7 cells. Upon 15 min of white light irradiation, TCP-DOX NPs remarkably lowered the MDAMB-231 cell viability to 30%, much lower than free DOX and TCP NPs (Figure 28c). More importantly, the viability of TCPDOX NP treated cells could be controlled by regulating the light irradiation time, which demonstrated the feasibility of ondemand synergistic PDT/chemotherapy. PDT has been found to increase the permeability of tumor vessels to facilitate the extravasation of nanocarriers via the EPR effect,470−472 which can largely elevate the drug accumulation within tumor for improved chemotherapeutic effect.473 Interestingly, Xie and co-workers performed a series of in vivo experiments to validate the “PDT-enhanced EPR effect” theory.474 In their study, RGD-modified ferritin (RFRT) was used as a nanocarrier of ZnF16Pc (denoted as P-RFRTs) to produce 1O2 for PDT (Figure 29a). After intravenous injection of IRDye800-labeled P-RFRTs into mice bearing bilateral 4T1 tumors, the right tumor upon light irradiation showed much higher uptake of P-RFRTs while the left tumor without light irradiation demonstrated little uptake (Figure 29c). Moreover, the immunofluorescence staining result showed that albumin penetrated much deeper in the irradiated tumor than that in the unirradiated tumors (Figure 29b), which further confirmed the PDT-mediated enhanced tumor accumulation of NPs. Importantly, P-RFRT-mediated PDT enhanced tumor-specific delivery of Doxil (a representative nanoparticle drug). Tumor growth was completely suppressed by the combination of P-RFRT and Doxil upon light irradiation, which was not possible by Doxil alone (Figure 29d). It is expected that such “PDT-enhanced EPR effect” will also enhance the tumor accumulation of other 13593


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Figure 31. (a) Schematic presentation of synergistic PDT/immunotherapy by IDOi@TBC-Hf. (b) Immunofluorescence images of CRT expression on the surface of MC38 cells treated with PBS and TBC-Hf upon LED irradiation. (c and d) Growth curves for (c) primary/treated and (d) distant/ untreated tumors after PDT treatment (+) with IDOi@TBC-Hf and injections of mouse IgG, anti-CD4, or anti-CD8 antibody, compared to PBS control without PDT treatment (−). Black, red, and blue arrows refer to the time of IDOi@TBC-Hf injection, light irradiation, and antibody injection, respectively. Reproduced with permission from ref 493. Copyright 2016 American Chemical Society.

(Figure 30a).478 The immunofluorescence staining result provided clear evidence of oxygen depletion and tumor hypoxia aggravation caused by PDT after light irradiation (Figure 30b), indicating favorable conditions for TPZ cytotoxicity for synergistic PDT/bioreductive chemotherapy, thus leading to a large scale hypoxic tumor apoptosis and necrosis. Recently, Gu et al. designed a TPZ-loaded anaerobe-inspired nanovesicle (denoted as TPZ/AI-NV) for the synergistic integration of PDT and bioreductive chemotherapy.479 The Ce6 in the polymeric AI-NV converted molecular O2 to 1O2 for PDT upon 650 nm laser irradiation, which not only killed cancer cells and inhibited hypoxic tumor growth to some extent (Figure 30c) but also further elevated tumor hypoxia degree to improve the hypoxic cell-killing effect of TPZ. As a result, the synergistic PDT/bioreductive chemotherapy produced a remarkable antihypoxia effect for thorough inhibition of hypoxic tumor growth (Figure 30d). On the basis of the above four mechanisms (ROS-promoted intracellular drug delivery, ROS-controlled/accelerated drug release, PDT-enhanced EPR effect of nanocarriers, and PDTinduced hypoxia for activation of bioreductive drug), the synergistic interactions between PDT and chemotherapy with multiple kinds of PS/drug coloaded nanostructures have been employed to substantially improve the ROS/drug cokilling functionality,480−485 which results in pronounced tumor growth suppression and even regression. 3.3.2. PDT-Enhanced Immunotherapy. As a typical type of immunotherapy, checkpoint blockade immunotherapy uses antibodies to modulate the immune system and block negative regulatory receptors on T cells.486 However, very limited systemic antitumor responses are elicited to respond to

therapeutic agents (e.g., siRNA, photothermal compounds, radiosensitizers, etc.) via tumor-specific delivery of nanocarriers, thus leading to the synergistic use of PDT with GT, PTT, RT, or other treatments. The effectivenesses of PDT and chemotherapy are seriously undermined in the hypoxic environment, but their cooperative integration via nanotechnology can produce a remarkable synergistic effect for efficient killing of hypoxic cancer cells for two reasons. First, the codelivery of PSs and drugs via an oxygengenerating nanocarrier can supply sufficient O2 to the hypoxic tumor to greatly enhance the anticancer efficacy of both PDT and chemotherapy. For example, through the human serum albumin (HSA)-assisted assembly of MnO2, Ce6 and c,t,c-[Pt(NH3)2(O2CCH2CH2COOH)(OH)Cl2] (cis-Pt(IV)SA, a prodrug of CDDP),475 the resultant HSA-MnO2−Ce6 and Pt (abbreviated as HMCP) NPs could directly generate O2 in situ (arising from MnO2-induced decomposition of endogenous H2O2) for improved oxygenation of hypoxic tumor, simultaneously increasing the 1O2 yield and Pt-drug cytotoxicity, thus leading to oxygen-elevated synergistic PDT/chemotherapy for overcoming tumor hypoxia. Second, for PS and bioreductive drug coloaded nanostructures, PDT induces considerable O 2 consumption, and the aggravated tumor hypoxia can in turn improve the cell-killing effect of bioreductive drugs476,477 whose cytotoxicity is elevated with the decreased concentration of surrounding oxygen. To validate the synergism between PDT and bioreductive chemotherapy, Zhang et al. fabricated a multifunctional TPZ@MCMSN-Gd3+ nanoplatform based on TPPS4 (PS) and TPZ (bioreductive drug) coloaded Gd3+chelated MSNs, aimed at realizing the cooperation of lighttriggered cytotoxic 1O2 and subsequent hypoxia-activated TPZ 13594


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Figure 32. (a) Schematic of immunogenic ZnP@pyro PDT-induced sensitization of tumors to PD-L1 blockade immunotherapy for the treatment of metastatic tumors. (b) Representative pictures of tumor nodules in the lungs after different treatments. (c) Percentage of lung metastasis subjected to different treatments. (d) Weight of primary and distant 4T1 tumors at day 28 post-treatment. Reproduced with permission from ref 494. Copyright 2016 American Chemical Society.

checkpoint inhibition because of the difficulty in the activation of the host immune system as well as the reliance on the high expression of PD-1 on pre-existing tumor-infiltrating CD8+ T cells.198,487 Therefore, other treatments capable of enhancing T cell infiltration via induction of the immunogenic tumor microenvironment can sensitize tumors to checkpoint blockade for enhanced immunotherapy efficacy.488 As ROS is able to activate acute inflammation, increase the tumor immunogenicity, and enhance the T cell infiltration,489 PDT may trigger strong immunological responses for enhanced checkpoint blockade therapy. More importantly, the generated ROS in PDT can kill cancer cells both directly by inducing tumor cell apoptosis/ necrosis and indirectly by producing tumor-specific immunity,490−492 which leads to synergistic PDT/immunotherapy. Recently, Lin and co-workers performed a study on synergistic PDT/checkpoint blockade immunotherapy.493 In their work, a multifunctional nanostructure (denoted as IDOi@TBC-Hf) was constructed by encapsulating indoleamine 2,3-dioxygenase inhibitor (IDOi) into TBC-Hf (a typical chlorin-based nanoscale metal−organic framework). The ROS generation from lightactivated TBC-Hf caused both cell apoptosis and ICD to release antigens that might act on T cells, while the released IDOi was able to induce systemic antitumor immunity, including T cells (Figure 31a). Thus, the combination of ROS and IDOi played a cooperative role in causing T cell proliferation and infiltration for efficient treatment of malignant tumors as well as inducing an active immunological response for effective systemic cancer therapy. The in vitro immunofluorescence result showed that the combination of TBC-Hf and light irradiation caused significant CRT expression on the MC38 cell surface (as shown by the green fluorescence, Figure 31b), indicating that PDT indeed triggered ICD for enhanced immunotherapy. The in vivo result showed that the combination of IDOi@TBC-Hf and light irradiation caused both primary and distant tumor regression (Figure

31c,d), demonstrating the featured advantage of synergistic PDT/immunotherapy in treating distant tumors. Another study by Lin et al. reported that the combination of PDT and checkpoint blockade therapy could produce a synergistic effect to overcome tumor metastasis, which contributed to efficient treatment of both primary and metastatic tumors. They designed a core/shell ZnP@pyro NP composed of Zn-pyrophosphate (ZnP) as the core and pyrolipid (pyro, a PS) as the shell for 670 nm light-excited PDT in combination with a PD-L1 antibody.494 Due to the strong synergism between PDT and PD-L1 checkpoint blockade immunotherapy (Figure 32a), the treatment of ZnP@pyro plus 670 nm light irradiation and anti-PD-L1 not only regressed and eradicated primary tumors, but also remarkably decreased the percentage of metastasis in the lung (Figure 32b,c). The resultant synergistic PDT/immunotherapy could further trigger a systemic tumor-specific cytotoxic T cell response for the complete inhibition of nontreated metastatic tumors in addition to primary tumors (Figure 32d). It is expected that the synergistic use of PDT and checkpoint blockade immunotherapy will play an irreplaceable role in overcoming distant tumor metastasis by activating the whole immune system to generate systemic antitumor immunity, which is highly desirable for the efficient killing of distant metastatic cancer cells and thorough suppression of tumor metastasis, which carries important implications for clinical translation. 3.3.3. PDT-Enhanced RT. PDT works through photochemical reaction to yield ROS (mainly 1O2) upon light excitation to destroy cancer cells and induce DNA lesions,495 while RT also generates ROS (mainly free radicals) upon highenergy X/γ-ray radiation to break down DNA strands.496 As the principal target of PDT and RT is the nuclear DNA, there exist potential synergistic interactions between these two modalities in cell-killing due to the inhibition of RT-induced DNA repair by PDT, which may result in permanent cell death.301,302,497 13595


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Figure 33. (a) Schematic of Hf-TCPP NMOFs for light-triggered 1O2 generation by TCPP for PDT and X-ray absorbance by Hf for enhanced RT. (b) Surviving fractions of 4T1 cells treated with NMOF-PEG upon different dosages of X-ray irradiation (0, 2, 4, 6, and 8 Gy). (c) Relative fluorescence intensity of hypoxia in immunofluorescence images of tumor slices at different times post RT. (d) Relative 4T1 tumor volume changes curves after various treatments. Reproduced with permission from ref 498. Copyright 2016 Elsevier.

Figure 34. (a) Schematic of intranuclear synergistic PDT/RT by nucleus-targeting UCSPs-PEG/TAT. (b) Bio-TEM images of HT-1080 cells after coincubation with (b1) UCSPs-PEG/TAT and (b2) UCSPs-PEG for 24 h. (c) Viabilities of HT-1080 cells after treatment with intranuclearly delivered UCSPs-PEG/TAT and intracellularly delivered UCSPs-PEG upon NIR/X-ray irradiation. (d) Comet assay for DNA damage of HT-1080 cells subjected to different treatments: (d1) control, (d2) UCSPs-PEG, (d3) UCSPs-PEG + RT, (d4) UCSPs-PEG + NIR, (d5) UCSPs-PEG + RT + NIR, (d6) RT, (d7) UCSPs-PEG/TAT, (d8) UCSPs-PEG/TAT + RT, (d9) UCSPs-PEG/TAT + NIR, and (d10) UCSPs-PEG/TAT + RT + NIR. Reproduced with permission from ref 88. Copyright 2015 Elsevier.

