Near-Infrared Light-Triggered Polymeric Nanomicelles for Cancer

Review Cite This: ACS Biomater. Sci. Eng. 2018, 4, 1928−1941

Near-Infrared Light-Triggered Polymeric Nanomicelles for Cancer Therapy and Imaging Lei Li,† Xin Pang,† and Gang Liu*

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State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics and Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China ABSTRACT: Early diagnosis and efficient therapy are very important for cancer management. Among the various intelligent delivery systems, near-infrared (NIR) light-triggered polymeric nanomicelles (PNMs) have emerged as a promising approach for imaging and photoactive delivery. This platform can be used for spatially and temporally controlled remote release of therapeutic payload molecules under NIR light irradiation. This review discusses the design and characteristics of PNMs as well as their recent application in imaging, drug delivery, and theranostics in photothermal and photodynamic therapy. The challenges and potential of PNMs in biomedical applications are also highlighted. KEYWORDS: near-infrared light, polymer, nanomicelles, cancer therapy, cancer imaging

1. INTRODUCTION Cancer is a major public health problem and is responsible for ∼8.2 million deaths around the world.1 There have been considerable advances in knowledge about cancer in the past few decades. Conventional therapeutic options to combat cancer include surgery, radiotherapy, chemotherapy, and combinations of them.2,3 Surgery is the most important approach to remove solid tumors but is highly invasive and can hardly eliminate all tumor cells, especially when metastasis has already happened.4 Chemotherapy and radiotherapy also have significant concerns, such as severe toxic side effects, limited therapeutic efficacy, induced drug resistance, and longterm damage to the immune system.5−8 Therefore, big challenges still remain for early diagnosis and highly targeted and controlled cancer treatments. In recent years, nanotechnology has become a promising alternative approach for cancer “theranostics”, which Funkhouser coined in 2002 to explain the integration of concurrent diagnosis and treatment modalities at the same dosage range.9,10 Nanomaterials with high targeting ability and multifunctionality are a significant focus in theranostics. Nanomaterials can reach the site of disease by passive and/or active targeting,11−15 and they play an important role in cancer diagnosis in reporting the location of the disease, its stage, or the response to treatment.16−19 Nanomaterials can also deliver therapeutic agents to a targeted site at necessary concentrations in response to external stimuli or molecular signals. This reduces the risk of toxicity to normal tissues around the lesion and other organs.20−22 In addition, nanomaterials that absorb a specific wavelength of light have also been exploited in drug delivery and molecular imaging for cancer theranositics. Nearinfrared (NIR) light is defined as light with wavelengths of © 2017 American Chemical Society

700−1100 nm, which can be exploited to distinctively avoid autofluorescence in the range of 270−665 nm in vivo. This allows penetration for deep-tissue imaging with higher contrast.23,24 NIR nanomaterials such as gold nanoparticles,25 carbon nanotubes (CNTs),26 graphene oxide (GO),27 and upconversion nanocrystals (UNCs)28 have become efficient tools to visualize, detect, and treat cancer.29,30 Such materials could realize drug release with on-demand control or molecular imaging remotely triggered by exposure to NIR light. Furthermore, nanomaterials doped with organic NIR fluorescent molecules are also emerging as another promising candidate for in vivo imaging and cancer treatment, demonstrating many advantages over pristine molecular NIR fluorescent probes. Nanoparticle formulations could provide multimodal imaging as well as complementary anatomical and physiological information by codoping with imaging agents of other modalities, such as magnetic resonance imaging (MRI)31 or PET/SPECT imaging.32,33 Inert and biocompatible polymers such as polyethylene glycol (PEG) could also be used easily to modify the surfaces of nanoparticles and allow them to evade capture and degradation by the reticuloendothelial system (RES).34,35 Interestingly, nanoparticles could be preferentially taken up by malignant tissues through passive targeting by virtue of the enhanced permeability and retention (EPR) effect.36,37 Special Issue: Biomaterials Science and Engineering in China Received: September 2, 2017 Accepted: October 30, 2017 Published: October 30, 2017 1928

DOI: 10.1021/acsbiomaterials.7b00648 ACS Biomater. Sci. Eng. 2018, 4, 1928−1941

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ACS Biomaterials Science & Engineering

Figure 1. Schematic illustration of multifunctional NIR agents for cancer imaging and phototherapy.

Figure 2. Chemical structures of commonly used polymers as micellar carrier.

