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Boosting Cancer Therapy with Organelle-Targeted Nanomaterials peng gao, Wei Pan, Na Li, and Bo Tang ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.9b01370 • Publication Date (Web): 28 May 2019 Downloaded from http://pubs.acs.org on May 29, 2019

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ACS Applied Materials & Interfaces

Boosting Cancer Therapy with Organelle-Targeted Nanomaterials Peng Gao, Wei Pan, Na Li,* and Bo Tang* College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan 250014, P. R. China. KEYWORDS: cancer therapy, organelle-targeted, nucleus, mitochondrion, endoplasmic reticulum, lysosome, Golgi apparatus, nanodrugs

ABSTRACT: The ultimate goal of cancer therapy is to eliminate malignant tumors while cause no damage to normal tissues. In the past decades, numerous nano-agents have been employed for cancer treatment owing to their unique properties over traditional molecular drugs. However, lack of selectivity and unwanted therapeutic outcomes severely limited the therapeutic index of traditional nanodrugs. Recently, a series of organelle-targeted nanomaterials that can accumulate into specific organelles (nucleus, mitochondrion, endoplasmic reticulum, lysosome, Golgi apparatus) intra cancer cells have received increasing interest. These rationally designed nanoagents can either directly destroy the subcellular structure or effectively deliver drugs into the proper targets, which can further activate certain cell death pathways, enabling them to boost the

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therapeutic efficiency, lower drug dosage, reduce side effects, avoid multidrug resistance and prevent recurrence. In this review, the design principles, targeting strategies, therapeutic mechanisms, current challenges and potential future directions of organelle-targeted nanomaterials will be introduced.

1. Introduction Cancer is a group of diseases that can affect almost any part of human body, which has continuously brought heavy social burdens and severe health problems.1-6 Currently, the clinical cancer therapeutic efficiency is still unsatisfactory due to the lack of effective schemes. Therefore, developing novel medicine for highly efficient cancer treatment is a worldwide concern.7-9 Many strategies, including surgery, chemotherapy, radiotherapy, phototherapy, immune therapy etc., have been explored to eliminate malignant tumors and increase survival rates of patients.1-10 Unfortunately, only limited therapeutic effects can be achieved due to the intrinsic disadvantages of each approach.11-16 As an example, chemotherapy usually involves the frequent administration of high dosage therapeutic drugs with poor selectivity toward cancerous cells, which can bring deadly side effects to the patients, including liver/kidney toxicity, break down the immunity systems and so on.17,18 Meanwhile, via mutation, cancer cells can quickly become resistant to the drugs due to the development of drug resistance system, further restricting the therapeutic effects.19,20 Moreover, increasing evidences have suggested that chemotherapy may cause cancer metastasis, which can cause extra burden for patients.21-26 Accordingly, many efforts have been devoted to the modification of drugs to improve the bioavailabilities and reduce side effects. Nevertheless, chemical conjugation can reduce the pharmaceutical effects of the drugs, and only limited therapeutic drugs can be easily functionalized.27-30 Therefore, research focus has been shifted to the design and fabrication of


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novel drug delivery vehicles, including inorganic materials, organic materials as well as their hybrids.31-45 These studies revealed that both passive and active targeting modality of these vehicles can lead to positive outcomes, and some of them have been clinically employed due to their higher therapeutic index.46-56 However, nonspecific bio-distribution and relatively low therapeutic efficiency still have yet to be further resolved. In vivo experiments indicated that only a small percentage of the administered drugs can reach tumor sites.57-64 Thus, highly efficient tumor targeted therapy is still challenging and desired.65-73 Organelles are indispensable for cellular function.74-83 Lysosome takes part in digestion, autophagy and cellular defense; mitochondrion takes charge of the ATP synthesis, calcium ion cycle and apoptosis regulation; endoplasm reticulum and Golgi apparatus participate in protein fabrication and transportation, nucleus controls the gene expression as well as cell proliferation.84,90 Benefiting from the critical biological effects of diverse organelles, driving proper therapeutics into specific organelles may take new opportunities for cancer therapy.91-102 For example, the first line chemotherapeutic drug, cisplatin, can crosslink the tumor DNA and reduce the gene repression of a wide range of cancer cells.64,103 By delivering cisplatin into the nucleus of cancer cell, higher therapeutic index can be realized compared to diffusing it to the cytoplasm. Therefore, side effects and recurrence could be avoided.104 More importantly, organelle dysfunction can usually activate specific cell death signal, since organelles are closely related to diverse signal pathways, which can be employed for cancer treatment with enhanced efficiency and specificity.105-107 During the past several years, organelle-targeted therapeutics have arose increasing interest.108111

Earlier studies revealed that organelle-targeted nano-objects are beneficial for overcoming

several obstacles, including drug resistance, drug premature leakage, and high dosage


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requirement.112-121 Moreover, by virtue of their superior designability, multi-functional nanosystems can be easily constructed by integrating multiple imaging and therapy modality into the designed nano-platforms, which will further potentiate cancer theranostics. This review mainly focuses on the recent achievements of functional nanomaterials for organelle-targeted therapy, which covers mitochondria-targeted therapy, nucleus-targeted therapy, lysosome-targeted therapy, endoplasmic reticulum, and Golgi apparatus-targeted therapy (Figure 1). The design principle, working mechanisms and advantages of diverse nano-formulations are illustrated. Meanwhile, their limitations and potential future development directions are also pointed out. The major objectives of the current review are to emphasize the broad potential of advanced organelle-targeted nanomaterials for cancer therapy applications, and to offer valuable information for medical chemists to further resolve involved challenges.

Figure 1. Schematic of the precise cancer therapy with boosted therapeutic index based on organelle-targeted nanomaterials. 2. Nucleus-targeted therapy As the most important organelle of eukaryotic cells, nucleus contains the vast majority of DNA and controls the gene expression of the cells.84,85,122 The main origin of cancer is believed to be the uncontrolled growth of cells caused by gene mutation, and many cancer treatment modality have


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been developed to inhibit the cellular proliferation by taking nucleus/nucleic acids as targets.123126

Therefore, nucleus-targeted cancer therapy has intrinsic superiority because the drugs are more

accessible to their ultimate targets.127-130 The nucleus is surrounded by two-layered nuclear envelope, which can separate the genomes from cytoplasm to ensure DNA replication and gene repression in a secure environment. To maintain the transport of diverse RNA as well as enzymes between nucleus and cytoplasm, the nuclear membrane is traversed by a series of protein machines (nuclear pore complexes, NPCs).105,131,132 Although some ultra-small nanoparticles might diffuse into the nucleus17,123,129, those nanoparticles still suffer from low nucleus-entry efficiency since they must penetrate a series of complicated biological membrane barriers in cancer cells. Therefore, vehicles with nucleartargeting ligands are critical for nucleus-targeted delivery. Up to now, many virus-inspired peptides that could interact with the NPCs has been used to modify nanoparticles to render them nucleus locating capacity. Chemical molecules with strong nucleus membrane receptor affinity and some other nucleus membrane opening strategies were also reported.118,127,133-136 (Table 1) Based on these nano-carriers/medicine, nucleus-targeted chemotherapy, photodynamic therapy, photothermal therapy, radiotherapy as well as combined therapy have been reported. Table 1. Typical nanomaterials for nucleus-targeted therapy.

Therapy modality

Nanomaterials

Chemotherapy

PEG-PCL QDs@mSiO2

PTT

Targeting mechanisms

Amidized TAT TAT

Acid responsive TAT activation, importin guided nuclear entry Enzyme responsive TAT exposure, importin guided nuclear entry Magnet guided tumor accumulation, receptor mediated endocytosis, importin guided nuclear entry Nanostructure enhanced uptake, charge accelerated nuclear entry ROS break nuclear membrane integrity Importin mediated nuclear entry Receptor-mediated targeting, importin mediated nuclear entry Importin mediated nuclear entry

Fe3O4@MSN

Magnet, TAT, FA

oligopeptide-drug aggregates RB functionalized POSS-PEG NPs Au nanorods Fe3O4



CuS@MSN PDT

Targeting ligands

MSNs

 TAT Tf, TAT TAT, RGD RGD, TAT

IC50

Cell type

Tumor model

Administration route (i.v./i.t.)