Ahmadi et al. observed the synergistic PDT/RT effects of ICG upon NIR light and X-ray irradiation.91 They found that ICG was

only a PS rather than a radiosensitizer. The viability of MCF-7 cells subjected to single PDT (ICG plus 60 J/cm2 NIR 13596


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Figure 35. (a) Schematic of the mechanism of X-ray-induced synchronous PDT/RT without oxygen dependence. (b) Relative DCF fluorescence intensities (measured by flow cytometry analyses) for probing ROS in hypoxic (2% O2) HeLa cells treated with SZNPs under 3 Gy of X-ray radiation. (c) Viabilities of hypoxic HeLa cells treated with SZNPs plus varied doses of X-ray irradiation (0, 2, 4, and 6 Gy). (d) Relative HeLa tumor volume change curves after exposure to different treatments. Reproduced with permission from ref 505. Copyright 2015 Wiley-VCH.

sensitizers into the cytoplasm rather than the nucleus, thus seriously diminishing the PDT and RT efficacy. Therefore, in order to further enhance synergistic PDT/RT efficacy, PSs and radiosensitizers should be directly transported into the nucleus via a nucleus-targeting nanocarrier to generate intranuclear ROS for breaking down the double stranded DNA more efficiently.500,501 To achieve this goal, a nucleus-targeting biophotonic agent (denoted as UCSPs-PEG/TAT, Figure 34a) was developed by covalent coencapsulation of silicon phthalocyanine dihydroxide (SPCD) and protoporphyrin IX (PpIX) in a single UCNP/SiO2 system followed by surface modification with PEG and TAT.88 Both SPCD and PpIX could absorb the luminescence emission from UCNPs upon NIR light irradiation to generate 1O2 for enhanced PDT,502 while PpIX could serve as a radiosensitizer to accelerate the X-ray-induced radiolysis of water to yield more free radicals for enhanced RT.503 The bioTEM images clearly showed the intranuclear delivery of UCSPsPEG/TAT (Figure 34b1) but not UCSPs-PEG (Figure 34b2), which confirmed that the TAT coating assisted nucleustargeting. Upon coirradiation of NIR light and X-ray, UCSPsPEG/TAT caused much more significant DNA damage (Figure 34d) and led to much lower HT-1080 cell viability (Figure 34c) than UCSPs-PEG, which demonstrated the greater treatment efficacy of intranuclear synergistic PDT/RT oversimple intracellular synergistic PDT/RT. As HT-1080 cells exhibit intrinsic resistance to ionizing radiation, the intranuclear synergistic PDT/RT technique may provide an effective strategy to destroy radio-resistant tumors. As two typical oxygen-dependent treatment paradigms, the PDT/RT in combination with O2 supply can result in an oxygenelevated synergistic PDT/RT effect for ROS-mediated hypoxic cell death. Moreover, the respective use of NIR light and X-ray to excite PDT and RT is conducive to treat hypoxic tumors in deep tissues. A theranostic 2D nanomaterial was designed by anchoring UCNP/SPCD nanoprobes on MnO2 nanosheets for simultaneous realization of in situ O2 generation, NIR light-

irradiation) and single RT (ICG plus 4 Gy X-ray radiation) were 26% and 84%, respectively, but their combination (ICG plus coirradiation of 60 J/cm2 NIR light and 4 Gy X-ray) achieved a synergism in reducing the cell viability to only 3%. The remarkable synergistic PDT/RT effect was ascribed to the PDT-inhibited replication of DNA after RT, so that DNA was permanently damaged, resulting in complete cancer cell death. More importantly, thanks to the synergistic use of PDT and RT, the light power density and X-ray dose could be largely reduced to minimize the side effects. If a PS and a radiosensitizer are coloaded within one nanostructure, PDT and enhanced RT can be simultaneously achieved upon light/X-ray irradiation to produce a synergistic effect. For example, Liu and co-workers designed multifunctional nanoscale metal organic frameworks (NMOFs) composed of Hf4+ and tetrakis(4-carboxyphenyl) porphyrin (TCPP), which demonstrated high biocompatibility and easy biodegradability after surface modification of PEG (Figure 33a).498 The TCPP in NMOF-PEG could generate 1O2 upon 661 nm laser excitation to yield a stronger anticancer effect than free TCPP. The high-Z Hf4+ with strong X-ray attenuation ability could serve as a radiosensitizer that interacts with X-ray radiation to produce reactive free radicals for enhanced RT (Figure 33b). As both RT and PDT are oxygen dependent, the interval between RT and PDT should be taken into consideration for the tumor oxygenation after X-ray irradiation. It was found that the tumor oxygen recovered to normal levels at 8 h post X-ray radiation due to oxygenated blood flow (Figure 33c). Therefore, PDT should be carried out around that time. Upon sequential irradiation of Xray and 661 nm laser, NMOFs produced a remarkable synergistic PDT/RT effect for fully suppressing tumor growth (Figure 33d) and causing large scale tumor destruction. Only when the DNA in the nucleus is damaged, can the cancer cell be killed. Due to the short lifetime and diffuse distance,499 most ROS would disappear before reaching the nuclear DNA because many nanocarriers can only deliver PSs or radio13597


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Figure 36. Schematic of the mechanisms behind PTT-based bimodal synergistic therapy.

excited PDT, and X-ray-excited RT.504 The resultant oxygenelevated synergistic PDT/RT not only overcame tumor hypoxia and angiogenesis via downregulation of hypoxia-inducible factor1 alpha (HIF-1α) expression and suppression of vascular endothelial growth factor (VEGF) expression, but also caused massive apoptosis and necrosis for hypoxic tumor volume reduction. Although most type II PDT processes rely heavily on O2 to generate 1O2, type I PDT involves the decomposition of H2O into hydroxyl radicals without the need of oxygen participation (Figure 35a), thus the oxygen-independent feature enables type I PDT to overcome tumor hypoxia. Furthermore, if type I PDT is excited by X-ray radiation, the type I PDT and RT can be concurrently excited to maximize the bimodal synergistic therapeutic effect without oxygen dependence and tissue penetration depth limitation. Shi et al. developed the technique of X-ray-excited synchronous PDT/RT via the fabrication of CeIII-doped LiYF4@SiO2@ZnO nanostructure (denoted as SZNP).505 The conversion of ionizing radiation into UV light via the CeIII-doped LiYF4 scintillator could trigger ZnO to yield hydroxyl radicals in both normoxic and hypoxic environments (Figure 35b). Upon X-ray irradiation, the generated highly reactive hydroxyl radicals were more effective than 1O2 in killing hypoxic cells (Figure 35c) and thoroughly inhibiting solid tumor growth (Figure 35d). Thanks to the oxygen independence of type I photochemical reaction and high permeability of X-rays, the developed synchronous type I PDT/RT promises superior advantages in treating deep-seated hypoxic cancers.

3.4. PTT-Based Bimodal Synergistic Therapy

Apart from thermally ablating tumors, the generated heat in PTT also accelerates intracellular delivery and release of drugs, genes, immunologic adjuvant, or PSs for enhanced chemotherapy, GT, immunotherapy, or PDT, respectively. Additionally, the intratumoral blood flow can also be sped up by heat for improved tumor oxygenation, thus enhancing the RT efficacy for treating hypoxic tumors. In this subsection, the most representative studies will be introduced to clarify the synergistic mechanisms between PTT and the above five types of monotherapy (Figure 36). 3.4.1. PTT-Enhanced Chemotherapy. PTT-enhanced chemotherapy and their synergistic interactions have been well documented.506−513 It has been observed that some anticancer drugs may exhibit synergistic interactions with heat and show increased cytotoxicity upon high temperature, which makes it possible that the heat arising from PTT can directly improve the cell-killing effect of drugs. For instance, Chan et al. reported that the cytotoxicity of cisplatin could be increased by hyperthermia induced by light irradiation of gold nanorods.81 The combination of cisplatin and hyperthermia resulted in a much lower cell viability than their projected additive value (calculated by multiplying the cell viability from cisplatin by the cell viability from hyperthermia, Figure 37a), which suggested the cooperative enhancement effect of hyperthermia on cisplatin for synergistic PTT/chemotherapy. It should be noted that the encapsulation of the heat-sensitive drugs in a photothermal nanocarrier could further increase the PTT-activated drug cytotoxicity while reducing its side effect. Li et al. covalently 13598


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Figure 37. (a) Synergistic behavior of OCI AML3 cells treated with GNR hyperthermia, cisplatin, and GNR hyperthermia plus cisplatin. The projected additive value is calculated by multiplying the surviving fraction of cells from one independent treatment by the surviving fraction of the second independent treatment. Reproduced with permission from ref 81. Copyright 2008 Wiley-VCH. (b) Schematic of the PEG-NGO-Pt nanocomposite as a multifunctional platform for synergistic PTT/chemotherapy. (c) Relative viability (versus untreated control) of 4T1 cells treated with PEG-NGO, PEGNGO-Pt, and Pt(II) in the dark or under photothermal heating via NIR irradiation. (d) Biodistribution of the Pt(II) and PEG-NGO-Pt in tumor, heart, liver, spleen, lung, and kidney of 4T1 tumor-bearing mice at 24 h after systemic administration and NIR laser irradiation at the tumor site. (e) Representative photos of 4T1 breast tumors subjected to various treatments by PBS, PEG-NGO, PEG-NGO-Pt, and Pt(II) respectively, with or without NIR laser irradiation. Reproduced with permission from ref 514. Copyright 2015 Elsevier.

Figure 38. (a) Schematic of DOX-CuS@PMOs for synergistic PTT-enhanced chemotherapy. (b) Mean fluorescence intensity (MFI) of U87MG cells after incubation with varied concentrations of DOX-CuS@PMOs for 30 min without or with 808 nm laser irradiation. (c) Relative uptake of CuS@ PMOs by U87MG cells after coincubation for 30 min with or without 808 nm laser irradiation. (d) Viabilities of U87MG cells treated with free DOX and DOX-CuS@PMOs, with or without 808 nm laser irradiation. (e) DOX fluorescence signal in tumors treated by injection of free DOX and DOX-CuS@ PMOs, with or without 808 nm laser irradiation. (f) Tumor growth curves subjected to different treatments. Reproduced with permission from ref 522. Copyright 2017 Elsevier.

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Figure 39. (a) Schematic of IR-780/DOX coloaded polymeric micelle for synergistic chemotherapy/PTT to overcome tumor MDR. (b) Subcellular localization of free DOX, free IR-780, IPM, and IPM plus NIR laser irradiation after coincubation with MCF-7/ADR cells. (c) MCF-7/ADR tumor growth curves subjected to different treatments. Reproduced with permission from ref 530. Copyright 2016 Wiley-VCH.