Polymeric nanomicelles (PNMs) are a class of 1−200 nm nanoparticles prepared by amphiphilic copolymers. They contain two individual functional sections: an “inner core” and an “outer shell”. The outer shell is usually composed of a

hydrophilic block like PEG, which controls the pharmacokinetic properties in vivo. The inner core is made up of a hydrophobic block, which is responsible for drug entrapment, stability, and drug-release characteristics.38,39 The uniqueness of 1929


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tumor sites.54 The PEGylated phospholipid-based block copolymer family includes PEG-distearoylphos-phatidylethanolamine (PEG-PE). This family can also self-assemble into nanostructured micelles. Their advantages are their simpler and more reproducible preparation, the avoidance of macrophage phagocytosis system (MPS) uptake, longer circulation times, biocompatibility, and almost no toxicity55 Recently, micelle-forming di- and triblock copolymers have been of particular interest as a long-circulating pharmaceutical carrier.56,57 Micelle-forming copolymers are usually synthesized by anionic polymerization, ring-opening polymerization, or polymerization using poly(ethylene oxide)-based initiators.58 These allow for the synthesis of amphiphilic copolymers with different molecular masses and different hydrophobic-lipophilic balance by controlling the lengths of the hydrophobic/ hydrophilic blocks. Different physicochemical and biological characteristics can be realized by varying the molecular size of different blocks and their molar ratio in the copolymer. Larger hydrophobic blocks result in a bigger core size and greater ability to entrap hydrophobic drugs. Increasing the length of the hydrophilic block leads to an increase in the critical micelle concentration (CMC). These nanoparticulate drug delivery systems for solid tumor treatment usually undergo the steps of circulation, accumulation, penetration, internalization, and release to deliver drugs into cancer cells, which is determined by surface properties, stability, targeting groups, shape, and size of nanoparticles. Generally, smaller micelles (e.g., 30 nm) exhibit better tumor penetration and result in high anticancer activity.59 Because of such attractive characteristics, a series of novel PNMs with different chemical structures and biological behaviors were recently developed and increasingly applied to the field of NIR-triggered drug delivery systems. As a typical carrier material for PNMs, the biodegradable diblock copolymer has been developed from poly(ethylene glycol)block-poly(ε-caprolactone) (PEG-b-PCL) decorated by a fluorescent moiety (Cy7) on the surface. It could be simultaneously used for anticancer drug delivery and noninvasive optical imaging.60 Additionally, efficient probes have been obtained from NIR phosphorescent dye [Pt (II)tetraphenyltetranaphthoporphyrin, Pt (TPNP)] encapsulated by polymeric nanomicelles.61 They have a crucial advantage over conventional NIR-fluorescent probes due to the large spectral separation between the absorption and phosphorescence emission. This ensures a dramatic decrease in the level of background autofluorescence and scattered excitation light in the spectral range where the signal from phosphorescent probe is observed. Recently, a novel acid-sensitive polymeric prodrug of PMPC-b-P(MEMA-hydrazide-DOX) was also introduced to NIR-triggered PNMs.62 After loading with cyanine dye IR-780, such polymeric prodrug micelles could effectively release DOX in acidic endosomal compartments and tumor mass while remaining pharmacologically inactive in blood circulation. Benefiting from the localized hyperthermia induced by codelivered IR-780 upon NIR laser irradiation, the intracellular DOX accumulation and anticancer efficacy in vitro and in vivo were significantly increased. Widespread use of PNMs is expected in the field of drug and gene delivery. Therefore, much more work should be done to develop prototypes of novel polymer micelles with NIR fluorescence imaging capabilities.

PNMs is that their copolymeric structures can encapsulate hydrophobic drugs in the inner core, and the outer shell can be easily modified or engineered to achieve desired properties. This creates promising opportunities for using PNMs in drug delivery and targeting. Polymeric micelles with high stability both in vitro and in vivo show good biocompatibility and can solubilize a broad variety of poorly soluble pharmaceuticals as well as improve their biological behavior.40 Micelle-incorporated anticancer drugs, such as doxorubicin (DOX) and paclitaxel, have better accumulation in tumors than in nontarget tissues, which could minimize the toxicity of drugs toward normal tissue.41−43 Such drugs can also be protected from biodegradation in the body and achieve prolonged half-lives in vivo, resulting in enhanced efficacy.44 Recently, PNMs encapsulating NIR phosphorescent dye have been increasingly investigated as efficient candidates for optical bioimaging probes and drug delivery systems.45−47 In this review, we mainly focus on the NIR polymeric nanomicelles and present strategies for their design and modification (Figure 1) as well as introduce their NIR response characteristics and theranostic applications in cancer. Their future prospects and new challenges for theranostic applications in cancer treatments are also discussed.