Treatment times

Treatment period

Refs

Bcap-37

i.v.

6

15

116



SKOV3 A549









133



HeLa









137

42 nM

A549/ 4T1 A549

4T1

i.v.

4

21

104











138

 

HeLa A549

HeLa A549

i.v. i.v.

1 1

15 14

128 139



HeLa

HeLa

i.v.

1

14

140



HeLa

HeLa

i.v.

1

15

141

(μg/mL)

Receptor-mediated targeting, importin mediated nuclear entry

2


5


Peptide nanoparticles Gene therapy Combined therapy

UCNPs@TiO2-Ce6 AuNP aggregates

PKKKRK V TAT TAT

UCNP@MSN

TAT

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Acid mediated NLS exposure



HeLa

H22

i.v.

1

11

142

Importin mediated nuclear entry Photothermal triggered cargo release, importin mediated nuclear entry Importin mediated nuclear entry

 

MCF-7 A375

MCF-7 human melanoma

i.t. i.t.

1 10

14 20

122 143



MCF-7

MCF-7

i.t.

1

16

144

2.1 Nucleus-targeted chemotherapeutic agents As discussed above, a large number of clinical employed drugs are DNA replication associated toxins, including platinum based drugs (DNA crosslinker), doxorubicin (topoisomerase II inhibitor), 5-fluorouracil (thymidylate synthase inhibitor), camptothecin (topoisomerase I inhibitor) and so on.104,117,137,145,146 These drugs can inhibit DNA replication by interacting with double-standard DNA or deactivating related enzymes, which indicated that nucleus is the ultimate target for these chemotherapeutic drugs. Direct delivering drugs into the nucleus can enhance the therapeutic efficiency compared to traditional drug delivery strategies, because it significantly reduced the risks of these drugs being denaturalized or pumped out during their intracellular travel.127,147-149 Brinker’s group reported a mesoporous silica nanoparticles (MSNs) based platform for cancer nucleus-targeted drug delivery in 2011.80 MSNs was employed as the core of their “protocell”, which can load diverse nucleus localization signal (NLS) peptide functionalized model drugs (calcein, double-stranded DNA, red fluorescent protein, CdSe/ZnS quantum dots), the targeting peptide, fusogenic peptide and PEG co-modified lipid bilayer was encapsulated on the surface of the MSNs to reduce the immunogenicity, enhance the target efficiency and promote endosomal escape. The results revealed that this “protocell” significantly enhanced the intra-nuclear accumulation of NLS modified drugs, while the bare fluorescent protein and quantum dots loaded by MSNs stayed in cytoplasm. Compared to liposomes, higher drug loading efficiency and 106fold of therapy efficiency enhancement toward drug-resistant human hepatocellular carcinoma cell was observed, which proved the superiority of nucleus-targeted drug delivery strategy. Thereafter,


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MSNs, upconversion nanoparticles (UCNPs), polymeric nanoparticles, gold nanoparticles and quantum dots (QDs) have been investigated as nuclear-targeted chemotherapeutic drug vehicles.116,117,130,133,136,137,142,150-153

Figure 2. (A) Schematic illustration of the general preparation protocol of MSNs-TAT. (B) Schematic diagram of transport of DOX@MSNs-TAT across the nuclear membrane. (C) TEM images of MSNs with different sizes. Scale bars: 100 nm. CLSM (top) images and line-scan profiles (bottom) of fluorescence intensity for Hela cells incubated for 4 h with (D) free DOX, (E) DOX@MSNs (25 nm), and (F) DOX@MSNs-TAT (25 nm). The red fluorescence is from DOX, and the blue fluorescence is from DAPI. (G) Hela cell viabilities after 24 h of incubation with DOX-loaded MSNs and MSNs-TAT nanoparticles with different sizes at different DOX concentrations. Adapted and modified with permission from ref 117. Copyright 2012 American Chemical Society. Shi’s group investigated a series of TAT modified MSNs (MSNs-TAT) with different diameters (25, 50, 67 and 105 nm) for nucleus-targeted DOX delivery (Figure 2A-C).117 TAT peptides can bind with the import receptors importin α and β, and then translocate nanomaterials into the


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nucleus. They found small MSNs-TAT (25 nm 50 nm) could efficiently enter the nucleus of drug resistant HeLa cells, while MSNs-TAT with larger sizes (67 and 105 nm) can only accumulate at the perinuclear region. They also demonstrated NLS peptides modified MSNs with suitable size can improve the anticancer effect of DOX (Figure 2D-G).

Figure 3. (A) Schematic illustration of the aTAT modified nanoparticles for enhanced blood circulation, tumor/lysosomal acidic microenvironment responsive activation and nucleus-targeted delivery. (B) Cellular uptake and intracellular localization of aTAT-PEG-PCL/nile red micelles at different time points: (a) 1, (b) 5, (c) 12, and (d) 24 h. (e-g) Lysosomal colocalization of aTATPEG-PCL/nile red in the cells after incubation for 5 h at 37 ºC. (h) An amplification of one cell in (c). (C) Blood circulation of the micelles. (D) In vivo tumor growth curves after treated with DOX or DOX-loaded micelles. (E) The concentration of DOX in tumor tissues after different treatments. Adapted and modified with permission from ref 116. Copyright 2012 American Chemical Society.


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Although promising, it is noteworthy that the NLS peptides modified materials are usually positively charged, which can result in strong non-specific binding between nanoparticles and serum proteins and lead to the rapid blood clearance of nano-drugs. In the other hand, these nanoformulations with neutral or negative charge suffer from poor cell internalization. Thus, novel strategies that could overcome multiple biological barriers for hierarchical targeting are highly attractive. Shen et al. reported the amidation of TAT with succinyl amides as a charge shielding method for potentiating the in vivo targeting performance of TAT modified nano-carrier (Figure 3A).116 The cationic charge of TAT was reduced after amidation (aTAT). The amides in aTAT were quickly hydrolyzed in the acidic extracellular interstitium and lysosomes microenvironments owing to the acid sensitivity, afterwards the nuclear targeting capability of TAT was fully reactivated. aTAT was employed as the corona of DOX loaded poly(ethylene glycol)-block-poly(εcaprolactone) (PEG-PCL) micelles. In vitro and in vivo experiments suggested such drug delivery system significantly enhanced the anticancer efficiency of DOX on account of the prolonged blood circulation time and enhanced cancer cell nucleus drug accumulation (Figure 3B-E). Xing’s group reported the naturalization of cationic NLS peptide (CRRRQRRKKR) with a cathepsin B -responsive peptide (PGFK) linked anionic sequence (EEEEEE).133 Because of the shielding effect of anionic peptide, such peptide (CRRRQRRKKR-PGFK-EEEEEE) modified mesoporous silica coated quantum dots (CPP-QDs@mSiO2) located in cytoplasm of cells without cathepsin B expression, but were nucleus-targetable in cancer cells with cathepsin B due to the specific cleavage of the PGFK sequence. Benefiting from the outstanding fluorescent properties of QDs, imaging guided nucleus-targeted DOX delivery was performed in a series of cell lines. Unlike the rapid DOX expelling observed in drug resistant cells, DOX loaded CPP-QDs@mSiO2


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specifically accumulated into the nucleus region of cancer cells, which demonstrated this drugloading system is a potential candidate for highly efficient and specific chemotherapy.