DOX fluorescence signal in the tumor treated by DOX-CuS@ PMOs with NIR irradiation over tumors treated by free DOX or DOX-CuS@PMOs without NIR irradiation (Figure 38e). The remarkably elevated intratumoral DOX concentration resulted in thorough tumor growth suppression (Figure 38f). This mechanism of hyperthermia-accelerated drug delivery and release may bridge the interaction between PTT and chemotherapy for the development of synergistic PTT/chemotherapy, which will give rise to a substantially improved anticancer effect for considerable tumor regression and elimination.523−528 Different from the anti-MDR mechanism of GT and PDT by using siRNA and ROS to inhibit the P-gp protein expression for enhanced chemotherapy, the hyperthermia involved in PTT not only directly enhances the MDR cell uptake of nanocarriers for elevated intracellular drug concentration, but also increases the sensitivity of MDR cells to chemotherapeutics, both of which contribute to overcoming tumor MDR by synergistic use of PTT and chemotherapy.529 As an example, Ji et al. designed an acidresponsive polymeric micelle loading IR-780 (a PTCA) and DOX for overcoming MDR via synergistic PTT/chemotherapy (Figure 39a).530 The confocal luminescence images (Figure 39b) clearly showed that the combination of IR-780/DOX coloaded polymeric micelles (denoted as IPM) and NIR light irradiation resulted in much stronger DOX fluorescence signals in the MCF7/ADR cell cytoplasm, mainly attributed to the hyperthermiaenhanced cytoplasm permeability for augmented DOX accumulation within MCF-7/ADR cells. With the aid of hyperthermiaenhanced MDR cell uptake and sensitivity toward DOX, IPM plus NIR laser irradiation yielded a synergistic heat/drug cokilling effect for causing considerable MCF-7/ADR cell death. After intravenous injection, IPM exhibited rich accumulation within MCF-7/ADR tumor and resulted in fast tumor regression upon NIR laser irradiation (Figure 39c), which showed the high-performance of synergistic chemotherapy/PTT in overcoming MDR in vivo. The shortcoming of PTT is the limited tissue penetration of NIR light, so the treatment of deepseated MDR tumors requires the combination of chemotherapy

conjugated a Pt(IV) drug (one analog of cisplatin) on the surface of PEGylated nanographene oxide (PEG-NGO) for tumorspecific Pt drug delivery/release in the intracellular reductive microenvironment (Figure 37b).514 The NGO exhibited a drastic temperature increase upon NIR irradiation, and the generated heat not only directly killed cancer cells but also cooperatively improved the cell-killing effect of the released Pt drug, which reduced cell viability to a greater extent than free Pt drug or PTT (Figure 37c). Moreover, PEG-NGO-Pt showed obviously much higher Pt concentrations within the tumor than free Pt drug owing to the passive tumor-targeted Pt drug delivery via NGO (Figure 37d), which validated the enhanced tumorspecific drug delivery by using nanocarriers. Accordingly, the in vivo therapeutic results confirmed that the synergistic PTT/ chemotherapy by PEG-NGO-Pt + NIR achieved much higher treatment efficacy than PTT by PEG-NGO + NIR or chemotherapy by PEG-NGO-Pt and even resulted in complete tumor elimination without recurrence (Figure 37e). Another mechanism behind the PTT-enhanced chemotherapy is based on PTT-induced hyperthermia that can enhance tumor cell uptake of nanocarriers and accelerate drug release from nanocarriers for increased intracellular drug concentration and elevated drug cytotoxicity.515−521 CuS-doped periodic mesoporous organosilica nanoparticles (CuS@PMOs) as a photothermal nanocarrier of DOX were synthesized to investigate the mild-hyperthermia-enhanced tumor cell uptake (Figure 38a).522 Through the precise control of CuS concentration and NIR irradiation period, the temperature could be maintained at 41− 43 °C to provide mild hyperthermia devoid of heat damage, which could boost the cell membrane permeability for enhancing tumor cell uptake of CuS@PMOs (Figure 38c), accompanied by delivery of high concentrations of DOX into the cells (Figure 38b). The accelerated intracellular DOX delivery and release from CuS@PMOs with NIR irradiation caused a higher cell death rate than that without NIR irradiation (Figure 38d). Moreover, the mild hyperthermia also enhanced the tumor uptake of CuS@PMOs in vivo, as shown by the much stronger 13600


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Figure 40. (a) Schematic of the RBC-mimetic NPs (PTX−PN@DiR-RV) for NIR-driven drug release. (b) Quantitative analysis of fluorescence intensities of 4T1 cells after 1, 2, and 4 h of incubation with free PTX, PTX−PN@DiR-RV, and PTX−PN@DiR-RV + L. (c) Quantitative analysis of the lung metastatic nodules after different treatments. (d) Representative images of the lungs after different treatments. White arrows and yellow circles indicate the pulmonary metastases. Reproduced with permission from ref 532. Copyright 2016 Wiley-VCH.

Figure 41. (a) Schematic of hyperthermia-triggered endosomal escape. (b) Transfection of the BPEI (1.8K and 25K), PEG-BPEI-GO, and PEG-BPEIrGO in NIH/3T3 cells with or without NIR irradiation. Reproduced with permission from ref 537. Copyright 2014 Wiley-VCH. (c) Schematic of pING4-loaded OP (OPI) for synergistic PTT/GT. (d) Cell viability of MCF-7 cells subjected to different treatments. (e) Tumor volume changes subjected to different treatments. Reproduced with permission from ref 539. Copyright 2016 Elsevier.

with other highly penetrating therapeutic modalities like X-rayexcited RT. As shown in many studies, PTT is able to completely eradicate primary tumors but fails to kill metastatic tumor cells. On the contrary, chemotherapy is a systemic treatment paradigm for killing both primary and metastatic tumor cells. Therefore, the

combined use of PTT and chemotherapy is also able to produce a synergistic effect for thermal eradication of local tumors as well as effective suppression of distant tumor metastasis.531 However, in order to achieve the optimized antimetastasis efficacy, it is highly desirable to design an advanced DDS with long blood circulation time and stimuli-responsive drug release. To this end, Li et al. 13601


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Figure 42. (a) Schematic of the mechanism of antitumor immune responses induced by PLGA-ICG-R837-based PTT in combination with checkpointblockade. (b) Schematic of PLGA-ICG-R837 in combination with anti-CTLA-4 antibody for inhibiting tumor growth at distant tumor sites. (c) The growth curves of secondary tumors in different groups of CT26-tumor-bearing mice after different treatments to eliminate their primary tumors. Reproduced with permission from ref 547. Copyright 2016 Nature Publishing Group.

PEI resulted in much higher gene transfection efficiency than that without laser irradiation, which further validated the PTTenhanced GT for the synergistic use of PTT and GT. Huang et al. successfully fabricated a hyperthermia-enhanced gene delivery/transfection system for in vivo cancer therapy.539 They synthesized PEI-modified oxidized mesoporous carbon nanospheres (OP), which served as a NIR-absorbing nanocarrier for encapsulation of pING4 (therapeutic gene; Figure 41c). The photothermal effect of NIR-activated OP could significantly accelerate the loaded DNA release for enhanced DNA transfection. With the assistance of pING4 to repress cell proliferation, the PTT effect not only directly killed cells but also accelerated the pING4 release, thus leading to a remarkable synergistic cell-killing effect (Figure 41d). Moreover, the synergistic PTT/GT by pING4-loaded OP combined with NIR light irradiation (OPI + NIR) led to thorough tumor regression (Figure 41e) and much prolonged median survival, indicating high in vivo anticancer efficacy. By making full use of the synergistic interactions between PTT and GT, various multifunctional gene-loaded photothermal nanocarriers have been designed for improved anticancer outcomes.540−542 3.4.3. PTT-Enhanced Immunotherapy. Similar to anticancer drugs and genes, hyperthermia can also enhance cancer cell uptake and release of immunologic adjuvant from nanocarriers for enhanced immunotherapy. For instance, Qu et al. synthesized PEG/PEI-functionalized GO as a photothermal nanocarrier to load CpG for PTT-enhanced immunotherapy.543 The NIR light-triggered photothermal effect was able to promote the intracellular delivery and release of CpG for strengthening both the immunostimulatory effect and immunostimulation responses, which led to synergistic PTT/immunotherapy for efficient tumor regression. Furthermore, as PTCAs also serve as an immunological adjuvant to promote dendritic cell maturation and antitumor cytokine production,544 PTT can generate vaccine-like functions in situ,545 which can be combined with checkpoint blockade approaches to elicit strong antitumor immune responses for enhanced immunotherapy. Moreover, the immunotherapy based on CTLA-4 blockade can get rid of regulatory T cells at distant

fabricated a distinctive kind of RBC membrane-camouflaged DDS by inserting 1,1-dioctadecyl-3,3,3,3-tetramethylindotricarbocyanine iodide (DiR, an NIR-absorbing cyanine dye) and PTX-loaded polymeric cores in the membrane shell and thermoresponsive lipid, respectively (Figure 40a).532 Due to the presence of the RBC membrane, the well-designed PTX− PN@DiR-RV exhibited prolonged circulation lifetime, decreased immune system attack, as well as enhanced tumor accumulation/ penetration. Moreover, upon NIR laser irradiation, the DiRinduced hyperthermia could enhance the tumor cell uptake of PTX−PN@DiR-RV NPs (Figure 40b) and decompose the structure to accelerate PTX release for enhanced chemotherapy. As a result, the PTT-enhanced chemotherapy (PTX−PN@DiRRV + L) gave rise to a synergistic therapeutic effect for completely inhibiting 4T1 tumor growth and suppressing over 98% of lung metastases (Figure 40c,d). Featuring outstanding antitumor and antimetastasis efficacy, the synergistic PTT/ chemotherapy based on hyperthermia-enhanced tumor accumulation/cell uptake/drug release may open up new possibilities for the efficient treatment of metastatic breast cancers. 3.4.2. PTT-Enhanced GT. As discussed above, GT can cooperatively enhance the PTT efficacy via specific suppression of HSP expression and through the reduction of cancer cells’ resistance against heat damage. More interestingly, PTT can in turn enhance the GT efficacy by enhancing the tumor cell uptake of genes and by accelerating gene release from nanocarriers.533−536 Therefore, there exist cooperative enhancement interactions between PTT and GT, which may produce strong synergistic therapeutic effects. Kim et al. found that the photothermal effect could cause the rupture of endosomal membranes to facilitate the endosomal escape of gene-loaded nanocarriers (PEG-BPEI-rGO) for promoting intracellular gene delivery (Figure 41a).537 The designed PEG-BPEI-rGO with NIR laser irradiation exhibited about 2-fold enhancement in gene transfection efficiency than that without NIR laser irradiation (Figure 41b). Liu et al. synthesized a PFG/PEI-modified nanoGO complex (NGO−PEG-PEI) for hyperthermia-enhanced siRNA delivery.538 Upon 808 nm laser irradiation, the hyperthermia-induced elevated intracellular delivery of NGO−PEG13602


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Figure 43. (a) Scheme of Ce6-loaded plasmonic GVs for synergistic PTT/PDT. (b) Temperature increase curves of MDA-MB-435 tumors upon 671 nm laser irradiation. (c) Fluorescence intensity changes at the characteristic peaks of SOSG and Ce6 (528 and 662 nm) as a function of 671 nm laser irradiation time. (d) MDA-MB-435 tumor growth curves of mice subjected to various treatments. Reproduced with permission from ref 559. Copyright 2013 American Chemical Society.