2. DESIGN AND CHARACTERISTICS OF PNMS Micelles are self-assembling nanosized colloidal particles with a hydrophobic core and hydrophilic shell that have successfully been used as pharmaceutical carriers for water-insoluble drugs.17 Some commonly used micellar carriers are shown in Figure 2. PEG with a molecular weight from 1 to 15 kDa is the polymer most commonly used for the hydrophilic shell because of its physicochemical characteristics, including high water solubility, significant chain mobility, and low toxicity. Poly(Nvinyl-2-pyrrolidone) (PVP) is considered as a primary alternative to PEG.48 PVP is highly biocompatible and has been used in formulations of particulate drug carriers such as liposomes49 and diblock polymer micelles.50 Another hydrophilic candidate is poly(vinyl alcohol) (PVA). Poly(vinyl alcohol-co-vinyloleate) copolymer was used to prepare micelles to enhance the transcutaneous permeation of retinyl palmitate.51 In the case of the hydrophobic core, the most commonly used polymers are polyesters, polyethers, and polyamino acids. The main advantage of polyesters is that many have been approved by the Food and Drug Administration (FDA) for biomedical applications in humans, including poly(lactic acid) (PLA), poly(lactic-co-glycolic acid) (PLGA), poly(ε-caprolactone) (PCL), poly(trimethylene carbonate) (PTMC), and poly(propylene oxide) (PPO).52 Biodegradable hydrophobic blocks of polyesters are usually covalently bonded to hydrophilic blocks (mainly PEG) and then self-assembled into polymeric micelles. Other biodegradable hydrophobic block copolymers are composed of polyanhydrides, such as poly sebacic anhydride (PSA). These are also covalently bonded to hydrophilic blocks of PEG and have advantages of biocompatibility and degradation into nontoxic diacid compounds in vivo.53 The poly(L-amino acid) (PAA) family includes poly(Lhistidine) (polyHis), poly(L-aspartic acid) (polyAsp), poly(Lglutamic acid) (polyGlut), and poly(L-lysine)(polyLis). These are also employed as nanosized vehicles that are covalently bonded to hydrophilic blocks of PEG. These vehicles are not only biodegradable and biocompatible,53 but they also have pH sensitivity and potential use in pH-dependent drug release at 1930


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Figure 3. Preparation of semiconducting polymer nanoparticles for NIR-II PA imaging. (a) Synthetic route of poly(diketopyrrolopyrrole-altthiadiazoloquinoxaline). (b) Chemical structure of poly[diketopyrrolopyrrole-alt-thiophene]. (c) Schematic illustration for preparation of the polymer nanoparticles. Reproduced with permission from ref 72. Copyright 2017, American Chemical Society.

3. NIR-TRIGGERED PNMS FOR IMAGING Light in the NIR range (700−1000 nm) exhibits unique advantages, such as deep tissue penetration, low fluorescence background, and limited photodamage. NIR light is minimally absorbed by the major light absorbers in living systems, including water, lipids, and some intrinsic proteins, such as hemoglobin (Hb) and oxyhemoglobin (HbO2). Combined NIR fluorescence and molecular imaging techniques have promising capabilities for noninvasive visualization of biological structures.63 Such techniques could provide a new route for NIR dye-encapsulated nanoparticles for cancer targeting and imaging. 3.1. NIR Fluorescence Imaging. An excellent NIR probe is necessary for satisfactory NIR fluorescence imaging of cancer. Compared to computed tomography (CT) and magnetic resonance imaging (MRI), which have been of great help in characterizing diseases but not useful for intraoperative assessment, NIR fluorescence imaging has exhibited great success as an optical technique for real-time imaging of surgical targets with high imaging resolution and distinct intraoperative sensitivity. Recently, the use of a photostable, biocompatible, bright, and tumor-specific NIR fluorescent agent has been approved for intraoperative imaging in clinical trials and has demonstrated importance. Examples include indocyanine green (ICG) and methylene blue.64 However, their disadvantages include poor aqueous stability, low sensitivity, low specificity, and low temporal resolution in bioimaging. As a smart drug delivery system, PNMs can improve the physiochemical properties and biological behavior of NIR probes and therefore show great potential in intraoperative surgical guidance and disease diagnosis. Wu et al. developed ICG-encapsulated micelles using PEG-PLL-PLLeu copolymer as a carrier skeleton. These self-assembled ICG micelles exhibited improved quantum yield and fluorescence stability as well as high cellular uptake rates in vitro. They also showed excellent passive tumor targeting capability and long circulation time in animal experiments, indicating broad prospects of the fluoroprobe for tumor diagnosis and targeted imaging.65 Heptamethine dyes feature simultaneous tumor targeting and NIR imaging capabilities and have shown great advantages in experiments and in a clinical setting. With low molecular weight

(usually less than 1000 Da), these dyes show some similarity to biomacromolecules and are well suited for imaging with superior pharmaceutical and dynamic properties.66 They also have great stability and persist in tumors for more than 2 weeks. This makes it possible for repeated imaging after a single administration of these dyes. IR-780 iodide and IR-783 are two prototypical dyes that reach the NIR region at around 780 nm. They can be detected conveniently by an NIR fluorescent detection system without significant autofluorescence interference.67 Recently, amphiphilic micelles based on D-α-tocopheryl polyethylene glycol succinate (TPGS) and D-α-tocopheryl succinate (TOS) were developed for IR780 delivery. The IR780-loaded micelles have a narrow size range of 115 to 123 nm, and they present optimal characteristics for cellular uptake and imaging under NIR irradiation at 808 nm.68 Borondipyrromethane (BODIPY) dyes have a general structure of 4,40-difluoro-4-bora-3a,4a-diaza-s-indacene and are potential candidates for laser dyes, molecular photonic wires, fluorescent switches, and bioprobes. These dyes have advantages of sharp fluorescence with high quantum yield and excellent thermal and photochemical stability.69 Recently, a novel BODIPY-Br2-loaded pH-responsive polypeptide micelle was developed by Liu’s group using N-carboxyanhydride (NCA) monomer via a ring-opening polymerization and click reaction.70 Because of the inherent fluorescence emission, these BODIPY-Br2 PNMs enable the possibility for biomedical imaging. Therefore, their cellular internalization by cancer cells could be successfully traced by NIR fluorescence imaging. Upon light irradiation, the loaded BODIPY-Br2 could effectively generate reactive oxygen species and induce NIR imaging-guided photodynamic therapy (PDT). A variety of dye-encapsulated micelles have been prepared for cancer fluorescence imaging and treatment, but desirable biodegradability and biocompatibility are still urgent needs for the development of NIR naonoprobes in future research. 3.2. Photoacoustic Imaging (PAI). PAI combines the high contrast of optical imaging with the spatiotemporal resolution of ultrasound imaging.71 When laser pulses are applied, contrast agents or biological tissues absorb some of the delivered optical energy and convert it into heat. Then, the heat-induced transient thermoelastic expansion leads to the generation of 1931