Figure 4. Schematic illustration of vasculature-to-cell membrane-to-nucleus sequential targeted drug delivery based on RGD and TAT peptides co-conjugated MSNs for effective cancer therapy. (A) CLSM images and line-scanning profiles of fluorescence intensity for HeLa cells incubated with (a1) free DOX, (a2) DOX@MSNs, (a3) DOX@MSNs-RGD, (a4) DOX@MSNs-TAT, and (a5) DOX@MSNs-RGD/TAT. (B) Effects of different groups on the growth of HeLa cancer xenografts. (C) Photographs of the mice taken before (day 0) and after 10 and 17 days of chemotherapy with different treatments. Adapted and modified with permission from ref 130. Copyright 2014 WILEY-VCH. To endow nanocarriers with tumor recognition capability and fulfill the requirement of system administration, Shi’s group reported tumor-targeting peptide RGD and TAT co-functionalized ultrasmall (30 nm) MSNs for vasculature-to-cell membrane-to-nucleus-targeted DOX delivery


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(Figure 4).130 The facile prepared nanosystem can first reach tumor vasculature, and then target the integrin αvβ3 on the cell membrane. After entering cancer cells, the nanosystem can further enter the nucleus under the direction of TAT (Figure 4A). This highly dispersed DOX loaded nanosystem exhibited 98.6% tumor growth inhibition rate during in vivo experiments (Figure 4BC). By introducing magnetic guidance performance, Qu et al. reported a Fe3O4 based triple targeted theranostic system.137 MSN encapsulated Fe3O4 (FMSN) was functionalized with TAT, and the positive charge of TAT was subsequently protected by citraconic anhydride (Cit) and folate (FA) modified charge reversible chitosan (FA-CS-Cit). After intravenously administration (i.v.), these nanoparticles could first accumulate in the tumor site under the guidance of local magnetic field (stage I). Subsequently, the FMSN-TAT/FA-CS-Cit nanoparticles could enter cancer cells under FA receptor mediated endocytosis (stage II). Due to the acid sensitivity of citraconic amides, the protective moiety detached from the FMSN-TAT in lysosomal environments, and the re-exposed TAT finally directed the nuclear targeted delivery (stage III). Anticancer drug CPT could be delivered into the nucleus of cancer cell more effectively, thereby higher therapeutic index and fewer side effects were demonstrated with this smart nanosystem. Moreover, FMSN-TAT/FA-CSCit nanoparticles were used as MRI guided therapy because Fe3O4 nanoparticles are superparamagnetic. Apart from the surface charge, the size distribution of nanoparticles is another key point closely associated with the pharmaceutical parameters of nano-drugs. Since nanoparticles with larger size (~100 nm) are beneficial for long-term circulation and tumor accumulation, while smaller particles are more penetrable in cancer tissue/cells, developing size reducible smart systems is beneficial for in vivo cancer therapy. Huang et al. reported a nanovehicle with stepwise size reduction and


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on-demand NLS exposure for systemic delivering drugs into nucleus.142 The large sized nanoparticles (55 nm) were facile assembled from cationic and charge reversal anionic N-(2hydroxypropyl) methacrylamide (HPMA) polymer. The anti-cancer drug DOX and dualfunctional peptide R8NLS (cell-penetrating peptide (R8) and NLS tandem fused peptide) conjugate was connected with cationic HPMA via hydrazone bonds. Benefiting from their appropriate size and surface charge, these nanovehicles possess long-time circulation and enhanced tumor accumulation. After reached tumor tissues, the mild acidic tumor microenvironments caused the disassembly of these NPs into smaller conjugates (10 nm) through charge reversal, the exposed cationic peptides guaranteed enhanced cellular uptake rate. In the endo/lysosomes, these copolymers could release the drug-peptide conjugates owing to the acidic sensitivity of hydrazone bonds and thus facilitated the final intra-nuclear drug transferring. 4.5fold drug accumulation enhancement and higher antitumor efficiency were achieved with this smart drug delivery system. In addition to using NLS peptides152,154,155 (TAT, SV40 large T antigen, oligo-L-lysine and so on) as nuclear targeting ligands, many other strategies have been explored to enhance the intranuclear accumulation of chemotherapeutic drugs.105,107 Yang and co-workers reported a supramolecular drug self-assembly nanosystems for enhanced nuclear-targeted delivery.104 The complexes assembled from negatively charged HCPT-peptide (HP) amphiphile and positively charged cisplatin showed different morphology under different ratios: long nanofibers like complex I was assembled in 1 equivalent of cisplatin while nanoparticle like complex II was prepared in 1.5 equivalent of cisplatin. The cellular membrane barrier was subtly broken by the assemblies due to the formation of nanostructures, while the surface charge of the nanoformulations accelerated the intra-nuclear accumulation of two chemotherapy drugs.


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Therefore, synergistic effects between nanostructures and surface charges rendered the complexes with enhanced drug release kinetics and significantly enhanced the intra-nuclear availability of the chemotherapeutic drugs, which is like the “Trojan Horse” to deliver fighting soldiers (anticancer drugs) into the castle by penetrating the walls (plasma membranes and nuclear envelope). Wu et al. recently demonstrated 1O2 as a novel nucleus envelope opening agent (Figure 5A).138 PEG and rose Bengal (RB) co-functionalized polyhedral oligomeric silsesquioxane (POSS) could self-assembled into nano-photosensitizers (PPR NPs). These nanoparticles first located in the acidic lysosomes after entered A549 cells. Under white light irradiation, the generation of 1O2 accelerated the lysosomal membrane disruption and photosensitizer release. Continuous laser irradiation (2 mW/cm2, 3 min) resulted in the oxidation of the nuclear membranes, accelerating the intra-nuclear photosensitizer accumulation. Molecular agents (10-hydroxycamptothecine, docetaxel and DiD) and inorganic nanomaterials (Prussian blue and gold nanorods) were all successfully delivered into the nuclei with this platform (Figure 5B-C). This method opened new avenue for designing nucleus-targeted drug delivery systems and would inspire more therapeutic systems.

Figure 5. (A) Schematic illustration of the pH-responsive and light-triggered nucleus-targeted delivery. (B) CLSM images of A549 cells stained by Hoechst 33342 after incubation with PPR


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NPs (3 μM RB) for 2 h before and after white light irradiation. Scale bars = 10 μm. (C) The corresponding fluorescence intensity profiles of the areas marked by white lines in the confocal images in B. The green-shaded areas indicate the nuclear regions. Adapted and modified with permission from ref 138. Copyright 2018 American Chemical Society. 2.2 Nucleus-targeted photothermal agents Photothermal therapy (PTT), as an emerging cancer treatment modality, has been clinically employed for cancer treatment.43,44,140 The working mechanism of PTT is to induce heat damage in cancer cells through the hyperthermia generated from photothermal conversion agents.156-161 Benefiting from the employment of light, PTT undergoes high spatio-temporal controllability and good repeatability.158-161 However, the cancer cells may rapidly produce large amount of heat shock proteins to enhance their thermal resistant capability.162,163 As a result, long-term and high power density laser irradiation become essential to completely eliminate tumor tissue, which inevitably causes serious side effects to normal tissues due to the heat diffusion. To overcome this “Achilles’ Heel” of PTT, nucleus-targeted PTT has become an alternative modality. Nucleustargeted PTT can in situ denaturalize a large quantity of important enzymes and interdict the cancer proliferation, avoiding the requirement of long irradiation time or high laser power density.118 Vo-Dinh et al. reported the preparation of TAT functionalized gold nanostars for nucleustargeted PTT in vitro.118 Experiments revealed that the gold nanostars specifically accumulated in the nuclear region. Under ultra-low density (0.2 W/cm2, 3 min) laser irradiation, BT549 breast cancer cells were obviously eliminated, while the eliminating efficiency of non-targeted groups were insufficient under the same condition. This report demonstrated nucleus-targeted PTT as a novel therapeutic strategy for enhancing the efficiency of PTT.


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Shi et al. reported the TAT functionalized gold nanorods (GNRs) as PTT agents for cancer therapy under ultralow energy intensity irradiation (Figure 6A-B).128 In vivo experiments revealed the nucleus-targeted GNRs significantly inhibited the growth of xenografted HeLa tumor under 0.2 W/cm2 light treatment for 5 min even though mild temperature increment was detected in the tumor region. The PTT efficiency was comparable to non-TAT modified GNRs (GNRs-NLS) irradiated with a high power density of 2 W/cm2 (Figure 6C-D). This work proved the great promise of nucleus-targeted therapy—it can eliminate malignant tumor under faint laser irradiation, with a density even below the maximal permissible exposure of skin. Besides gold nanomaterials, Fe3O4 has also been investigated for nucleus-targeted PTT. Yang et al. reported the transferrin and TAT co-functionalized Fe3O4 (IONP-20-TAT-Tf) for nucleustargeted PTT.139 Benefiting from the admirable photo-thermal conversion efficiency (about 37%) and 45-fold higher intra-nuclear accumulation, the reported monodispersed nanoparticles effectively ablated tumor xenograft under NIR irradiation (3 W/cm2, 5 min). Meanwhile, the Cy7 modified IONPs are promising candidates for MRI and near infra-red fluorescence imaging.