loaded nanocarriers, the intracellular PS concentration can be increased by mild PTT effect to improve the intracellular ROS concentration for enhanced PDT efficacy.287,548−552 Besides, the mild hyperthermia accelerates the blood flow to increase the vascular saturated O2 concentration, which is also conducive to elevate the 1O2 yield in the oxygen-dependent type II PDT. Therefore, PDT should be implemented after PTT. The hyperthermia-enhanced intracellular ROS production leads to synergistic PDT/PTT via the integration of PTCAs and PSs within one nanostructure.288,553−557 For instance, the photothermal effect of GO nanosheets upon 808 nm laser irradiation was found to promote the intracellular delivery of Ce6 or methylene blue (MB), thus elevating the intracellular ROS generation amount upon 660 nm laser irradiation for improving the PDT effect.93,558 However, it is inconvenient to activate the PTCA and PS for PTT and PDT using different wavelengths of lasers, which also adds to the equipment/time cost and undermines their synergistic interactions. The simultaneous realization of PDT and PTT via the coactivation of PTCA and PS upon a single laser irradiation would be able to avoid the time interval between PDT and PTT and achieve optimal synergistic PTT/PDT efficacy. Ce6-loaded gold vesicles (GVs, composed of assembled gold NPs) for synergistic PTT/PDT using a single 671 nm laser irradiation were realized in this manner (Figure 43a).559 The enhanced fluorescence intensity of SOSG at 528 nm with increasing time of 671 nm laser irradiation confirmed the 1O2 generation from GVCe6 (Figure 43c), while GV-Ce6 produced a stronger PTT effect than GV alone, as shown by the higher tumor temperature caused by GV-Ce6 over GV upon 671 nm laser irradiation in Figure 43b, thanks to the partial absorbance of loaded Ce6 at 671 nm. After direct injection into tumor, GV-Ce6 plus 671 nm laser irradiation (GV-Ce6/Laser(+)) gave rise to simultaneous yet

tumors and promote the infiltration of effective T cells. Therefore, the combination of PTCAs and anti-CTLA-4 antibody may result in synergistic PTT/immunotherapy not only for eradicating primary tumors but also for potentiating the immunological effects to suppress cancer metastasis. Liu and coworkers applied PEGylated single-walled carbon nanotubes (SWNTs) for photothermal ablation of primary tumors.546 As well, PTT-induced strong immunological responses in combination with anti-CTLA-4 antibody successfully reduced the lung metastasis and prolonged mice survival. Moreover, the synergistic PTT/immunotherapy may give rise to adaptive immunological responses for killing the remaining tumor cells in the body, which demonstrates superior advantages in overcoming tumor metastasis by suppressing cancer metastasis at distant sites. In a subsequent study, PLGA−PEG-ICG-R837 NPs coencapsulating ICG (a photothermal agent) and imiquimod (R837, a Toll-like-receptor-7 agonist; Figure 42a) were constructed for prolonged blood circulation time and tumor specific accumulation.547 Upon NIR laser irradiation, the photothermal PLGA−PEG-ICG-R837 NPs not only directly ablated the primary tumors but also generated strong vaccine-like immune responses that were combined with anti-CTLA-4 antibody to achieve greatly enhanced immunotherapy for combating residual tumor cells, thus yielding an optimized synergistic anticancer strategy (Figure 42b,c). Therefore, the synergistic PTT/immunotherapy may be very useful in treating both primary and distant metastatic tumors, as well as in preventing tumor relapse. 3.4.4. PTT-Enhanced PDT. PDT relies on the direct intracellular generation of ROS to destroy cancer cells, so the effective intracellular PS delivery is the key to achieving high PDT efficacy. As mild hyperthermia is able to increase the membrane permeability to enhance the tumor cell uptake of PS13603


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Figure 44. (a) Schematic of CSNT for synergistic PTT/RT. (b) Polymer gel experiments for assessing the X-ray radiation dose enhancement effect. The change in X-ray radiation dose could induce variation in MRI-T2 signal intensity. (c) Viabilities of HeLa cells after incubation with CSNTs at varied concentrations with or without NIR laser irradiation and RT. (d) Viabilities of HeLa cells after treatment with RT, PTT, and synergistic PTT/RT. The projected additive value is calculated by multiplying the cell viability of the CSNT + RT group by the cell viability of the CSNT + NIR group. Reproduced with permission from ref 572. Copyright 2013 American Chemical Society.

Figure 45. (a) Schematic of the construction of MnSe@Bi2Se3−PEG for synergistic PTT/RT. (b) Immunoperoxidase staining of tumor slices without (left) or with (right) MnSe@Bi2Se3−PEG induced PTT treatment. (c) Relative fluorescence intensities of Ir-PVP in tumors for different groups of mice at different time points after NIR irradiation. (d) Tumor volume change curves of mice subjected to different treatments. Reproduced with permission from ref 573. Copyright 2015 Wiley-VCH.

improved synergistic PTT/PDT effects for considerable tumor elimination, but neither single PDT by Ce6/Laser(+) nor PTT

by GVs/Laser(+) was able to inhibit the tumor growth (Figure 43d), which confirmed the large synergistic therapeutic output 13604


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Figure 46. Schematic of the mechanisms behind MHT or HIFU-enhanced chemotherapy.

Figure 47. (a) Schematic of DOX-encapsulated supramolecular magnetic NPs (DOX⊂SMNPs) for on-demand DOX release upon the remote application of an AMF. (b) AMF-responsive DOX release profiles in a single pulse (red line; 2 min of pulse duration) or in multiple pulses (black line; 2 min of pulse duration with 8 min of nonpulsed intermittence). (c) Fluorescence microscopy images of DLD-1 colon cancer cells treated with DOX⊂SMNPs with and without exposure to a 10 min continuous AMF. (d) Viabilities of DLD-1 cells treated with and without DOX⊂SMNPs before and after exposure to AMF for 10 min. (e) DLD-1 xenografted tumor growth curves after different treatments. Reproduced with permission from ref 580. Copyright 2013 Wiley-VCH.

their synergistic interactions. In addition, hyperthermia can effectively suppress the nonlethal damage repair of X-ray radiation, which gives rise to remarkable synergistic PTT/RT effects via the enhancement of PTT on RT.90,262,567−571 Shi et al. designed a multifunctional core/satellite nanotheranostic (denoted as CSNT) for synergistic PTT/RT by decorating ultrasmall CuS NPs on silica-coated UCNPs (Figure 44a).572 CSNT absorbs NIR light energy to generate heat for PTT and amplifies the localized radiation dosage for enhanced RT due to the presence of high Z elements (Yb and Gd), as shown by the much darker gray signal of the gel (Figure 44b) and lower cell viability in the CSNT + RT group than in the RT only group (Figure 44c). Upon NIR light/X-ray irradiation, CSNT + NIR +

by the single laser-activated PTT/PDT. For this reason, similar setups have been explored for the integrated use of PTCAs and PSs with similar absorbance wavelength regions, which can achieve much enhanced synchronous PTT/PDT upon a single laser irradiation.560−564 3.4.5. PTT-Enhanced RT. It is well-known that the oxygendeficient tumor microenvironment severely decreases the cancer cells’ sensitivity to X-ray irradiation, which makes RT ineffective in treating hypoxic solid tumors. Hyperthermia arising from PTT has been observed to be able to speed up the intratumoral blood flow for improved tumor oxygenation,565 which counteracts the hypoxia-induced radio-resistance for enhanced RT efficacy.566 Therefore, RT should be implemented after PTT to establish 13605


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Figure 48. (a) Schematic of HMSN-LM and its applications in HIFU-triggered drug release. (b) Release profiles of CPT-11 from HMSN-LM-CPT-11 upon two different parameters of HIFU irradiation; Black lines showed G1 (group 1 of HIFU radiation) was treated with continuous HIFU radiation for 3 min without interruption, while red lines showed G2 (group 2 of HIFU radiation) was treated by pulse radiation with a radiation duration of 1 min followed by an interval of 1 min, with three applications of radiation per cycle, so as to guarantee the same HIFU mechanical effect with G1 during testing. Reproduced with permission from ref 37. Copyright 2014 Elsevier. (c) Schematic of HMPBs-DOX/PFH for synergistic HIFU/chemotherapy. (d) Fluorescence microscope images of DOX signal in bovine liver ex vivo before and after HIFU exposure. (e) Necrotic volumes of ablated bovine livers subjected to different treatments. (f) Tumor volume change curves of VX2 tumor bearing rabbits subjected to different treatments. Reproduced with permission from ref 578. Copyright 2016 Ivyspring International Publisher.

3.5. MHT/HIFU-Enhanced Chemotherapy

RT substantially decreased the cell viability to 29.6%, lower than 43.4% of the projected additive value of combined PTT and RT (Figure 44d), which confirmed the strong synergistic interactions between PTT and RT. Liu et al. further elucidated the mechanism of hyperthermiaimproved tumor oxygenation.573 They designed core/shell structured MnSe@Bi2Se3 with PEG modification for synergistic NIR-activated PTT and X-ray-induced RT (Figure 45a). The corresponding imaging result (Figure 45b) showed that the hypoxic zone within the MnSe@Bi2Se3−PEG + NIR treated tumor was remarkably decreased in comparison to that treated by MnSe@Bi2Se3−PEG without NIR irradiation, suggesting that the PTT effect was indeed able to greatly alleviate the degree of hypoxia for improved tumor oxygenation. Moreover, a hypoxiaspecific fluorescence probe, poly(N-vinylpyrrolidone)-conjugated iridium(III) complex (Ir-PVP), was used to probe the tumor’s oxygen content. For the tumor treated by MnSe@ Bi2Se3−PEG + NIR, the Ir-PVP fluorescence intensity was decreased and then quickly increased after NIR laser irradiation (Figure 45c), further confirming the PTT-assisted tumor oxygenation. As the PTT-induced hypoxia alleviation greatly decreased the tumor’s radio-resistance and enhanced the RT efficacy, the synergistic PTT/RT by MnSe@Bi2Se3−PEG + NIR + RT resulted in remarkable tumor regression (Figure 45d), which was unattainable by single PTT or RT alone.

MHT and HIFU are the other two thermal treatment paradigms that involve the conversion of AMF and high-intensity US waves into heat to cause cancer cell death. Similar to PTT, MHT and HIFU can also increase the temperature to accelerate the intracellular drug delivery and release from nanocarriers for enhanced chemotherapy efficacy, leading to synergistic MHT/ chemotherapy574−577 and HIFU/chemotherapy,37,89,578,579 respectively (Figure 46). Compared to MHT/HIFU-accelerated drug release, the precise control of drug delivery and release achieved by regulating the AMF frequency and US intensity is highly desirable for realizing on-demand synergistic MHT/ chemotherapy and HIFU/chemotherapy, respectively, which is helpful to achieve optimized treatment efficacy with minimal side effects. By encapsulating drugs in a magnetic nanocarrier, the MHTenhanced chemotherapy can be achieved upon exposure to AMF. Furthermore, both the heat generation and drug release can be controlled for on-demand synergistic MHT/chemotherapy by facilely regulating the AMF frequency. Tseng et al. designed DOX-encapsulated supramolecular magnetic NPs (DOX⊂SMNPs) for AMF-controlled DOX release and ondemand synergistic MHT/chemotherapy (Figure 47a).580 Figure 47b shows that the first AMF pulse caused about 50% DOX release while the subsequent AMF pulse triggered the stepwise DOX release percentage up to 100%. Moreover, the DOX fluorescence signal and nucleus fragmentation were 13606


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Figure 49. Schematic of the mechanisms behind MHT or HIFU-enhanced GT/immunotherapy/PDT/RT.

from HMPBs (Figure 48d) through thermal/mechanical cavitation effects for increased DOX cytotoxicity, thus leading to synergistic HIFU/chemotherapy. Both the ex vivo and in vivo experimental results showed that HMPBs-DOX/PFH + HIFU resulted in much larger necrotic volumes of ablated bovine livers (Figure 48e) and higher VX2 tumor growth suppression ratios (Figure 48f) than HMPBs-DOX/PFH or HMPBs-PFH + HIFU, indicating strong synergistic HIFU/chemotherapeutic effects over the corresponding monotherapy. To further maximize the synergistic HIFU/chemotherapy efficacy while minimizing the adverse heat damage and systemic toxicity, it is necessary to design multimodal imaging guided HIFU-controlled drug release systems, which are expected to achieve HIFU intensitydependent drug release as well as on-demand synergistic therapy.