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developed for cancer treatment. Increasing attention has been drawn to the delivery of therapeutic payloads using delivery systems based on engineered nanomaterials, such as polymeric micelles.77−79 The development of various stimuli-responsive delivery platforms has made it possible to have greater control over the delivery and release of anticancer agents in a temporal or spatial manner. Some of the release strategies that have been developed are pH alterations, redox activities, enzymatic reactions, overexpression of biomolecules (e.g., adenosine triphosphate, glutathione),80 and external triggers such as thermal energy, ultrasound waves, light irradiation, mechanical forces, and electromagnetic fields.81,82 Among these external stimuli, light activation offers unprecedented control with ease of production, noninvasive nature, controllable intensity, and spatially confined application for finely controlled durations.83,84 Different mechanisms have been involved in the light-activated drug delivery/release systems, which include bond-cleavage, isomerization, crosslinking, electrostatic assembly/disassembly, reduction, oxidation, photocaging/uncaging, and nonlinear photoconversion mechanisms (shown in Figure 5).85 However, problems with inevitable cellular phototoxicity and poor tissue penetration depth have limited the clinical potential of ultraviolet (UV) (wavelength: 100−400 nm) and short visible light (400−750 nm) as external stimuli for some photoactive delivery platforms. Nanomicelles that use NIR provide advantages over quantum dots and organic fluorescent materials in biological applications, such as low photodamage, enhanced tissue penetration,86,87 minimal autofluorescence background,88 and improved resistance to photobleaching and blinking. Therefore, more and more attention has been given to NIR nanomicelles as targeted delivery systems. 4.1. NIR PNMs Delivering Anticancer Drugs. Chemotherapeutic drugs for cancer with low molecular weight generally have a short circulation time and form low concentrations in tumors and metastases when they are administrated intravenously. Recently, nanoscale drug delivery systems have been developed as indispensable platforms for modern cancer therapy, such as liposomes and polymeric micelles. These could allow administered anticancer drugs to achieve a proper circulation time and tumor concentration, as well as attenuate their accumulation in potentially endangered healthy organs and tissues.89,90 However, acquired drug resistance and poor targeting have limited the application of liposomes and lipid-based drug delivery systems. In the early 1990s, Kataoka’s group reported DOX-conjugated block copolymer micelles as a drug delivery system, which has been used for the delivery of many anticancer agents in preclinical and clinical studies.91 PNMs could overcome multiple drug resistance through absolute targeting using various approaches, such as passive targeting, folate-mediated drug delivery systems, and pH-sensitive and thermosensitive drug delivery systems. Another important problem of anticancer agents is their poor water solubility, which has great concerns in therapeutic applications such as limited absorption and bioavailability and drug aggregation-related complications like embolism.92,93 PNMs could significantly increase the water solubility of anticancer drugs by 10- to 5000-times94 and have an inner core made up of hydrophobic block copolymer nanomicelles in which poorly water-soluble anticancer drugs can be entrapped. They also have an outer shell of hydrophilic block copolymer that reduces the interactions of drugs with the aqueous environment and keeps them stable.95 The release of

broadband ultrasonic emission, which can be detected by an acoustic detector and analyzed to reconstruct PA images.72,73 Recently, a new PA organic contrast agent based on semiconducting polymer nanoparticles has been developed for PAI in both the first NIR window (NIR-I, 650−950 nm) and second NIR window (NIR-II, 1000−1700 nm) (Figure 3). Because of the weaker background PA signals from biological tissues in NIR-II window, 1.4-times higher signal-to-noise ratio (SNR) of contrast-enhanced PA images at 1064 nm could be detected as compared with that at 750 nm at the imaging depth of 3 cm.72 PAI exhibits greater performance on functional information imaging compared with positron emission tomography (PET) and single photon emission computed tomography (SPECT). These nuclear imaging modalities depend on the use of nuclear radioisotopes for gamma-ray detection but have poor spatial resolution. Optical imaging, another technique to obtain functional information, is limited by the strong light absorption/scattering of skin, tissue, and blood, leading to poor tissue penetration. Acoustic scattering in tissue, however, is several orders of magnitude weaker than optical scattering.74 A combination of labels for different imaging modalities has been widely used in applications ranging from diagnosis of vulnerable atherosclerotic plaques to the detection of cancer. Liang et al. prepared CT/PA imaginable PNMs through conjugating hyaluronic acid (HA) with NIR dyes as hyaluronidase−active cancer theranostics.75,76 Recently, a series of perylene diimide (PDI) nanoparticles have been synthesized as dual PET/PA probes and PTT agents. It has been demonstrated that PDI nanoparticles with a size of 60 nm appear to be the best for tumor imaging and photothermal cancer therapy due to the maximum tumor accumulation efficiency (Figure 4).73