Figure 6. Schematic illustration of the (A) preparation and (B) nucleus-targeted photothermal therapy of GNRs-NLS. (C) Tumor growth curves of mice after different treatments during PTT


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period. (D) Tumor weights of mice in different groups in 15 days of PTT. Schematic Illustration of the (E) synthesis of the CuS@MSN-TAT-RGD NPs and (F) in vivo tumor recurrence-targeted therapy. (G) Photographs of nude mice tumor recurrence with different treatments after tumor resection. Adapted and modified with permission from refs 128 and 140, respectively. Copyright 2017 American Chemical Society and 2018 American Chemical Society. Our group reported nucleus-targeted PTT as a promising strategy for preventing tumor recurrence (Figure 6E-G).140 CuS nanoparticles were employed as the photothermal agent due to its easy preparation, good biocompatibility, high NIR adsorption and molar extinction efficiency. After coating with amino-functionalized MSN layer, dual-targeted CuS@MSN-TAT-RGD can be obtained via further functionalization of TAT and RGD through EDC/NHS coupling reaction. Confocal experiments indicated the nanoparticles effectively accumulated in the nucleus of cancer cells under the guidance of TAT, which ensured the high anticancer efficiency. In vivo fluorescence and photoacoustic imaging experiments revealed the RGD functionalization was a beneficial step for boosting the tumor targeting efficiency of the photothermal agents. As a result, such dual-targeted CuS nano-agent was employed to eliminate the tumor completely with onetime treatment (1.5 W/cm2, 5 min), and also was successfully employed for preventing postoperative recurrence due to their superiority in destroying cancer cell nucleus function. 2.3 Nucleus-targeted photosensitizers Nucleus-targeted photodynamic therapy (PDT) is also promising for highly efficient cancer treatment.122,141,164 The intrinsic mechanism of PDT is that photosensitizers (PSs) can be excited by light with specific wavelength and the excited PSs could transfer energy to the biomolecules, H2O or oxygen molecules in the ground state, denaturalizing bio-species or generating highly reactive oxygen species (O2•−, 1O2, •OH, etc.) to further hamper cellular function.165-167


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Unfortunately, the short diffusion distance and lifespan of ROS or excited PSs, hypoxia and reductive tumor microenvironments restricted the direct damage of critical biomolecules in cancer cells during PDT, resulting in unsatisfied therapy efficiency and requirement of repeated treatment.168 Directly delivering PSs into nucleus offers extraordinary superiority for PDT, which is beneficial for overcoming drug resistance, hypoxia and recurrence due to the direct dysfunction of nucleus with abundant ROS is a more powerful cancer therapy strategy. Ce6 is one of the most investigated PSs in PDT, it can generate 1O2 under red light irradiation in the existence of O2. However, the weak solubility, poor in vivo distribution of Ce6 and analogous molecular PSs sparked the interest of finding novel carriers for boosting the tumor selectivity and PDT efficiency. Just like traditional chemotherapeutic drugs, molecular PSs could also be expelled out by P-gp from the drug resistant cancer cells.122 Thus driving molecular PSs into nucleus has emerged as an alternative strategy for enhanced PDT effects.115 On the basis of previous work, Shi et al. reported the nucleus-targeted delivery of Ce6 with MSNs.141 MSNs were employed as the vehicles owing to their properties of easy preparation, high morphology, size and surface area controllability, ideal physiochemical stability and biocompatibility. The TAT and RGD cofunctionalized 30 nm MSNs showed admirable vasculature to nuclear targeting capacity, and significantly potentiated the PDT efficiency due to the in situ intra-nuclear ROS generation and DNA destroy. Extraordinary high tumor inhibition efficiency under ultralow power density (0.02 W/cm2) irradiation of 5 min was demonstrated, which also indicated the nucleus-targeted PDT systems had potential for deep-seated tumor treatment. In 2016, Han and co-workers demonstrated an amphiphilic chimeric peptide (PAPP-DMA) for tumor microenvironment activated nucleus-targeted PDT (Figure 7A-B).164 The peptide was constructed from alkylated protoporphyrin IX, PEG and 2,3-dimethylmaleic anhydride (DMA)


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shielded NLS peptide PKKKRKV. The amphiphilic property enabled the peptides self-assembled into nanoparticles smaller than 200 nm. The zeta potential of assembled nanoparticles was −19.1 mV after DMA shielding, which is beneficial for enhancing the blood circulation period. In the acidic tumor microenvironment, DMA detached from the PKKKRKV, resulted in the surface charge of nanoassemblies reversion, which enhanced cancer cell internalization, and realized intranuclear photosensitizer accumulation after the re-exposure of cationic NLS peptide. Enhanced cancer PDT efficiencies were demonstrated both in vivo (200 mW/cm2, 10 min) and in vitro (10 mW/cm2, 2 min). (Figure 7C-E)

Figure 7. Schematic illustration of (A) tumor and intranuclear delivery of photosensitizer for enhanced PDT and (B) the synthesis of PAPP-DMA and the detachment of DMA in the acidic environment. (C) Relative tumor volume after different treatments. (D) Post-sacrifice tumor images at the 11th day. (E) Average tumor weight at the 11th day. Adapted and modified with permission from ref 164. Copyright 2016 WILEY-VCH. Since molecular PSs often suffer from efflux effects caused by the over expressed P-gp, nanoPSs should offer more opportunities for highly efficient PDT. Recently, our group reported a nucleus-targeted NIR responsive dual-PS with multiple ROS generation capacity for tumor


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treatment (Figure 8A-D).122 Molecular PS Ce6 was decorated onto the surface of pre-synthesized nanoscale core/shell upconversion@TiO2. Then nucleus-targeted peptide TAT was further decorated onto the surface of the dual-PS to obtain the nucleus-targetable UCNPs@TiO2-Ce6TAT. The successful FRET effects between UCNPs and TiO2 as well as Ce6 resulted in multiple ROS (O2•−, 1O2 and •OH) generation under 980 nm laser irradiation. Accurate nuclear location and efficient 980 nm laser triggered nuclear DNA damage was realized with UCNPs@TiO2-Ce6-TAT (Figure 8E-F). In vivo tests (1 W/cm2, 5 min) revealed the nucleus-targeted dual-PS could be used as a novel candidate for the treatment of drug resistant tumor (Figure 8G-H).

Figure 8. (A) Schematic illustration of the synthetic process of UCNPs@TiO2-Ce6-TAT, multiple ROS generation under NIR laser excitation and inducing DNA double strand breaks. High resolution TEM images of (B) oil acid coated UCNPs; (C) UCNPs; (D) UCNPs@TiO2; Scale bars are 25 nm. (E) Colocalization images of UCNPs@TiO2-Ce6-TAT and the nuclei. (F) The quantification of fluorescence intensity of the line scanning profiles of the corresponding confocal


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images in E. (G) Photographs of the xenograft MCF-7/Dox tumor mice taken before treatment (0 days) and at 14 days with different treatments: control, UCNPs@TiO2-Ce6, UCNPs@TiO2-TAT, and UCNPs@TiO2-Ce6-TAT with irradiation for 5 min in all groups; H) Tumor growth curves of different treatment groups. Adapted and modified with permission from ref 122. Copyright 2016 Royal Society of Chemistry. 2.4 Nucleus-targeted gene silence systems Direct silencing of pathogenic genes or introducing therapeutic genes into cells, which were called gene therapy, have become a popular strategy for treating series of major disease including cancer in recent years.169 Gene therapy can be divided into the transcriptional level and the posttranscriptional level. Transcriptional level involves knocking down the DNA in the nucleus to stop the expression of diseased-related proteins, post-transcriptional level is to silence mRNA, siRNA or microRNA in the cytoplasm.155,169 Because of the easy degradation of therapeutic genes in cytoplasm, nucleus-targeted gene silencing systems should be better choices due its advantages of long-term silencing effects and avoidance of repetitive administration of post-transcriptional gene silencing agents. However, the major question regarding nucleus-targeted gene therapy is the absence of appropriate vehicles which could be capable of overcoming several intracellular barriers and deliver enough genes into nucleus. In 2014, Shi et al. reported the nucleus-targeted delivery of plasmid DNA with a micelle/precursor

co-templating

assembly

method

prepared

mesoporous

organosilica

nanoparticles (MONs) (Figure 9A-B).170 Benefiting from their large pore volume and small size, the MONs exhibited signiﬁcantly reduced hemolytic effect and improved biocompatibility, which were used for highly efﬁcient intra-nuclear gene delivery after surface modified with PEI and TAT (MONs-PTAT). Owing to the good plasmid DNA binding and protecting capacity, the transfection