increased in the DLD-1 colon cancer cells treated with DOX⊂SMNPs and AMF exposure (Figure 47c), suggesting AMF-accelerated intracellular DOX delivery/release for effective cell killing (Figure 47d). After a single intravenous injection of DOX⊂SMNPs and a single AMF exposure, the tumor growth was inhibited for only 1 week. However, the double injection of DOX⊂SMNPs and twice AMF exposure resulted in effective tumor growth suppression for at least 2 weeks (Figure 47e), which demonstrated the unique role of on-demand synergistic MHT/chemotherapy in the control of tumor growth. Thanks to the high body permeability of AMF, the synergistic MHT/ chemotherapy will be more effective in treating deep-seated orthotopic tumors than the above synergistic PTT/chemotherapy. In some cases, the mechanical cavitation effect during HIFU exposure can break the noncovalent π−π stacking and weak hydrophobic−hydrophobic interactions, which has been successfully applied to trigger DOX release from hollow mesoporous organosilica nanoparticles (HMONs)581 or hollow mesoporous carbon nanocapsules (HMCNs).582 Generally, the hyperthermia arising from HIFU-induced temperature rise can further speed up the drug release and enhance the tumor uptake for enhanced chemotherapy. Interestingly, the HIFU intensity-dependent drug release also contributes to on-demand synergistic HIFU/ chemotherapy. For example, when L-menthol (LM, triphase transition medium) and CPT-11 (chemotherapeutic) were coencapsulated in hollow mesoporous silica nanoparticles (HMSNs), the HIFU-triggered temperature rise caused the solid−liquid phase transition of LM to accelerate CPT-11 release (Figure 48a), also showing the HIFU-mediated temperatureresponsive CPT-11 release (Figure 48b).37 In order to evaluate the anticancer efficacy of synergistic HIFU/chemotherapy in vivo, Zheng et al. synthesized hollow mesoporous Prussian blue (HMPB) for coencapsulation of DOX and PFH into its internal cavity (denoted as HMPBs-DOX/PFH, Figure 48c).578 The HIFU stimulus not only caused the liquid−gas phase transformation of PFH to generate numerous bubbles for enhancing the HIFU therapy efficacy, but also accelerated DOX release

3.6. Other Potential Forms of Bimodal Synergistic Therapy

Apart from the various types of bimodal synergistic therapy that have been reported and studied in the literature, there are still several examples that remain to be explored. All of the major cellkilling mechanisms for PTT, MHT, and HIFU are working through hyperthermia, which is also a main contributor to the enhancement of other types of monotherapy. Similar to PTTbased bimodal synergistic therapy, MHT and HIFU can also cooperatively enhance the treatment efficacy of GT, immunotherapy, PDT, and RT in addition to chemotherapy, as shown by the corresponding synergistic mechanism in Figure 49. With the help of nanotechnology in designing multifunctional magnetic nanocarriers or HIFU-responsive nanocarriers to load drug, siRNA, immunologic adjuvant, PS, and radiosensitizer, various kinds of MHT or HIFU-based bimodal synergistic therapies can be realized for effective treatment of deep-seated tumors by taking advantage of the high body permeability of AMF and HIFU stimuli, thus surmounting the tissue penetration limitation of PTT-based synergistic therapy. 3.7. Featured Applications of Bimodal Synergistic Therapy

Until now, tumor MDR,583−588 hypoxia,589−594 and metastasis595−600 have been the three major obstacles in the achievement of complete cancer remission. With consideration 13607


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Table 5. Summary of the Featured Applications of Bimodal Synergistic Therapy in Overcoming Tumor MDR/Hypoxia/Metastasis applications overcoming tumor MDR

types of bimodal synergistic therapy chemotherapy/RT GT/chemotherapy

overcoming tumor hypoxia

PDT/ chemotherapy PTT/ chemotherapy chemotherapy/RT PDT/ chemotherapy PDT/RT

overcoming tumor metastasis

chemotherapy/ immunotherapy PTT/GT PDT/ immunotherapy PTT/ chemotherapy PTT/ immunotherapy

working mechanisms

refs

high energy X-ray radiation decreases the P-gp expression for promoting the radiosensitizing drug delivery into MDR cells P-gp siRNA specifically knockdowns and disrupts the P-gp function for enhancing the drug transport into MDR cells ROS generated in PDT can destroy the P-gp protein for promoting the drug delivery into MDR cells hyperthermia can enhance the MDR cell uptake of drug-loaded nanocarriers and also increase the sensitivity of MDR cells toward drugs radiosensitizing bioreductive drugs combined with X-ray for hypoxia-specific synergistic therapy, or radiosensitizing drugs combined with X-ray and in situ tumor oxygenation for oxygen-elevated synergistic therapy drugs combined with light-triggered ROS generation and in situ tumor oxygenation for oxygen-elevated synergistic therapy, or PDT-induced hypoxia aggravation for increasing the cytotoxicity of bioreductive drugs light-triggered ROS generation combined with X-ray and in situ tumor oxygenation for oxygen-elevated synergistic therapy, or X-ray-excited synchronous PDT/RT without oxygen dependence chemotherapeutics selectively trigger strong immune responses to prevent the metastatic cancer cells from infiltrating the liver and lung twist siRNA downregulates the expression of metastasis-driving proteins to inhibit distant tumor metastasis in combination with hyperthermia light-triggered ROS generation in combination with checkpoint blockade immunotherapy can produce systemic antitumor immunity to overcome distant tumor metastasis chemotherapy serves as a systemic treatment paradigm to kill distant metastatic tumor cells in combination with hyperthermia hyperthermia can generate vaccine-like functions in situ to trigger strong systemic immunological responses, which can significantly suppress cancer metastasis in combination with anti-CTLA-4 antibody

329 426, 427 458, 466 530 318, 411 475, 479 504, 505 386 457 494 532 547

Figure 50. (a) Scheme of modification of circulating leukocytes with ES/TRAIL unilamellar liposomes. Reproduced with permission from ref 602. Copyright 2014 National Academy of Sciences. (b) Scheme of tethering biodegradable polymeric particles to the tumor cell surface through NHS-PEGbiotin linkers. Reproduced with permission from ref 604. Copyright 2017 Nature Publishing Group. (c) Scheme of the design and synthesis of carfilzomib-loaded neutrophil-mimicking NPs (NM-NP-CFZ). (d) Scheme of NM-NP-CFZ for selectively targeting and depleting CTCs. Reproduced with permission from ref 605. Copyright 2017 American Chemical Society.

MDR and hypoxic tumors and simultaneously prevent cancer cell metastasis. The success of chemotherapy for MDR tumors hinges upon the delivery of sufficient drugs into the MDR cell cytoplasm or nucleus through weakening of drug efflux pump activities of P-gp. It has been reported that P-gp siRNA, ROS, hyperthermia, or Xray radiation can effectively suppress P-gp protein expression for promoting intracellular drug delivery. Therefore, the combination of chemotherapy with GT, PDT, PTT, or RT can establish a synergistic platform for killing MDR tumor cells with a much lower requisite drug dose, which may realize the dual goals of

of the intrinsic limits of monotherapy, multimodal synergistic therapy may provide an advanced strategy for the effective treatment or even successful elimination of refractory (MDR/ hypoxic/metastatic) tumors by taking advantage of the cooperative enhancement interactions among these individual treatments. Table 5 presents a summary of the featured applications of bimodal synergistic therapy in overcoming tumor MDR/hypoxia/metastasis, as well as the corresponding working mechanisms, which shed light on rational combinations for the design of multifunctional nanomaterials to eradicate 13608


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Figure 51. Schematic of the mechanisms behind the five representative types of trimodal synergistic therapy: (a) chemotherapy/PDT/PTT, (b) chemotherapy/GT/PTT, (c) chemotherapy/PDT/RT, (d) chemotherapy/immunotherapy/PDT, and (e) GT/immunotherapy/PDT.

substantially to deep-seated MDR cancer therapy without drug overdose. Through the assistance of tumor oxygenation, the vascular saturated O2 concentration within the hypoxic tumor can be greatly increased to recover and enhance the treatment efficacy of chemotherapy, PDT, and RT. Moreover, hypoxia-specific bioreductive chemotherapy and hypoxia-independent type I PDT also remain very active in killing hypoxic solid tumor cells. Therefore, the hypoxic tumors can be effectively treated and

enhanced anti-MDR efficacy and reduced systemic toxicity. Moreover, the active/passive targeted delivery of nanocarriers is also bound up with the consideration of drug accumulation within MDR tumors for advanced chemotherapy. Owing to the precise positioning, deep tissue penetration, and easy spatial/ temporal regulation of X-ray radiation, the development of ondemand synergistic chemotherapy/RT, based on the X-ray dosecontrolled release of radiosensitizing drugs, may contribute 13609


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Figure 52. (a) Schematic of DOX-loaded BP nanosheets for synergistic chemotherapy/PDT/PTT. (b) Photothermal effect of BP and BP-DOX in water upon 808 nm laser irradiation. (c) Evaluation of 1O2 generation from BP and BP-DOX under 660 nm laser irradiation by using 1,3diphenylisobenzofuran (DPBF) as a probe. (d) Release profiles of DOX from BP-DOX at pH 5.0 and 7.4, with or without 808 nm laser irradiation. (e) Flow cytometry analysis of DOX fluorescence in 4T1 cells after incubation with BP-DOX, with or without 808 nm laser irradiation. (f) MTT assay for viabilities of 4T1 cells subjected to different treatments. Reproduced with permission from ref 612. Copyright 2017 Wiley-VCH.

from human blood samples as well as from mice. Owing to the special potency of TRAIL for inducing apoptosis to CTCs within the bloodstream rather than normal cells in combination with the strong binding ability of ES to the carbohydrate ligands on many types of CTCs, the ES/TRAIL codelivered circulating leukocytes could also prevent the spontaneous formation of metastatic prostate tumors in an orthotopic xenograft model or other types of cancer spreading through the bloodstream.603 Later, in order to overcome TRAIL resistance, Langer et al. developed polymeric mechanical amplifiers (fabricated by tethering biodegradable polymeric particles to the tumor cell surface through NHS-PEG-biotin linkers, as shown in Figure 50b)604 to enhance TRAIL-mediated tumor cell apoptosis in the presence of fluid shear stress by about 50% compared with that under static conditions, which resulted in considerable reduction of CTCs and distant tumor cell metastases with very few toxic effects on normal cells. Inspired by the targeting property of inflammatory neutrophils toward the CTC and premetastatic niche, Chen et al. further designed neutrophil-camouflaged NPs (NM-NPs) by coating a neutrophil-derived membrane on the surface of PLGA NPs (Figure 50c).605 By the loading of carfilzomib (CFZ, a second-generation proteasome inhibitor) into NM-NPs, the resulting NM-NP-CFZ was able to selectively target and deplete CTCs in the blood, thus preventing early cancer metastasis as well as suppressing the already-formed metastases (Figure 50d). More importantly, this biomimetic technology will be helpful to realize “personalized therapy” by using the patients’ own neutrophil membrane to camouflage other types of DDSs with minimum immunogenicity, which may hopefully be extended to clinical translation.