4. NIR-TRIGGERED PNMS FOR DRUG DELIVERY Controlled drug delivery systems that can selectively release chemotherapy agents at a target site have been actively

Figure 4. Schematic illustration of the application of PDI nanoparticles as PET and PA imaging probes. Reproduced with permission from ref 73. Copyright 2017, American Chemical Society. 1932


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Figure 5. Different light-activated mechanisms used for drug delivery systems. Reproduced with permission from ref 85. Copyright 2017, American Chemical Society.

Figure 6. Structure of ligand-targeted copolymer conjugated with DOX and NIR probe, micellization, selective accumulation in liver cancer cells, and imaging of the endocytosis of the micelle with subsequent pH-triggered drug release. Reproduced with permission from ref 115. Copyright 2015, American Chemical Society.

late) (POEGMA-b-PFMA).114 When encapsulated with NIR dye indocyaninegreen (ICG) and DOX, the PNMs could deliver the drug efficiently without premature drug leakage and release. Upon NIR irradiation at 805 nm, ICG located in the inner core of micelles potently generated a photothermal effect. Such local increased temperature of the micellar cores could induce fast drug diffusion, resulting in the effective release of DOX from micelles. Similarly, a novel galactose-targeted pHresponsive amphiphilic multiblock copolymer conjugated with both drug and NIR probe has been designed and exerted fast and enhanced endocytosis for HepG2 cells (Figure 6).115 Therefore, NIR-responsive PNMs provide a promising platform for anticancer drugs with the possibility of controllable drug release, which could maximize the therapeutic efficacy and minimize their adverse side effects. 4.2. NIR PNMs Delivering Therapeutic Genes. Recently, novel nucleic acid-based therapies such as plasmid DNA and siRNA have been developed as an innovative medicine. This has been enabled by the great progress in the understanding of biological mechanisms of life processes at the molecular level.116,117 However, they are unstable under physiological conditions and have low cellular uptake efficiency because of

chemotherapeutic drugs by the drug delivery system can be controlled by light irradiation,96−98 pH,99−101 temperature,102−104 enzymatic hydrolysis,105−107 and redox reactions.108,109 Among these strategies, light irradiation works as an efficient and readily operated external stimulus because of its precise temporal and spatial control. The high-energy light of UV or visible light, which are frequently needed, are limited by poor tissue penetration and damage to healthy tissue. Longerwavelength NIR light irradiation exhibits great priority due to its capability of deeper penetration into tissue and minimal damage to living cells.110 Therefore, the controlled-release of molecules irradiated by NIR provides an alternative method of drug delivery and targeted therapy, and they have gained significant attention in recent years.111,112 Recently, novel PEG and pyrene-oxabicycloheptenealkyne (POA)-modified PPy nanomaterials were synthesized to covalently append hydrophobic anticancer molecules.113 Under NIR irradiation, PPy could mediate photothermal effect, thereby triggering retro D−A reaction for drug release. Li et al. developed an NIR-responsive drug delivery system based on thermosensitive block copolymer micelles of poly(oligo(ethylene glycol)methacrylate)-block-poly(furfuryl methacry1933


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tion.125−128 Nanomicelles with small sizes of 10−100 nm have excellent tumor accumulation due to the EPR effect through atypical and leaky vasculatures as well as poor lymphatic drainage in solid tumors.129,130 Antibody fragments installed in polymeric micelles via maleimide−thiol conjugation have been developed to deliver platinum drugs selectively to pancreatic tumors, which achieve efficient drug delivery. A number of proteins are usually overexpressed in neovascular endothelial cells and some kind of tumor cells, such as vascular endothelial growth (VEGFR) and APN/CD13.131 Therefore, it is promising to synthesize nanomicelles with double-targeting ability toward upregulated proteins in the endothelial cells of both angiogenic vessels and tumor cells. This would maximize the utility of anticancer drugs by combining blood vessel destruction with conventional antitumor actions.132 NIRtriggered nanomicelles could provide a much more targeted and precise platform for protein drug delivery. Although much attention has been focused on the development of nanomicelles as a carrier for protein antitumor drugs, little work has been done on NIR-triggered nanomicelles for this purpose. Therefore, there is a promising opportunity for developing NIR nanomicelles as a protein drug carrier for cancer treatment.