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efficiency of the dual-modified carriers was as high as 36.5%, which was significantly higher than PEI (13.5%) or TAT (4.97%) mono-functionalized groups. The successful construction of organicinorganic hybrid nanoparticles with controllable structure and composition provided new opportunities to design new platforms for nucleus-targeted gene therapy. Recently, our group demonstrated nucleus-targeted delivery of siRNA with TAT modified 13 nm gold nanoparticles (AuNPs) to directly initiate the cancer associated DNA methylation.155 The nucleus-targeted gene delivery system was suggested could deliver siRNA into the nucleus of diverse cell lines, including MCF-7, HeLa and HepG2. The siRNA dramatically interacted with the promoter of cancer related Thymidine Kinase 1 (TK1), and long-term gene silencing was achieved due to the efficient suppression of the TK1 protein and TK1 mRNA expression. The silencing time was tested to be longer than 30 days, which enormously inhibited the in vivo tumor formation.

Figure 9. Schematic illustration of (A) the synthesis process and (B) the nucleus-targeted gene delivery of the MONs-PTAT@pDNA. Adapted and modified with permission from ref

170.

Copyright 2014 WILEY-VCH.


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Figure 10. Schematic diagram of (A) the synthesis process of LACP and (B) laser-enhanced knock-outs of targeted genes by LACP in A375 cells. (C) Sizes of tumors treated by different CP formulations. (D) Weights of tumors treated by different CP formulations. Adapted and modified with permission from ref 143. Copyright 2018 WILEY-VCH. CRISPR systems are recently emerging gene editing techniques, which have been reported to be useful toolbox for a series of genetic diseases. However, the intracellular transfection efficiency as well as specificity are main challenges for their practical application. Compared to virus vehicles, nano-transfection agents hold virtues of easy preparation, high designability and controllability. Jiang’s group143 (Figure 10A-B) reported laser controlled nucleus-targeted delivery of Cas9-sgPlk-1 plasmids (CP). 20 nm cationic gold nanoparticles (AuNPs) were prepared via decorating AuNPs with TAT peptides, which were employed to condense CP through electrostatic interaction. After further encapsulation with lipids, multi-AuNPs-lipid complex (LACP) with good solubility was obtained. There are 4-15 AuNPs in each LACP, the plasmid encapsulation efficiency was 97%, under 514 nm laser irradiation for 20 min (24 mW/cm2), 79.4% CP was


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released due to the photothermal conversion effect of the Au core, the released CP could enter the nucleus under TAT guiding. By virtue of the enhanced intracellular uptake and controlled release manner, LACP exerted enhanced antitumor effect during the intratumoral injection (i.t.) experiments (Figure 10C-D). 2.5 Nucleus-targeted combined therapy systems Rational combination of two or more treating modality is helpful to potentiate the therapy index in many resistant cancers. Nucleus-targeted combined therapies have also been reported recently.144,147,148,171 Hwang et al. reported the simultaneous nucleus-targeted PDT and gene delivery with NIR responsive gold clusters.147 The TAT modified gold clusters (TAT peptide-Au NCs) possessed admirable photostability, biocompatibility and nucleus-targeting capacity. Compared to commercial LP2000 liposome gene carrier, 3.2-fold higher gene transfection efficiency was demonstrated owing to the enhanced cellular uptake and nucleus accumulation. TAT peptideAu NCs were also demonstrated as novel photosensitizers because they could cause intra-nuclear DNA damage by the 980 nm laser induced ROS (500 mW/cm2, 30 min). Therefore, TAT peptideAu NCs was a powerful platform for imaging guided nucleus targeted gene and PDT synergistic therapy. It is well known that many tumors are radiotherapy (RT) resistant due to their intrinsic hypoxia environments, and some cancer cells could stay at RT-insensitive phase (such as G1 and S phase). Therefore, delivering radiosensitizers into the nucleuses of cancer cells have intrinsic superiority. Further combination of nucleus-targeted RT with other treatment modality may cause extra efficiency. Shi’s group realized the nuclear targeted combined chemo-radio therapy with sub 50 nm yolk-shell structured upconversion-mesoporous silica (Figure 11A).144 Chemotherapy drug Mitomycin C, a type of DNA toxin, was loaded into the rattle-like nanoparticles and served as the


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radiosenstitizer. Such nucleus-targeted chemo-radio therapy platform significantly enhanced the RT efficiency (8 Gy, 5 min) compared to monotherapy strategy or cytoplasmic localized combined therapy (Figure 11B-C). As the mechanisms of RT and PDT are both ROS inducing biomolecules damage, combining nucleus-targeted PDT and RT may also reduce the radio-dosage and irradiation time. Shi’s group further demonstrated the nucleus-targeted combined photodynamic-radio therapy with a UCNPs based core-shell nanocomposite (Figure 11D).171 By rational covalently coating/separation of radiosenstizer and photosensitizer on the out silica layers of UCNPs and further PEG/TAT functionalization, nucleus-targeted UCSPs-PEG/TAT nanoparticles were obtained to generate abundant ROS under either NIR or X-ray irradiation. As a result, synergistic enhancement effect was observed in the radioresistant HT-1080 cells. Significant tumor growth suppress effect was demonstrated (6 Gy, 5 min for RT; 1.5 W/cm2, 20 min for PDT), which further verified the significant potential of nucleus-targeted combination therapy (Figure 11E).


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Figure 11. (A) Schematic illustration of nucleus-targeted chemo combined radiotherapy. (B) Tumor growth curves of MCF-7 tumor-bearing mice over a period of half a month after different treatments. (C) Relative MCF-7 tumor volumes of different groups after different treatments. Adapted and modified with permission from ref 144. Copyright 2015 Royal Society of Chemistry. (D) Schematic illustration of the nucleus-targeted PDT-RT combined therapy using UCSPsPEG/TAT. (E) Relative tumor volumes of HT-1080 tumor-bearing mice during half a month after different treatments. Adapted and modified with permission from ref 171. Copyright 2015 Elsevier Ltd. 3. Mitochondria-targeted therapy Mitochondrion is a two-layer membrane-coated organelle with the diameter of 0.5-1.0 μm.84 As the “power house” of eukaryotic cells, it takes charge of energy production, electron transport, calcium metabolism, ROS generation and even immunity regulation.172-174 Targeted delivery of therapeutic drugs to mitochondria and efficiently regulating mitochondrial function may offer great potentials for efficient tumor treatment, which should have diverse advantages over traditional cytoplasmic drug delivery modality on account of the extremely high biological significance of mitochondria. Interestingly, mitochondria possess negative potential because the protons intra mitochondria are pumped into the mitochondrial intermembrane space, and cancer cells usually undergo stronger mitochondrial transmembrane potential (-180 mV).173,175 Therefore, lipophilic molecular or nanodrugs with delocalized cationic structures may effectively accumulate into mitochondria.87 Some peptides or functional groups with high affinity to the mitochondrial protein have also been used for vehicle modification to deliver specific drugs into the mitochondria. (Table 2) In this section, we will introduce the recent advances of mitochondria-


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targeted therapeutic agents for chemotherapy, PDT, PTT, RT, and combined therapy with enhanced therapeutic efficiency. Table 2. Typical nanomaterials for mitochondria-targeted therapy. Therapy modality

Nanomaterials

Cell type

Tumor model


Treatment times

Treatment period

Refs

Chemotherapy



HeLa, MCF-7









175

Mitochondrial transmembrane potential mediated accumulation



Drug-resistant A549/cDDP

drug-resistant A549/cDDP

i.v.

5

26

176

TPP

GSH triggered TPP exposure

5.22

MCF-7

MCF-7

i.v.

1

18

177

UCNPs@TiO2

TPP




MCF-7

MCF-7

i.t.

1

14

178

PS-peptide NPs

MLS

ROS accelerated cellular internalization, cationic hydrophobic peptide mediated targeting

40

HeLa

H22

i.v.