eliminated by the synergistic activities among chemotherapy, PDT, and RT, together with tumor oxygenation. As heat is able to kill all kinds of cancer cells without oxygen dependence, the synergistic interactions of PTT and other treatments can also destroy hypoxic tumors. However, in consideration of the deep tissue location of hypoxic tumors, the development of synergistic therapy based on highly penetrating MHT, HIFU, and RT will demonstrate distinctive advantages in overcoming deep tumor hypoxia, which may meet the requirements of future clinical trials. Complete remission of cancer is difficult to achieve mainly due to the metastasis of cancer cells throughout the body. In order to effectively kill metastatic cancer cells to overcome tumor metastasis and meanwhile eliminate primary tumors, the local monotherapy (PDT and PTT) and systemic monotherapy (chemotherapy, GT, and immunotherapy) must be used in combination to produce remarkable synergistic therapeutic effects. As PTT or PDT is able to trigger strong immunological responses in killing distant metastatic cancer cells, future research should be focused on the development of trimodal synergistic PTT/PDT/immunotherapy, which is highly desirable for the complete removal of local tumors, efficient suppression of tumor metastasis, as well as substantial extension of survival. Arising from the intravasation of cancer cells from the primary tumor into the peripheral circulation, circulating tumor cells (CTCs) have been thought of as the root of distant cancer metastasis,601 which must be addressed to suppress the dissemination and colonization throughout the body. Toward this end, a series of novel nanotechnology/cell-based approaches using immune cytokines have been developed to directly target and kill CTCs in the bloodstream, which holds great promise in preventing both the metastasis of cancer cells and the formation of distant tumors. For example, King et al. functionalized the surface of circulating leukocytes with the tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) and Eselectin (ES) adhesion receptor under shear flow through ES/ TRAIL unilamellar liposomes (Figure 50a),602 which created an effective form of “unnatural killer cells” to remove CTCs in vitro

4. NANOTECHNOLOGY FOR TRIMODAL SYNERGISTIC THERAPY Although the above diverse types of bimodal synergistic therapy exhibit much higher anticancer efficacy than monotherapy, the treatment efficacy can be further enhanced by trimodal synergistic therapy built on the cooperative enhancement interactions among three treatments and through the integration 13610


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Figure 53. (a) Schematic of the construction of NP-DTS-PDA for NIR laser-triggered NP collapse for release of drug and siRNA. (b) Release profile of DOX and paclitaxel (TAX) from NP-DTS-PDA modified with different amounts of PDA. (c) Cell viability after different treatments for 48 h. Reproduced with permission from ref 614. Copyright 2017 Elsevier. (d) Schematic of PHCNs−PEI-PEG for chemotherapy and GT-enhanced PTT. (e) Respective and coloading capacity of DOX and BAG3 siRNA in PHCNs−PEI-PEG. (f) Viabilities of A549 cells under different treatment conditions: (1) cell culture medium, (2) cell culture medium + NIR, (3) DOX, (4) PHCNs−PEI-PEG@DOX, (5) PHCNs−PEI-PEG + NIR, (6) PHCNs−PEIPEG@BAG3-siRNA + NIR, (7) PHCNs−PEI-PEG@DOX + NIR, and (8) PHCNs−PEI-PEG@DOX@BAG3-siRNA + NIR. Reproduced with permission from ref 615. Copyright 2017 Wiley-VCH.

realization of chemotherapy, PDT, and PTT, respectively, which yielded much improved anticancer effects in vitro and in vivo.255 However, the structure was rather complicated and also encountered potential drug/PS leakage. If one compound could simultaneously act as a PS, PTCA, and nanocarrier, the final nanostructure would be much easier to synthesize.608−610 A representative PS/PTCA dualistic compound is BP, which can generate both heat and ROS upon appropriate light irradiation.266,611 Moreover, the large surface area makes BP nanosheets an excellent nanocarrier with a high drug loading capacity. Guo et al. designed DOX-loaded BP nanosheets for synergistic chemotherapy/PDT/PTT (Figure 52a).612 BP was able to increase the temperature (Figure 52b) and produce 1O2 (Figure 52c) for PTT and PDT upon 808 and 660 nm laser irradiation, respectively. The extremely high DOX loading capacity (950% in weight) did not weaken the heat and 1O2 generation ability of BP. In turn, the heat could enhance the cell uptake of BP-DOX (Figure 52e) and accelerate the DOX release from BP (Figure 52d) for increased cytotoxicity. Accordingly, BP-DOX plus 808 and 660 nm laser irradiation produced more drastic synergistic PTT/PDT/chemotherapeutic effects than any monotherapy or bimodal therapy (Figure 52f), thus displaying the satisfactory in vivo anticancer efficacy of trimodal synergistic therapy for complete tumor eradication.

of three kinds of therapeutic agents within a single nanostructure. Besides, another advantage of trimodal synergistic therapy is the realization of optimal treatment efficacy under much lower doses of therapeutic agent administration, which is expected to further minimize the side effects. Herein, five representative types of trimodal synergistic therapies (Figure 51) are listed and discussed in this section. Moreover, the corresponding synergistic mechanisms are also clarified by representative studies, which shed new light into the design of multifunctional nanomaterials for trimodal synergistic therapy. 4.1. Chemotherapy/PDT/PTT

The integration of drug, PS, and PTCA within a single nanostructure is able to realize the combination of chemotherapy, PDT, and PTT.606,607 Interestingly, the heat produced by light-activated PTCA can enhance the tumor cell uptake of nanocarriers and accelerate the release of drug and PS into the cytoplasm, which substantially increases the probabilities of drug/ROS-induced DNA damage for enhanced chemotherapy and PDT efficacy. Besides, the generated ROS in PDT can also promote the intracellular drug delivery by avoiding endosomal uptake. Therefore, PTT-enhanced chemotherapy/PDT together with PDT-enhanced chemotherapy may result in synergistic trimodal PTT/PDT/chemotherapeutic effects, much stronger than their bimodal combinations. For instance, Lin et al. developed yolk-structured mesoporous GdOF:Ln@SiO2 microcapsules to load DOX, ZnPc, and carbon dots for simultaneous 13611


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Figure 54. (a) Design of a smart hydrogel-nanoparticle patch for local gene/drug delivery combined with PTT, before and after surgical removal of the tumor in an in vivo mouse model of CRC. (b) Experiment design for in vivo synergistic trimodal chemotherapy/GT/PTT. (c) Tumor burden of mice treated with GT (siRNA-gold nanospheres), chemotherapy (drug-gold nanorods), PTT (gold nanorods), or bimodal (chemo + gene, gene + photo, chemo + photo) and trimodal therapy (gene, chemo, and phototherapy combination), as measured by luciferase activity. (d) Venn diagram from various gene expression heat maps of mice subjected to synergistic trimodal therapy at different time points post-treatment. (e) Pathway analysis of significantly altered genes of mice subjected to synergistic trimodal therapy at different time points post-treatment. Reproduced with permission from ref 616. Copyright 2016 Nature Publishing Group.

4.2. Chemotherapy/GT/PTT

triggered release of BAG3-siRNA and DOX together with BAG3siRNA-inhibited HSP expression contributed to the PTTenhanced chemotherapy/GT in combination with GT-enhanced PTT, which brought about more significant synergistic GT/ PTT/chemotherapeutic effects for reducing the A549 cell viability to only 5% by PHCNs−PEI-PEG@DOX@BAG3siRNA + NIR (Figure 53f). This study might provide some insights on the future design of drug/siRNA coloaded photothermal nanocarriers for maximizing the synergistic chemotherapy/GT/PTT efficacy. Recently, Artzi et al. developed an implantable hydrogel patch composed of drug-gold nanorods and siRNA-gold nanospheres for localized trimodal chemotherapy/GT/PTT,616 which succeeded in promoting tumor ablation, minimizing side effects, and preventing tumor recurrence in a colon cancer model (Figure 54a−c). The unique feature of this study was the systematic implementation of the KEGG (Kyoto Encyclopedia of Genes and Genomes) and GO (Gene Ontology) pathway analysis to identify the molecular pathways and the contributions of each monotherapy to finalize a therapeutic platform for tumor elimination (Figure 54d,e). Interestingly, the altered genes for the mice treated with synergistic trimodal chemotherapy/GT/ PTT changed over time and increased in number, which might provide instructive biomarkers to guide future nanomaterial design as well as bridge the gap between theoretical genetic analysis and observations in preclinical trials. This study also sparked new inspiration for discovering new therapeutic targets,

By the coencapsulation of drug and siRNA into a photothermal nanocarrier, the combination of chemotherapy, GT, and PTT can be realized within a single nanostructure. Moreover, the hyperthermia arising from PTT enhances the tumor cell uptake of drug and siRNA for enhanced chemotherapy and GT efficacy, which results in a remarkable trimodal synergistic therapeutic effect.613 For this reason, Nie et al. constructed a NIR-absorbing polymer-dopamine nanocomposite (NP-DTS-PDA) for codelivery of two drugs (DOX and TAX) and siRNA for synergistic chemotherapy/GT/PTT (Figure 53a).614 The hyperthermia arising from NIR-irradiated PDA caused the dissociation of NPDTS-PDA for burst release of DOX/TAX/siRNA (Figure 53b), which demonstrated the enhancement of PTT on chemotherapy and GT. The combination of NP-DTS-PDA and NIR laser irradiation gave rise to synergistic trimodal GT/PTT/chemotherapeutic effects for reducing cell viability to a greater extent than other single or bimodal treatments (Figure 53c). Taking into consideration that GT could in turn enhance PTT efficacy by using some specific kinds of siRNA (such as BAG3 siRNA) to suppress the expression of heat shock proteins on cancer cells, the synergistic chemotherapy/GT/PTT can be further enhanced by the coloading of drug and BAG3 siRNA into a photothermal nanocarrier, as reported by the Qiao group.615 Porous hollow carbon nanospheres modified with PEG and PEI (PHCNs−PEI-PEG) were fabricated with a high coloading capacity of DOX and BAG3-siRNA (Figure 53d,e). The NIR13612


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Figure 55. (a) Schematic of HP/Dtxl coloaded UCMSNs (UCMSNs-HP-Dtxl) for synergetic trimodal chemotherapy/PDT/RT. (b) TEM image of UCMSNs. (c) Viabilities of HeLa cells subjected to different treatments. (d) In vitro study on the synergetic trimodal therapeutic interactions among NIR, RT, and UCMSNs-HP-Dtxl. The corresponding projected additive cell viability of the corresponding synergetic therapy is calculated by multiplying the cell viability of one treatment by the cell viability of the other. (e) 4T1 tumor growth curves over a period of half a month after various treatments. (f) Digital photos of mice at 120 days after treatment with UCMSNs-HP-Dtxl + RT + NIR. Reproduced with permission from ref 86. Copyright 2014 Elsevier.

coencapsulation of drug and PS into a scintillator-based nanocarrier for the combination of X-ray-excited synchronous PDT/RT and chemotherapy, which will further enhance trimodal synergistic efficacy.

optimizing clinical procedures, and improving trimodal synergistic therapeutic outcomes. 4.3. Chemotherapy/PDT/RT