their large molecular weight and anionic nature, which hinder their application in clinical treatment. DNA or RNA is rapidly eliminated by DNase and RNase when directly administered into the blood; thus, it is necessary to create a nanoplatform to encapsulate them to achieve effective accumulation within the targeted tissues and intracellular delivery to the nucleus for gene therapy. Viral vectors are commonly used as gene carriers, but there are problems associated with the immune response and possible oncogene effects due to their recombination with endogenous genes.117−119 Because of their advanced and tunable characteristics, PNMs offer a superior alternative as a gene carrier with regard to safety, mass production, and cost.120,121 They can be formed by anionically charged DNA or RNA and a block copolymer with hydrophilic and cationic segments through polyion complexation. Studies have shown that DNA in the PNMs have prolonged circulation in blood, which allows for the efficient gene expression in the diseased site after intravenous injection into mouse tail veins.122 The new biodegradable polyethylenimine derivatives of siRNA-PEG/polyethylene imine (PEI) polyplex micelles have been designed for siRNA delivery with raised hydrophilicity, decreased cytotoxicity, and increased transfection efficacy. PEG-PCL-PEI triblock copolymers and cationic micelles shaped from poly(ethylene glycol)-bl-poly(propylene sulfide)-bl-poly(ethylene imine) (PEG-b-PPS-bPEI) were designed for plasmid DNA (pDNA) transfection as nonviral vectors in a tumor model in vitro and in vivo. Some polymeric micelles have shown a high potential for use as a delivery system for gene therapy applications.123 One example is ERβ, which is a potent inhibitor of cell proliferation in the HCT-8 human colon cancer cell line, which occurs through the regulation of cell cycle components. The ERβ gene could therefore significantly inhibit tumor growth. SOC-ICG-Der-01 was formed by hydrophobic fluorescent dye ICG-Der-01 and amphipathic N-succinyl-N-octyl chitosan (SOC) micelles through hydrophobic association. The micelles were further combined with ERβ gene, resulting in significant inhibitory efficiency on tumor growth in a xenograft model of colon cancer.124 Therefore, considering the DNA-based therapeutics used in gene therapy including plasmid DNA (pDNA), oligonucleotides, DNAzymes aptamers, and small interfering RNA (siRNA), the PNMs show great promise in effectively delivering the therapeutic agents to the cytoplasm and further importing into the nucleus for pDNA. 4.3. NIR PNMs Delivering Therapeutic Protein Drugs. With the development of biotechnology, protein drugs have become to play an important role in cancer treatment. Efficient internalization of protein drugs into tumor cells is critical for gaining the desired therapeutic effect. However, the plasma membrane of the tumor cell is an effective barrier that limits the internalization of protein drugs with high molecular weight. The tumor microenvironment has distinctive characteristics with upregulated proteolytic enzymes such as matrix metalloproteinases, which are required for cancer progression. This decreases the efficiency of protein drugs in cancer therapy. Furthermore, the instability, immunogenicity, and short half-life of protein drugs also restrict their wide application in routine therapies against cancer. Polymeric micelles with improved tumor extravasation and penetration offer substantial benefits as nanocarriers for delivering protein drugs. Benefiting from the surface coverage by commonly used PEG strands, PNMs present high and versatile loading of bioactive molecules with controlled release and exhibit prolonged blood circula-

5. THERANOSTICS Theranostics involves the simultaneous diagnosis and treatment of tumors. In recent years, theranostics based on NIR nanomicelles have been emerging as a promising therapeutic paradigm because of their capabilities in diagnosis, drug delivery, and monitoring therapeutic responses.133−141 Photothermal therapy (PTT)- and PDT-based on NIR nanomicelles could enable targeted cancer treatment and reduce damage to normal tissue.142−145 The imaging properties of NIR PNMs also make it possible to detect and visualize tumor tissue while simultaneously ablating the tissues with the help of PTT and PDT. Thus, they may be advantageous in theranostics. 5.1. Photothermal Therapy. PTT is an emerging strategy in cancer therapy that involves directly converting light illumination into heat based on the strong absorption of thermally sensitive agents for targeted disease treatment. Photothermal conversion agents such as cyanine dyes can absorb high amounts of energy and release a great amount of heat upon irradiation with NIR light. This induces hyperthermia damage in the cancer cells and tumor mass with deep tissue penetration,146−148 eventually resulting in cell death. Hyperthermia is capable of killing tumor cells directly at >45 °C or in combination with other therapies at 39−42 °C.149 The hyperthermia effect of nanoparticles could also enhance therapeutic efficacy by augmenting the cytotoxicity of some chemotherapeutic agents in vitro and in vivo for cancer treatment without increasing the drug dosage.150,151 Effective photothermal conversion agents feature strong NIR light absorption, great photothermal conversion efficiency, excellent biocompatibility and biodegradability, and the opportunity for real-time visualization for therapy.152,153 Some promising photothermal conversion agents (including organic nanomicelles) have been widely employed for effective lighttriggered PTT treatment in vitro and in vivo. With NIR laser irradiation, the temperature of IR-780-loaded PNMs increased by 20.6 °C, which significantly changed the permeability and fluidity of the plasma membrane of MCF-7/ADR cells, enhanced the intracellular retention and accumulation of DOX, as well as reversed the drug resistance of tumor cells.62 After being exposed to 805 nm light irradiation, the ICG- and 1934