2

10

179

AIE dots

FA, TPP

Receptor mediated targeting, mitochondrial transmembrane potential mediated accumulation

10

MCF-7









180

Fe3O4

TPP




HeLa

HeLa

i.v.

1

21

181

Photothermal molecule loaded F127 NPs

Biotin, TPP

Receptor mediated targeting, mitochondrial transmembrane potential mediated accumulation



4T1

4T1

i.v.

1

14

182

RT

TiO2–Au

TPP




MCF-7, 4T1

MCF-7, 4T1

i.t.

1

14

183

Combined therapy

MOFs

Ru(bpy)32+


20.13 ± 8.58 µM

MC38

MC38

i.v.

1

22

184

PDT

PTT

Targeting ligands


Nanodiamonds

FA, MLS peptide

Receptor and protein mediated targeting

Liposome

TPP

PLGA

IC50 (μg/mL)

3.1 Mitochondria-targeted chemotherapeutic agents As mentioned above, most chemotherapeutic drugs are DNA replication associated toxins. It is well known that mitochondria also contain DNA (mtDNA) and these double-stranded circular DNA molecules take charge of the synthesis of tens of proteins.185 Thus, mitochondria should be another critical target for chemotherapy, and delivering DNA toxins into mitochondria is another wise choice toward enhanced chemotherapy.119,186-194 Platinum based drugs are famous DNA crosslinker, which can interact with DNA effectively and stop the proliferation of mammalian cells. However, the advanced DNA repair systems in nucleus (nucleotide excision repair, NEP) can cause cancer metastasis and drug resistance during


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traditional chemotherapy.195 In comparison, the mtDNA can be destroyed by platinum based drugs more easily due to the lack of NEP system in mitochondria. Transferring DNA toxins into the mitochondria has opened a new avenue for potentiated cancer therapy. In 2014, Dhar and coworkers constructed a mitochondria-targeted platinum prodrug delivery system for detouring the intra-nuclear DNA repair (Figure 12A-B).195 The lipophilic cationic triphenylphosphonium (TPP) functionalization of cisplatin prodrug Platin-M was conducted by the strain-promoted alkyne-azide cycloaddition reaction, making the prodrugs able to diffuse into the mitochondria under the driving of transmembrane potential. To further achieve in vivo application, terminal TPP functionalized decomposable poly (lactic-co-glycolic acid)-block-polyethyleneglycol was prepared as the delivery vehicle. The optimized drug loading nanoparticles possessed long blood circulation time and high brain-penetrating properties, thus the nanoparticles could deliver and release abundant Platin-M into the mitochondria of neuroblastoma cells (Figure 12C-F). About 17-fold higher anticancer activity toward cisplatin resistant cells could be realized by this nanomedicine compared to the original cisplatin, suggesting that the targeted delivery of DNA toxins into the mitochondria is rather favorable for drug resistant cancer therapy application.

Figure 12. (A) Schematic diagram for mitochondria-targeted delivery of cisplatin prodrug using a targeted NP and the mechanism of action. (B) Synthesis of mitochondria-targeted Pt(IV) prodrug Platin-M. (C-F) Pt concentration variation in plasma and organs following the i.v. administration


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of different NPs to male rats. Adapted and modified with permission from ref 195. Copyright 2014 National Academy of Sciences. Another important first-line chemotherapeutic drug, DOX, has also been reported to be significantly potentiated when delivered into mitochondria. Direct functionalization of chemotherapeutic drugs might compromise the bioactivity, thus novel nanovehicles are more optimal. Lo’s group reported the specific delivery of DOX into the mitochondria of cancer cells via functionalized nanodiamonds.175 The FA and mitochondria localizing sequence (MLS) peptides co-functionalized nanodiamonds possessed dual targeting capability. They first distinguished the cancer cells from normal cells based on the different expression levels of FA receptor. Subsequently these nanodiamonds could accumulate into the mitochondria under the guidance of MLS. With this system, the cellular drug uptake rate was dramatically increased, and the drug resistant MCF-7 cells were successfully killed owing to the enhanced mitochondrial DOX accumulation. Besides DNA toxins, many other chemotherapeutic drugs also take mitochondria as their targets, such as paclitaxel (PTX), a hydrophobic drug extracted from western taxus brevifolia. Lu et al. reported a mitochondria-targeted delivery system based on PTX liposomes.176 Mitochondriatargetable PTX liposomes were prepared via anchoring the mitochondria-targeted macromolecule TPGS1000-TPP to the liposomes and used for treating drug-resistant lung cancer. Owing to the suitable size distribution, prolonged blood circulation time, high cancer cell uptake rate and mitochondrial-specific PTX accumulation, the delivery system successfully induced the apoptosis of drug-resistant lung cancer through the activation of the mitochondrial apoptosis pathways ( including release of the cytochrome C, initiate of the cascade of caspase-9 and caspase-3 reactions,


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activation of the pro-apoptotic Bax and Bid proteins, and suppression of the anti-apoptotic Bcl-2 protein). To further improve the in vivo performances of liposomes, Gu and co-workers reported the dualfunctional liposomes for tumor pH/mitochondria-dual-targeted PTX delivery (Figure 13).196 DMA modified peptide

D[KLAKLAK]2

(KLA) was combined with 1, 2-distearoyl-sn-glycero-3-

phosphoethanolamine (DSPE) to obtain the dual-functional lipid (DKD). The DKD was further mixed with commercial lipids to construct the dual-functional liposomes. The surface charge of these liposomes was negative under healthy extracellular pH (7.4), which could reduce the protein adsorption and prolong the blood circulation time. Then the surface charge could be converted into positive in acidic tumor microenvironments due to the detachment of DMA (Figure 13A-B), facilitating the cancer cellular uptake. After entering lysosomes, the KLA peptide complete exposed and guided the mitochondrial PTX accumulation as well as subsequent drug release. These features endowed the smart liposomes (DKD/PTX-Lip) with high tumor growth inhibition (86.7%) in the drug-resistant lung cancer cells xenografted nude mice (Figure 13C-D), further proving the significance of mitochondria-targeted therapy.

Figure 13. Left: illustration of dual-functional liposome with pH response to the tumor microenvironment and mitochondria-targeted anticancer drug delivery. (A) Size distribution of


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PTX-loaded DKD-Lip (DKD/PTX-Lip). (B) Zeta potential of DKD-Lips at different pH values within 12 h. (C) Tumor volume of mice after different treatments. (D) Tumor growth inhibition rates of the treatment groups. Adapted and modified with permission from ref 196. Copyright 2015 Elsevier Ltd. Redox responsive nanocarrier has been reported by Huang et al. for mitochondria-targeted drug delivery.177 FDA approved PLGA was used as the carrier of PTX, and TPP-modified amphiphilic polymer (C18-PEG2000-TPP) was selected as the mitochondria targeting group. To shield the positive charge of cationic TPP, disulfide bond connected amphiphilic polymer DLPE-S-SmPEG4000 was employed as the protective moiety, which could completely shield the positive charge of TPP and enable the drug delivery system to be injected in vivo. In the cytoplasm of cancer cells, TPP was re-exposed due to the cleavage of disulfide bond and subsequent detachment of PEG4000, which made the carriers capable of accumulating into the mitochondria and resulted in enhanced mitochondrial PTX accumulation. This system effectively activated the apoptosis pathway of MCF-7 cells and higher in vivo tumor suppression efficiency was realized compared to the non-responsive group. 3.2 Mitochondria-targeted photosensitizers Mitochondria-targeted PSs delivery is another novel strategy for boosting the PDT efficiency. Mitochondria are the main places for ROS production, which hold a series of regulation systems for maintaining cancer cellular homeostasis. Mitochondrial ROS overexpression may disrupt the dynamic balance of mitochondrial microenvironments and cause serious mitochondrial dysfunction due to the oxidation stress.197 Mitochondria-targeted ROS generation is therefore highly attractive for enhanced cancer treatment owing to the potential in reducing the photo/PSs dosage and side effects.178,198 Up to now, a variety of PSs with mitochondria-localization capacity


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have been designed and synthesized for enhanced PDT, which could be roughly divided as porphyrins, transitional-metals, aggregation-induced emission dyes and others.199-209