By coloading drug and PS into a single nanocarrier, chemotherapy and light-triggered PDT can be simultaneously achieved in combination with X-ray-excited RT. Furthermore, if both the drug and PS increase the radiosensitivity of cancer cells, the RT effects can be substantially improved by chemotherapy and PDT, with the addition of PDT-enhanced chemotherapy via ROSpromoted intracellular drug delivery, which leads to trimodal synergistic chemotherapy/PDT/RT. According to this mechanism, a rattle-structured multifunctional Gd-UCNPs core/ mesoporous silica shell nanotheranostic system (UCMSNs) was designed for covalently conjugating hematoporphyrin (HP, a PS) into the mesoporous channel and encapsulating Dtxl (drug) into the cavity, respectively (Figure 55a,b).86 As both HP and Dtxl could serve as radiosensitizers,85,617 the trimodal synergistic chemotherapy/PDT/RT was achieved upon NIR light and X-ray irradiation, which reduced cancer cell viability to a greater extent than monotherapy or bimodal therapy (Figure 55c). Importantly, the resultant trimodal therapeutic effect was much stronger than the theoretically projected sum of the three treatments (Figure 55d) in vitro, which undoubtedly demonstrated their cooperative enhancement interactions. As well, the trimodal chemotherapy/PDT/RT (by UCMSNs-HP-Dtxl + NIR + RT) could effectively eradicate tumors in 2 days (Figure 55e) and even prevent tumor recurrence for up to 120 days (Figure 55f), which was unachievable by treatment with chemotherapy (by UCMSNs-HP-Dtxl) or bimodal chemotherapy/RT (by UCMSNs-HP-Dtxl + RT). Future optimization should be concentrated on nanomaterial design by the

4.4. Chemotherapy/Immunotherapy/PDT

As discussed above, PDT not only causes cancer cell death via apoptosis/necrosis but also stimulates the host immune system to present tumor-derived antigenic peptides to T cells, thus evoking the systemic antitumor immunity for enhanced immunotherapy.489,618,619 Some anticancer drugs (such as oxaliplatin) not only kill cancer cells to exert a chemotherapeutic effect but also act as a “vaccine” to activate preapoptotic CRT exposure (a distinct marker for ICD) for enhanced immunotherapy.620,621 Therefore, the combination of chemotherapy, PDT, and immunotherapy may produce a trimodal synergistic effect thanks to PDT/chemotherapy-enhanced antitumor immunity in addition to PDT-enhanced chemotherapy. Lin et al. reported the construction of nanoscale coordination polymer (NCP) NPs delivering oxaliplatin and pyrolipid (PS) for chemotherapy and PDT in combination with PD-L1 checkpoint blockade therapy (Figure 56a).622 After intravenous injection, the NCP@pyrolipid showed favorable tumor accumulation (Figure 56b) and produced remarkable PDT/chemotherapeutic effects upon 670 nm LED irradiation, which created an immunogenic tumor microenvironment and triggered systemic antitumor immunity for significantly enhanced PD-L1 checkpoint blockade immunotherapy. Therefore, the synergistic chemotherapy/immunotherapy/PDT via the combination of NCP@pyrolipid and anti-PD-L1 led to remarkable regression of both LED-irradiated primary tumors and nonirradiated distant tumors due to the induction of a strong systemic tumor-specific 13613


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Figure 56. (a) Schematic of chemotherapy and PDT of NCP@pyrolipid for potentiating the PD-L1 blockade to induce systemic antitumor immunity. (b) Biodistribution of NCP@pyrolipid in balb/c mice. (c and d) Primary and distant tumor growth inhibition curves subjected to different treatments. The MC38 model was implanted by subcutaneous injection of cancer cells into both the right and left flanks of mice. The right side tumors were designated as the primary tumors for light irradiation, and the left side tumors were designated as distant tumors and did not receive light irradiation. The arrows represented the times of drug administration (black) and irradiation (red). “+” and “−” referred to with and without irradiation, respectively. (e) Immunofluorescence staining of primary and distant tumors. (f) Densities of CD8+ T cells (number/mm2) in the primary and distant tumors. Reproduced with permission from ref 622. Copyright 2016 Nature Publishing Group.

enhance the PDT-mediated immunotherapy efficacy, thus leading to trimodal synergistic GT/immunotherapy/PDT. To validate the synergistic interactions among these three therapeutic modalities, Li et al. designed an acid-activatable versatile POP micelleplex coloaded with pheophorbide A (PPa, a PS) and siRNA for tumor-specific GT/immunotherapy/PDT by making full use of the acidic tumor microenvironment (Figure 57a).623 The siRNA exhibited specific targeting toward PD-L1 and remarkably suppressed the PD-L1 expression in cancer cells in a dose-dependent manner (Figure 57b). The combination of PDT-induced immunotherapy and siRNA-mediated PD-L1 knockdown resulted in a remarkable synergistic GT/PDT/ immunotherapeutic effect, which achieved complete elimination of B16−F10 tumors as well as efficient inhibition of tumor

T-cell response (Figure 56c−f). While PDT is a localized treatment for only primary tumors, the combination of PDT and chemotherapy/immunotherapy may give rise to synergistic effects for the regression of distant tumors, thus surpassing local administration limitations and providing promising potential clinical values. 4.5. GT/Immunotherapy/PDT

Although PDT can initiate a strong antitumor immune response for enhanced immunotherapy, their synergistic therapeutic effect is severely impaired by the programmed cell death 1 (PD-L1) and programmed cell death receptor 1 (PD-1) (PD-L1-PD-1)induced immunosuppression. Certain types of siRNA can block the PD-1-PD-L1 interaction to intensify PDT-induced immune activity, which marks an important instance where GT can 13614


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Figure 57. (a) Schematic of POP−PD-L1 micelleplex for synergistic GT/immunotherapy/PDT. (b) Western blot assay of PD-L1 knockdown in B16− F10 cells transfected with the POP−PD-L1 micelleplexes at varied siRNA concentrations. (c) B16−F10 tumor growth inhibition curves after different treatments. The B16−F10 tumor-bearing C57BL/6 mice were intravenously injected with the POP micelleplexes and illuminated with a 671 nm laser 2 h postinjection. (d) Evaluation of tumor recurrence prevention after different treatments. 1: PBS, 2: POP/NC, 3: POP/NC + laser, 4: POP/PD-L1, 5: POP/PD-L1 + laser. Reproduced with permission from ref 623. Copyright 2016 American Chemical Society.

tumor site. The benefit from such studies is often superficial as they are unable to be recapitulated to meet the rigorous demands of patient treatment. Therefore, a growing number studies have elected to adopt the systemic administration strategy to better answer clinical challenges, which again pose stringent requirements on the design of multifunctional nanomaterials for multimodal synergistic therapy. As discussed above in section 2.1, an ideal nanocarrier should be a hybrid of organic and inorganic nanoplatforms with high stability and good biocompatibility and be easily biodegradable. Moreover, the overall diameter of nanocarriers should be restricted to below 100 nm to exploit the passive tumor-targeting ability through the EPR effect.99,624 Meanwhile, the nanocarrier should be cleared by the kidney without accumulation of degradation products. Therefore, consideration of inherent factors (e.g., size, charge, hydrophilicity, etc.) for the design of nanocarriers may achieve the optimal balance between the EPR effect for enhanced tumor accumulation and renal clearance for minimized long-term toxicity. The surface modifier and targeting moiety make great contributions to blood circulation and active tumor-targeting of nanocarriers, respectively. Despite the widespread use of multiple polymers (e.g., PEG, PVP, PAA, etc.) to reduce RES clearance, the natural RBC membrane is expected to largely increase the blood circulation lifetime to maintain an influx of nanocarriers toward the tumor. More importantly, “personalized nanocarriers” could be designed to evade the immune system without host rejection and realize personalized therapy by collecting patient RBCs and extracting the RBC membrane to make stealth nanocarriers.625 In addition, the attachment of targeting antibody (e.g., Herceptin)626 or peptide (e.g., RGD)627 could greatly enhance the accumulation of nanocarriers at the corresponding receptor overexpressed tumors through active

recurrence (Figure 57c,d). This study provided a versatile strategy for amplifying the immune responses via blocking an immune checkpoint pathway using siRNA. 4.6. Other Potential Forms of Trimodal Synergistic Therapy

Considering the enhanced treatment efficacy of trimodal synergistic therapy over bimodal synergistic therapy, attention has shifted to the cooperative combination of three interrelated therapeutic modalities based on their cooperative interaction. Table 6 lists the potential, but unreported, types of trimodal synergistic therapy as well as the corresponding synergistic mechanisms. Assisted by nanotechnology in the construction of multifunctional nanomaterials, the diverse kinds of trimodal synergistic therapy listed below can be achieved to provide more alternative advanced strategies for conquering cancer.

5. DESIGN TIPS FOR MULTIFUNCTIONAL NANOMATERIALS FOR MULTIMODAL SYNERGISTIC THERAPY It has been widely accepted that the construction of multifunctional nanomaterials is a prerequisite to the realization of multimodal synergistic therapy. Advanced nanostructures consist of three major components: a nanocarrier as the core substrate, outer surface modifiers and targeting ligands, and diverse kinds of therapeutic agents encapsulated in the nanocarrier (Figure 58). The effective in vivo tumor-targeted delivery of nanocarriers through intravenous injection guarantees the sufficient accumulation of the payload (encapsulated therapeutic agents) within the tumor, which is essential for satisfactory synergistic therapeutic efficacy. However, in many “proof of concept” studies concerning multimodal synergistic therapy, intratumoral injection is frequently employed to artificially enhance accumulation of therapeutic agents at the 13615


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Table 6. List of Unreported Types of Trimodal Synergistic Therapy and the Corresponding Nanomaterial Design and Synergistic Mechanisms

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Table 6. continued

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Table 6. continued

agents to targeted tumors. Moreover, controlled payload release on-site via multiple internal and external stimuli (e.g., pH, light, X-ray, HIFU, etc.) has been a heated topic in the field of nanomedicine,630 which is helpful toward the realization of ondemand cancer therapy and dose regulation. Besides, in order to maximize the therapeutic index, other general principles should also be followed in the design of multifunctional nanomaterials (Figure 59). First of all, each therapeutic agent included in the nanomaterial should be active against the tumor alone, and the coencapsulation of several stand-alone therapeutic agents should produce a remarkable combinatory therapeutic effect. Moreover, the tumor-killing mechanism of each therapeutic agent should complement the other to realize the cooperative enhancement interactions among these individual treatments, which may produce synergistic superadditive effects to achieve superior treatment efficacy. For example, the siRNA-mediated GT can suppress the HSP70 protein expression to increase tumors’ thermal susceptibility, which will significantly improve the effectiveness of heat-related treatments like PTT/MHT/HIFU. In turn, the hyperthermia arising from PTT/MHT/HIFU will enhance the tumor cell uptake of nanomaterials and speed up the release of chemotherapeutics/siRNA/PSs/immunologic adjuvant/radiosensitizers to substantially enhance the efficacy of chemotherapy/ GT/PDT/immunotherapy/RT. It can be envisaged that the

Figure 58. Schematic of the three major components of multifunctional nanostructures for multimodal synergistic therapy.

targeting. Furthermore, targeting nanocarriers are also able to cross the blood-brain barrier628 and deliver therapeutic agents to brain tumors. Physical encapsulation and covalent conjugation are the two major strategies for the encapsulation of the diverse classes of therapeutic agents (e.g., drug, gene, immunologic adjuvant, PS, radiosensitizer, HIFU EA, etc.) into nanocarriers. Owing to the weak adsorption force between drugs and nanocarrier, physical adsorption is usually subjected to a low payload capacity and premature leakage. In comparison, covalent conjugation features high coloading efficiency, high stability, and negligible payload leakage,629 which promises delivery of sufficient therapeutic

Figure 59. General principles included in the design of multifunctional nanomaterials for multimodal synergistic therapy. 13618