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nanocarrier to encapsulate a hydrophobic porphyrin photosensitizer inside the micelle core. With efficient energy transfer (as much as 96%), such 2PA PNMs performed effective singlet oxygen generation under irradiation of NIR light at 800 nm and could be considered as a promising platform for cancer PDT. Although great progress has been achieved in the field of twophoton-activated photodynamic therapy (2P-PDT), the application of traditional photosensitizers in 2P-PDT remains a critical challenge in clinical practice due to their low 2PA cross sections. To address this issue, Huang et al. developed a Ce6-conjugated core−shell unimolecular micelle using a large two-photon-absorbing hyperbranched conjugated polymer (HCP) as the inner core and a thermoresponsive hyperbranched polyether (HPE) as the outer shell (HPE) (Figure 8).157 Under NIR irradiation, the local temperature increases,

DOX-coloaded POEGMA-b-POMFMA PNMs showed a significant temperature increase, achieving a synergistic effect of thermo-triggered drug release and PTT on HeLa cells. Recently, Yuan’s group also developed a new photothermal therapeutic agent based on PEG-IR-780-C13 micelles with NIR absorption.154 The micelles were stable in aqueous conditions and exhibited no observable toxicity to cells and mice at therapeutic doses. PEG-IR-780-C13 micelles showed higher photostability than free IR-780 and conventional micelles containing IR-780. Furthermore, they exhibited high tumor accumulation by the EPR effect and enabled fluorescence imaging of the tumor tissue. The micelles also acted as an excellent PTT agent for tumor ablation upon laser irradiation without rendering any appreciable toxicity. All these results clearly prove that NIR nanomicelles can be a safe theranostic agent for imaging-guided PTT. Future work is needed for optimization of the sizes, chemical treatments, sorting, and assembly of nanostructures. Other topics that should be explored are the colloidal stability, tumor-homing capacity, and resistance to protein adsorption on NIR nanomicelles, which will improve their potential of the nanomicelles in cancer PTT. 5.2. Photodynamic Therapy. PDT is another efficient light-triggered cancer therapy method that could induce the creation of singlet oxygen or other free radicals through photobiochemical processes. This selectively causes acute microvascular injury, blood vessel blockage, and cell apoptosis tumors, thus achieving the purpose of local treatment.155 Superior anticancer efficacy may be achieved from the synergistic effect between cyanine dye and therapeutic agent (Figure 7).156 The free radicals could be generated by the

Figure 8. Schematic of HCP@HPE-Ce6 micelles (A) and illustration of the combination of 2P-FRET and photothermal effect of NIR for cancer PDT (B). Reproduced with permission from ref 157. Copyright 2016, American Chemical Society.

Figure 7. Mechanism illustration of cyanine-based micelles as a multimodal platform for synergistic cancer therapy. Reproduced with permission from ref 156. Copyright 2014, Ivyspring International.

and the HPE shell collapses, which shortens the distance between the HCP and photosensitizer. As a result, the fluorescence resonance energy transfer (FRET) between HCP core and Ce6 can be readily switched “on” to enhance the 2PA activity of Ce6 and, in turn, amplify its production of cytotoxic singlet oxygen for cancer PDT. Compared with free Ce6, the HCP@HPE-Ce6 micelles showed greater promise for enhanced photodynamic antitumor therapy with high stability in the blood and selective accumulation in tumors. As a typical carrier material for PNMs, PLA−PEG copolymer recently was extended to the field of NIR-triggered PDT.158 After carrying a pH-responsive fluorescent probe and a robust NIR photosensitizer of R16FP, the PLA−PEG PNMs under 808 nm irradiation could generate reactive oxygen species to mediate lysosomal destruction and subsequently trigger lysosomal cell death. Moreover, the significant inhibition on tumor growth and obvious necrosis of tumor tissue further demonstrated the potent PDT efficacy of PNMs for cancer therapy.

activation of a photosensitizer (PS) initiated by light in the NIR region. Because of the intrinsical noninvasiveness, safety, and highly spatiotemporal selectivity after light irradiation, PDT exhibits great advantages in cancer therapy compared to those of traditional therapeutic modalities. On the other hand, NIR light-responsive photosensitizer molecules have some unavoidable drawbacks, such as complicated synthesis procedures, low water solubility, and limited accumulation capabilities in targeted areas. These drawbacks heavily restrict the clinical applications in deep-tissue therapy and imaging studies. Therefore, organic nanomaterials like polymetric nanomicelles with a large extinction coefficient in the NIR window have been extensively explored for PDT applications both in vitro and in vivo. Micelles containing a new water-soluble amphiphilic twophoton absorption (2PA) chromophore have been developed, which were realized by using a block copolymer as a 1935


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ACS Biomaterials Science & Engineering Table 1. Examples of Polymeric Micelles in Clinical Trialsa product name GenexolPM

drug paclitaxel

platform mPEG-PLA

NanoxelPM NC 4016

docetaxel

mPEG-PLA

oxaliplatin

NK911 NK105 NC-6004 NK012 SP1049C

doxorubicin paclitaxel cisplatin SN-38 doxorubicin

Lipotecan

camptothecin analogue

PEG-poly(glutamic acid) PEG and PAA PEG and PAA PEG and PGA PEG and PGA Pluronic L61 and F 127 polymeric micelle

a

status phase II/III/ IV phase II

therapeutic indication

refs

advanced, recurrent metastatic breast cancer

159−162

phase I/II phase I

advanced urothelial cancer, advanced head and neck cancer, and advanced non-small-cell lung cancer ovarian cancer and advanced or metastatic pancreatic cancer lung, ovary, and breast cancer