Figure 14. Schematic illustration of (A) the structure of the nano PS and ROS generation and (B) the NIR triggered nanophotosensitizer inducing domino effect on mitochondrial ROS burst for cancer therapy. Cell viability of MCF-7cells incubated with (C) UCNPs@TiO2-TPP and (D) UCNPs@TiO2 plus with 980 nm laser irradiation for different time. (E) Tumor growth curves and (F) mice body weight curves of different groups during 14 days. Adapted and modified with permission from ref 178. Copyright 2015 American Chemical Society. In 2015, our group reported the titanium dioxide-coated UCNPs (UCNPs@TiO2-TPP) for mitochondria-targeted PDT (Figure 14A-B).178 The nano-PSs possessed uniform size distribution and upconversion feature. Under 980 nm laser irradiation, it could effectively convert NIR light into UV light and activated TiO2 to generate abundant O2•−. Interestingly, the mitochondriatargeting capacity of UCNPs@TiO2-TPP make it rather favorable for highly efficient PDT due to


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the induction of domino effect on ROS burst. When the mitochondrial ROS concentration reached a threshold value, the mitochondrial function could be disrupted, and triggered continuous ROS generation, thus further resulted in the activation of apoptosis pathway (including the reduction of mitochondrial membrane potential, release of cytochrome C, activation of caspase-3 and caspase-7 and so on) (Figure 14C-D). Upon 90 s NIR light (3 W/cm2) irradiation, the tumor growth of treating group was completely suppressed, confirmed mitochondria-targeting as a powerful tool for highly efficient cancer treatment (Figure 14E-F). Porphyrin and its derivatives are famous PSs suffering from poor solubility, easy photobleaching, and low efficiency. Mitochondria-targeted nanocarriers offered new chance to the PDT efficiency of porphyrin based PSs. Wu et al. reported a dual-targeted strategy to enhance the PDT efficiency of cancer.210 Cationic porphyrin derivative (MitoTPP) was effectively loaded onto the FA functionalized PEG modified nanographene oxide via π-π staking. In this PDT system, the fluorescence of MitoTPP was quenched initially and almost no 1O2 could be detected during laser irradiation, which reduced the potential side effects of the PSs. After entering the FA receptor overexpressed HeLa cells, MitoTPP could be released in the acidic lysosomal microenvironments and subsequently accumulated into the mitochondria under the guidance of TPP. Under light irradiation (10 mW/cm2, 30 min), in situ accumulation of 1O2 resulted in remarkable cancer cell apoptosis due to the induction of mitochondrial oxidation damage. Zhang’s group demonstrated a self-assembled system (PPK) for mitochondria-targeted PDT (Figure 15).179 Protoporphyrin IX (PpIX) was covalently linked with an amphiphilic peptide (KLAKLAK)2 (a mitochondria-targeted proapoptosis peptide) through a short PEG linker, the Ce6 functionalized peptides further self-assembled into spherical nanoparticles with narrow size distribution and good solubility (Figure 15A-B). These nanoparticles possessed photochemical


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internalization (PCI) feature under short light irradiation: they showed enhanced cell penetrating capacity due to the short-time laser irradiation resulted ROS−induced lipid peroxidation. After 6 min laser irradiation, the PSs entered cancer cells under ROS assistance and accumulated in the mitochondria effectively. More ROS generated here under 18 min light irradiation and resulted in cancer cell apoptosis. MTT assay revealed the cancer inhibition efficiency of the PSs combined with two steps (6+18 min) laser irradiation was higher than one-step 24 min irradiation. The system achieved higher in vivo anticancer efficiency owing to the synergetic mitochondrial-targeted PDT (220 mW/cm2, 20 min) and proapoptosis effect (Figure 15C-D).

Figure 15. Left: Chemical structure of PPK and schematic diagram of the mitochondria-targeted self-delivering process. (A) Hydrodynamic size and (B) TEM image of PPK in DI water. (C) Relative tumor volume after post-treatment. (D) The average tumor weight at the 12th day after different treatments. Adapted and modified with permission from ref 179. Copyright 2015 WILEY-VCH. In 2016, a programmed supramolecular system was reported by Ji and co-workers.211 Ce6 modified β-Cyclodextrin (β-CD) interacted with the adamantine (Ad) terminated tri-blocked peptide (Ad-CGKRK-GFLG- EE-T7) and further self-assembled into well-defined nanostructures.


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T7 with highly affinity toward the cancer cell overexpressed transferrin receptor (TfR) endowed the nanosystem with high cancer cell uptake rate. Cathepsin B (CTSB) cleavable GFLG moiety and the mitochondria-targeted CGKRK peptide imposed the system responsive mitochondriatargeting capability. Therefore, higher PDT efficiency (IC50 = 0.9 mg L-1) was realized over nontargeted delivery systems, suggesting that the reported system can be used for highly efficient and specific cancer therapy. AIE-based PSs for mitochondria-targeted PDT have attracted increasing consideration recently, owing to their excellent photostability and the capability for overcoming aggregation-caused quenching phenomenon.207,212-215 Liu and Tang et al. reported an AIE dots for cancer cell-tomitochondria-targeted therapy.180 Dual-targeted AIE dots could be easily obtained by using lipidPEG as the encapsulation agent, FA and TPP as targeting group. The dual-targeted dots show enhanced PDT efficiency (100 mW/cm2, 10 min). The value of IC50 was 10 µg mL−1, which is lower than cellular or mitochondria-targeted nanoparticles owing to their higher mitochondrialaccumulation capability. By integrating TPP contained AIE based polymer with Tm3+ doped UCNPs, Gao et al. reported the first NIR activated mitochondria-targeted AIE based PDT system.212 The positive charge of this system was shielded by pH sensitive PEG layer (UCNP@PAIE-TPP-PEG) via benzoic imine bonds, which could avoid side effects caused by TPP. After entering cancer cells, the imine groups were split, and the UCNP@PAIE-TPP accumulated into mitochondria effectively. Under 980 nm laser irradiation (3W/cm2, 10 min), abundant ROS production resulted in mitochondrial ROS collapse as well as cancer cell apoptosis, suggesting that UCNP@PAIE-TPP-PEG is potential for enhanced in vivo cancer treatment (Figure 16 Left). Chao et al. reported the first example of AIEactive iridium(III) complexes (Ir1-Ir3) for mitochondria-targeted PDT (Figure 16 a-b).213 Ir1


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exhibits the most significant two-photon adsorption cross-sections (214 GM) and the most impressive lethality toward cancer cells, which make it an ideal candidate for highly efficient PDT (IC50 = 0.40 μM).

Figure 16. Left: schematic illustration for the pH responsive UCNP@PAIE-TPP-PEG NPs for mitochondria-targeted PDT. Adapted and modified with permission from ref 212. Copyright 2017 American Chemical Society. Right: (a) the structures of Ir1-Ir3. (b) Schematic illustration of mitochondria-targeted TPA-PDT with Ir1-Ir3. Adapted and modified with permission from ref 213. Copyright 2017 Royal Society of Chemistry. 3.3 Mitochondria-targeted photothermal agents In addition to chemotherapeutic drugs and ROS, mitochondria are also hypersensitive to heat. Mitochondria-targeted PTT can effectively reduce the activity of enzymes, disrupt the mitochondrial respiration, cause mitochondrial thermal damage, and further induce oxidation stress and activate mitochondrial apoptosis pathways. Therefore, design and preparation of mitochondria-targeted photothermal agents are promising for improving the tumor therapy efficiency, suppressing tumor growth and avoiding recurrence. In 2015, Kim et al. reported an iron oxide nanoparticle for mitochondria-targeted PTT.216 TPP coupled coumarin was surface functionalized onto iron oxide NPs via catechol group, yielding the