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Table 7. List of the Abbreviations and Their Corresponding Full Names full name

abbreviation

arginine-glycine-aspartic acid 9,10-anthracenediyl-bis(methylene)dimalonic acid alternating magnetic field adenosine triphosphate B-cell lymphoma-2 black phosphorus bovine serum albumin computed tomography calreticulin cisplatin chlorin e6 circulating tumor cell carfilzomib drug delivery system dibenzylcyclooctyne doxorubicin docetaxel 1,3-diphenylisobenzofuran enhanced permeability and retention enhancement agents 7-ethyl-10-hydroxycamptothecin E-selectin Förster resonance energy transfer folic acid 5-fluorouracil graphene oxide gemcitabine gene therapy gold vesicles high intensity focused ultrasound hollow mesoporous silica nanoparticles hollow mesoporous Prussian blue high mobility binding box 1 hyaluronic acid hydroxyethyl starch horseradish peroxidase heat shock protein human serum albumin hollow mesoporous organosilica nanoparticles hollow mesoporous carbon nanocapsules hematoporphyrin hypoxia-inducible factor-1 alpha interleukin-2 indocyanine green immunogenic cell death indoleamine 2,3-dioxygenase inhibitor Kyoto Encyclopedia of Genes and Genomes layer-by-layer L-menthol layered double hydroxide magnetic resonance imaging magnetic hyperthermia multidrug resistance mesoporous silica nanoparticles mitomycin C microneedle merocyanine 540 multidrug resistance protein 1 methylene blue near-infrared

RGD ABDA AMF ATP Bcl-2 BP BSA CT CRT CDDP Ce6 CTC CFZ DDS DBCO DOX Dtxl DPBF EPR EAs SN-38 ES FRET FA 5-FU GO GEM GT GVs HIFU HMSNs HMPB HMGB1 HA HES HRP HSP HSA HMONs HMCNs HP HIF-1α IL-2, rhIL-2 ICG ICD IDOi KEGG LbL LM LDH MRI MHT MDR MSNs MMC MN MC540 MRP1 MB NIR

full name

abbreviation

nanoparticles nuclear localization signal n-perfluoropentane N-methylpyrrolidone nanoscale coordination polymer oxaliplatin positron emission tomography photodynamic therapy photothermal therapy polyvinylpyrrolidone photothermal conversion agents polo-like kinase-1 Prussian blue paclitaxel perfluorocarbon perfluorohexane polyethylene glycol polyethylenimine poly-L-glutamate polylactic-co-glycolic acid poly-L-arginine poly(β-amino esters) phthalocyanine poly(sodium 4-styrenesulfonate) poly(diallyldimethylammonium chloride) protoporphyrin IX pheophorbide A programmed cell death protein 1 programmed cell death ligand 1 P-glycoprotein poly(acrylic acid) quantum dot radiotherapy reticuloendothelial system red blood cell reactive oxygen species single-photon emission computed tomography small interfering RNA singlet oxygen scintillating nanoparticles SrAl2O4:Eu2+ singlet oxygen sensor green selenoamino acid superoxide dismutase 1 silicon phthalocyanine dihydroxide single-walled carbon nanotubes tirapazamine two-dimensional two-photon absorption transferrin triple negative breast cancer tetrakis (4-carboxyphenyl) porphyrin tumor necrosis factor ultrasound ultraviolet upconversion nanoparticles visible vascular endothelial growth factor zinc phthalocyanine

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NPs NLS PFP NMP NCP OXA PET PDT PTT PVP PTCAs Plk-1 PB PTX, TAX PFC PFH PEG PEI PLG PLGA PLA PAE Pc PSS PDDAC PpIX PPa PD-1 PD-L1 P-gp PAA QD RT RES RBC ROS SPECT siRNA 1 O2 SCNPs SAO SOSG SeC SOD1 SPCD SWNTs TPZ 2D TPA Tf TNBC TCPP TNF US UV UCNPs Vis VEGF ZnPc


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complementary advantages of each therapeutic modality toward multimodal synergistic therapy will allow for a maximized therapeutic output with a minimized side effect. Finally, the nanomaterials should be easy to synthesize to satisfy the demands of future scale-up production. Taking the above basic rules into consideration, future designs should be focused on small-sized, scalable, long-circulating, and hierarchical targeting multifunctional organic/inorganic hybrid nanomaterials with stimuli-responsive release of multiple active therapeutic agents and complementary interactions among diverse therapeutic modalities, which may achieve the win−win goal of maximized synergistic therapeutic effectiveness and minimized adverse effects.

Figure 60. Schematic of future development directions of multimodal synergistic therapy.

accelerating the wide clinical applications of multimodal synergistic therapy in the future. (1) As many orthotopic tumors (e.g., liver cancer, lung cancer, etc.) are located inside the body rather than on the surface, it is reasonable to apply highly penetrating treatment paradigms (RT, MHT, and HIFU) for deep-seated cancer therapy thanks to the large body-permeability of X-ray radiation, magnetic fields, and US waves. Meanwhile, to overcome tumor metastasis or efficiently kill distant metastatic cancer cells, immunotherapy may be a good choice to “awaken” the immune system to target and remove the remaining cancer cells in the body. Consequently, the synergistic use of RT/MHT/HIFU and immunotherapy, featuring unique advantages in treating both deep-seated primary tumors and distant metastatic tumors, should be preferentially adopted, which will contribute substantially toward a comprehensive approach to treating cancer. (2) The optimal treatment efficacy of multimodal synergistic therapy hinges upon the concurrent use rather than the sequential use of multiple treatments. Only if these therapeutic modalities are integrated in a single nanostructure using a single excitation source can synergism be maximized. The conversion of X-ray radiation into UV− vis light via nanoscintillators for the excitation of synchronous PDT/RT is an excellent example of maximizing synergistic PDT/RT efficacy. As such, the exploration of X-ray-/magnet-/US-based conversion materials for exciting synchronous multimodal therapies is highly desirable for yielding an ideal therapeutic effect for deep-seated tumors. (3) Successful cancer therapy cannot be realized without precise cancer diagnosis, and multimodal imaging guidance provides accurate structural and functional information for tumor location, allowing for subsequent efficient treatment. Therefore, the designed nanomaterials should be nanotheranostics in nature, with both diagnostic and therapeutic functionalities for multimodal imagingguided synergistic therapy. (4) To meet the strict requirements of preclinical experiments and reflect the actual therapeutic effect, future evaluation of multimodal synergistic therapies should use orthotopic tumors implanted inside the body of large animals (such as dogs and monkeys) or more clinically relevant patientderived xenograft (PDX) tumors as models. Moreover, the in vivo observation period should be extended to at least half a year to yield a pertinent assessment report. (5) Finally, the implementation of multimodal synergistic therapy relies heavily on the update and improvement of

6. CONCLUSIONS AND PROSPECTS The recent years have witnessed enormous strides in the construction of multifunctional nanomaterials for the integration of several therapeutic modalities within a single nanoplatform. The combined use of multiple treatments often displays superior advantages over monotherapy in producing an improved therapeutic outcome. Furthermore, by exploiting the cooperative interactions between these treatments, multimodal synergistic therapy has become a paradigm shift in cancer therapy, which combines the advantages and offsets the disadvantages of each monotherapy, resulting in a synergistic therapeutic effect that is stronger than the theoretical combination of these monotherapies. Considering the unprecedented therapeutic enhancements through the use of two or three modes of therapy, this review systematically summarized the recent advances in the development of nanotechnology-mediated bimodal/trimodal synergistic therapy and, more importantly, explored the related in-depth synergistic mechanisms, guiding the future design of multifunctional nanomaterials for realizing various kinds of multimodal synergistic therapies. In this review, we first summarized the characteristics of eight major types of monotherapies (chemotherapy, GT, immunotherapy, PDT, PTT, RT, MHT, and HIFU) and also pointed out the advantages, disadvantages, and enhancement strategies of each monotherapy (Table 4), which laid the foundation for the synergistic interactions among these treatments. Second, a detailed introduction to various kinds of bimodal synergistic therapies via the construction of multifunctional nanostructures was accompanied by the illustration of the in-depth corresponding synergistic mechanisms and presentation of the representative cases. Of note, the featured applications of bimodal synergistic therapy in overcoming tumor MDR/hypoxia/metastasis were discussed in detail, which holds great promise for the efficient treatment of recalcitrant (MDR/hypoxic/metastatic) tumors. Subsequently, five representative types of trimodal synergistic therapies were described to demonstrate the superior antitumor efficacy over any monotherapy or bimodal therapy. Importantly, Table 6 lists the potential, but unreported, types of trimodal synergistic therapies as well as the corresponding nanomaterial design and underlying synergistic mechanisms, which greatly expands the repertoire of multimodal synergistic therapy and marks future research directions for nanomaterial design and biomedical application. Higher expectations are always followed by more stringent requirements. In addition to the design requirement on multifunctional nanomaterials discussed in section 5, there are other unsolved scientific issues and technical challenges that remain to be addressed (Figure 60), aimed at promoting and 13620


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the Basic Research Program of Shenzhen (JCYJ20170412111100742 and JCYJ20160422091238319), and the Intramural Research Program (IRP) of the NIBIB, NIH. The authors thank Dr. Can Xu from NIBIB, NIH for drawing schematic pictures.

instruments. The development of X-ray-AMF or X-ray-US combined instruments is a good strategy to realize the simultaneous use of three or more types of monotherapy, which will further optimize the therapeutic outcome and provide an advanced platform for future clinical applications.

REFERENCES

AUTHOR INFORMATION

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Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Peng Huang: 0000-0003-3651-7813 Xiaoyuan Chen: 0000-0002-9622-0870 Notes

The authors declare no competing financial interest. Biographies Wenpei Fan received his Ph.D. in 2015 from the Shanghai Institute of Ceramics, Chinese Academy of Sciences (SICCAS) under the direction of Prof. Wenbo Bu and Prof. Jianlin Shi. He then worked with Prof. Xiaoyuan (Shawn) Chen at the National Institutes of Health (NIH) as a postdoctoral fellow. His research interest focuses on the design and synthesis of multifunctional nanotheranostics for multimodal imaging guided synergistic therapy. Bryant Yung obtained his B.S. (2009) in Chemistry from the University of Cincinnati. Later on, he received his Ph.D. (2014) in Pharmaceutics from The Ohio State University. His dissertation research under the direction of Robert J. Lee evaluated several novel polymer and lipid based nanoparticles for cancer gene therapy. In 2015, he joined the National Institute of Biomedical Imaging and Bioengineering (NIBIB) as a member of the Laboratory of Molecular Imaging and Nanomedicine (LOMIN). His current research interests include the design of nanoparticles for cancer specific targeting, biomarker detection, and drug/gene delivery. Peng Huang received his Ph.D. in Biomedical Engineering from the Shanghai Jiao Tong University in 2012. Then he joined the Laboratory of Molecular Imaging and Nanomedicine (LOMIN) at the National Institutes of Health (NIH) as a postdoctoral fellow under the supervision of Prof. Xiaoyuan (Shawn) Chen. In 2015, he moved to Shenzhen University as a Distinguished Professor. His research focuses on the design, synthesis, and biomedical applications of molecular imaging contrast agents, stimuli-responsive programmed targeting drug delivery systems, and activatable theranostics. Xiaoyuan (Shawn) Chen received his Ph.D. in Chemistry from the University of Idaho in 1999. He joined the University of Southern California as an Assistant Professor of Radiology in 2002. He then moved to Stanford University in 2004 and was promoted to Associate Professor in 2008. In the summer of 2009, he joined the Intramural Research Program of the NIBIB as a tenured Senior Investigator and Chief of the LOMIN. He has published over 600 papers and numerous books and book chapters. He is the founding editor-in-chief of the journal Theranostics. He is interested in developing molecular imaging tools for early diagnosis of disease, monitoring therapy response, and guiding nanodrug discovery/development.

ACKNOWLEDGMENTS This project is financially supported by the startup fund from the Shenzhen University, the National Science Foundation of China (51602203, 81401465, 51573096, 51703132, and 31771036), 13621


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