163

phase I

solid tumors

164

phase phase phase phase phase

metastatic pancreatic cancer advanced or recurrent gastric cancer advanced solid tumors advanced solid tumors advanced adenocarcinoma of the esophagus and gastro-esophageal junction

165 166 167 168 160

liver and renal cancer

169

I/II II/III I/II I/II II/III

phase I/II

mPEG: methoxy polyethylene glycol; PLA: polylactic acids; PEG: polyethylene glycol; PAA: polyacrylic acid; PGA: polyglutamic acid.

tumors or metastasized cancer in PDT and PTT. Increasing evidence suggests that the physicochemical properties (e.g., size, charge, and shape) of PNMs play a vital role in controlling their biological performance, such as cellular internalization, blood circulation time, in vivo cancer targeting, and biodistribution. Therefore, more efforts are desirable to deeply understand the correlation between them, thereby precisely regulating the characteristics of PNMs to improve their penetration depth and effectiveness. Moreover, combination of photoinduced therapies with other disease treatments like magnetic/sonodynamic therapy, which is more potent in treating deeply located tumors, will also be one of the exciting tides in the future. Before testing in cancer patients, it is still a challenge to verify the metabolic processes related to PNMs, such as the pharmacodynamics and pharmacokinetics in human bodies. Their distribution, fate, translocation, long-term stability, and toxicity should also be addressed before applying them in clinical studies. Although PNMs have promising potential for cancer theranostics, it is still very challenging to develop PNMs commercially. Without abundant economic support, it is difficult to conduct the further toxicity research and synthesis according to current good manufacturing practices in a purely academic environment. Collaboration among highly specialized groups or laboratories is needed to accomplish clinical studies of PNMs. The future of advanced probe design for NIR fluorescence imaging mainly depends on multidisciplinary cooperation between chemists, physicists, biologists, and clinicians. With continuous efforts using multidisciplinary approaches, we believe that NIR PNMs will open new opportunities in cancer theranostics.

PDT has been approved by the FDA as a well-established and unique type of therapeutic modality for effective cancer treatment, and it is attracting more interest in cancer therapy. Great efforts should be made to develop improved PDT treatments and multimodality cancer imaging, including optical and PAI techniques for theranostics in vivo.

6. CONCLUSIONS AND CHALLENGES In this review, we have summarized the current research progress on NIR PNMs and their biomedical applications, such as imaging, PTT, PDT, and drug delivery. NIR PNMs have the following characteristics of absorbing NIR light and converting it to visible light or heat, thus serving as a drug carrier and enhancing tumor localization of therapeutic molecules. Despite the promising characteristics of PMs, few clinical trials have been done. Thus far, there have been only a few PMbased formulations composed of anticancer agents in clinical trials, which are summarized in Table 1. Genexol-polymeric micelles are a formulation of paclitaxel encapsulated in monomethoxy-PEG-b-poly( D , L -lactide) (MPEG-PDLLA), which is currently involved in 13 clinical trials and in a more advanced state of development. SP1049C, a Pluronic-based polymeric micelle formulation of DOX, is currently in phase III clinical studies and was designated as an orphan drug by the FDA in 2008. The clinical trials show highly promising results in these early stages of clinical development of the PNMs. There are still many challenges for NIR PNMs and their wide application in biomedicine. For NIR fluorescence imagingguided cancer therapy, it is necessary to optimize the imaging systems and NIR fluorescence probes. There are many fluorescent dyes available in the NIR spectrum, which are usually conjugated with specific cancer-targeting ligands to enable highly selective fluorescence imaging of cancer. However, ICG is the only NIR fluorescence dye approved by the FDA. It is urgent to find some other NIR fluorescence probes that are available clinically as well as sophisticated imaging instrumentation for detection. There are still some limitations for PNMs in the diagnosis and treatment of cancer. The therapeutic effects of PNM methods such as PTT, PDT, and drug delivery can only be applied to limited types of cancer because of the limited penetration depth and ineffectiveness of therapy on large-mass

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Gang Liu: 0000-0003-2613-7286 Author Contributions †

L.L. and X.P. contributed equally to this work.

Notes

The authors declare no competing financial interest. 1936


Review


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ACKNOWLEDGMENTS This work was supported by the Major State Basic Research Development Program of China (Grant Nos. 2017YFA0205201, 2014CB744503, and 2013CB733802), the National Natural Science Foundation of China (NSFC) (Grant Nos. 81422023, 81371596, 51273165, and U1505221), the Science Foundation of Fujian Province (2014Y2004 and 2014J05098), the Program for New Century Excellent Talents in University (NCET-13-0502), and the Fundamental Research Funds for the Central Universities, China (20720150206 and 20720150141).

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Near-Infrared Light-Triggered Polymeric Nanomicelles for Cancer

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