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mitochondria-targeted “nanoheater” (Mito-CIO). Confocal co-localization experiments revealed that Mito-CIO localized in mitochondria with a high Pearson’s coefficient (0.871), while the coumarin modified iron oxide (CIO) mainly located in the endoplasmic reticulum. Under 740 nm NIR irradiation (2W/cm2, 10 min), Mito-CIO induced higher in vivo therapy efficiency than nontargetable CIO, demonstrating the superiority of mitochondrial-targeted PTT. It is well known that NO is an important cellular signal molecule. Employing gas signal molecules (NO, CO, H2 and so on) for sensitized cancer therapy has been reported to be an alternative modality. In 2017, Liu et al. developed a Ru nitrosyl and TPP co-functionalized graphene quantum dots (N-GQDs@Ru-NO@TPP) for mitochondrial-targeted PTT.217 The TPP modification imposed the nanoplatform with ideal mitochondrial-targeting capability and the photothermal effect of GQDs ensured the 808 nm laser irradiation triggered NO release. Benefiting from the synergistic effect between NO sensitizing and mitochondria-targeted PTT, this nanoplatform exerted admirable tumor growth inhibition capability and the tumor could even be eradicated after single treatment (1.0 W/cm2, 10 min). Compared to nanomaterials, molecular photothermal agents with high photothermal conversion efficiency are also quite attractive, owing to their well-defined structure and performances. Mitochondria-targeted molecular photothermal agents may accelerate the clinical translation of mitochondria-targeted PTT. However, the in vivo PTT of the cationic photothermal agents are restricted due to their poor tumor targeting capabilities, thus efforts should be devoted to realize the mitochondria-targeted delivery.218 The first example of cancer cell-to-mitochondria-targeted photothermal agent was reported by our group (Figure 17A-B).182 A cyanine derived biotin and TPP co-functionalized photothermal agent was designed and synthesized. To improve the water solubility, FDA approved F127 was employed to encapsulate the photothermal agents to obtain


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the tumor-mitochondria-targeted photothermal nano agents (Bio-PPh3-PT). The photo-to-thermal conversion efficiency of the prepared photothermal molecule was 37.8%. In vitro experiments demonstrated that the dark toxicity of Bio-PPh3-PT was negligible while the phototoxicity remained high, mostly owing to the biocompatibility of organic small molecules as well as the thermal sensitivity of mitochondria. In vivo fluorescence and photoacoustic imaging experiments revealed the good tumor targeting capability (Figure 17C-E). More importantly, higher cancer treatment efficiency was demonstrated during in vivo anticancer therapy (0.5 W/cm2, 5 min) and no significant side effects can be detected (Figure 17F-H).

Figure 17. (A) Schematic illustration of the dual-targeted PTT. (B) The molecular structure of Bio-PPh3-PT. (C) In vivo fluorescence imaging of 4T1 tumor-bearing mice after i.v. injection of Bio-PPh3-PT or PT at different time points and (D) the related normalized fluorescence intensities. (E) Photoacoustic imaging of 4T1 tumor-bearing mice after i.v. injection of Bio-PPh3-PT. (F)


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Photographs of tumor-bearing mice with different treatments at day 1 and day 15. (G) Tumor growth curves and (H) the mice body weight curves of different groups. Adapted and modified with permission from ref 182. Copyright 2019 WILEY-VCH. 3.4 Mitochondria-targeted nano radio-sensitizers Clinically employed RT mainly use ionizing radiations to destroy the DNA and protein/enzymes of cancer cells to inhibit the growth of tumors. Nevertheless, the low tissue adsorption of tumor tissues toward radiations resulted the requirement of high energy and long-time radiation exposure, which usually resulted in serious side effects and limited therapeutic index.183 Moreover, chemotherapeutic drugs are frequently employed by doctors to ensure the elimination of cancer cells as more as possible, which usually cause extra burdens for cancer patients.219,220 In practice, cancer cells may stay in the RT insensitive phase, and the hypoxia tumor microenvironments may severely compromise the therapy efficiency. Therefore, it has sparked the interest of design and synthesis of radio-sensitizers, to enhance the radiation sensitivity of tumor tissues.219,220 The current methods for radio-sensitization including hypoxia relief, combination with other modality as well as radiation energy conversion enhancement with diverse sensitizers. Driving nano radiosensitizers into mitochondria is another wise choice toward enhanced cancer treatment. Recently, our group reported a mitochondria-targeted radio-sensitizer for triggering mitochondrial ROS burst with admirable RT efficiency (Figure 18).183 The ultra-small (3-5 nm) AuNPs modified 18 nm TiO2 showed enhanced O2•− productivity. After further modification with mitochondria-targeting ligand TPP, the obtained nano radio-sensitizer TiO2-Au-TPP NPs could effectively accumulate into the mitochondria. The mitochondria-specific ROS generation after Xray irradiation was observed and domino effect on ROS burst was demonstrated, which significantly potentiated the therapeutic effects of RT (Figure 18A-B). Upon one-time 6 Gy X-


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rays irradiation, MCF-7 tumor-baring nude mice as well as 4T1 tumor-baring Balb/c mice were effectively cured, suggesting that the mitochondria-targeted RT as an ultra-attractive cancer treatment modality (Figure 18C-E). High-Z element doping is another important strategy for improve the RT efficiency of nanomaterials. A mitochondria-targeted Gd-doped titania nanoparticles (TiO2(Gd)-TPP) was further developed by our group for enhanced cancer RT. Compared to the non-targeted group, the RT efficiency was effectively elevated by TiO2(Gd)-TPP owing to the generation of abundant ROS intra-mitochondria.221

Figure 18. Schematic illustration for (A) the preparation of the TiO2-Au-TPP NPs and (B) mitochondria-targeted RT with TiO2-Au-TPP NPs. Photographs of (C) the tumor bearing nude mice at 0 days and 14 days with different treatments. (D) The tumor growth curves and (E) body weight curves of different groups. Adapted and modified with permission from ref 183. Copyright 2018 Royal Society of Chemistry. 3.5 Mitochondria-targeted combined therapy systems


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Combining two or more treating modality is another bright pathway for further leveraging the therapeutic index of mitochondria-targeted cancer treatment, which could avoid the inherent disadvantages and limitations of single treatment modality. Therefore, many efforts have been devoted to mitochondria-targeted combined therapy to further improve the therapeutic index of advanced tumors. Up to now, mitochondria-targeted chemo-PTT, chemo-PDT, PTT-PDT, and trimodal therapy, have been investigated.90,96,97,145,181,184,215,222-235 Zhang et al. reported a gold nanostar (AuNS) based nanovehicle for chemo-PTT.229 Mitochondria-targeting pro-apoptotic peptide TPP-KLA, biocompatible PEG5000 and cationic peptide R8 were attached onto AuNS via Au-S bonds. Then the nanocomposites and DOX were co-encapsulated by the cellular targeting ligand, hyaluronic acid, yielding the multi-targeted nanodrug AuNS-pep/DOX@HA. AuNS-pep/DOX@HA effectively localized in the tumor site via EPR effect and CD44 receptor-mediated recognition. After entered cancer cells, HA was degraded by HAase and DOX was released. The AuNS further accumulated into the mitochondria and PTT was triggered under NIR irradiation (1 W/cm2, 5 min). Owing to the high photothermal conversion efficiency, mitochondrial hyperthermia blocked the drug efflux pathway due to the inhibition of energy generation. 97% of the drug retained in cancer cells after 22 h incubation, which was much higher than the control groups. PDT combined with chemotherapy is an interesting strategy to design subcellular organelle destructive systems for highly efficient cancer therapy. In 2017, Tan et al. reported a mitochondriatargeted prodrug (PNPS) for NIR imaging guided synergistic chemo-PDT.145 NPS, a mitochondria-targeted NIR fluorescent probe, was coupled with the anticancer drug 5′-DFUR via a H2O2 responsive bisboronate group connection. After entering cancer cells, the bisboronate group was cleaved by H2O2 in the mitochondria and resulted the release of NPS and 5′-DFUR.


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Subsequently, NIR triggered PDT and chemotherapy was activated. This prodrug offered an important signal for monitoring the real time drug release. Because the concentration of H2O2 in cancer cells (even up to 100 μM) was much higher than that in normal cells (~20 nM)87,236-238, the side effects was reduced. The IC50 values of PNPS towards HeLa and HepG2 cells under white light irradiation was 9.32 μM and 8.15 μM, respectively, indicating the promising application of the mitochondria-targeted prodrug for combined cancer theranostics.

Figure 19. Top: Scheme of the IR-DBI delivered by HSA via formation of dye-protein complex. (A) IR thermal images of 4T1-tumor-bearing mice injected with HSA@IR-DBI or PBS during 5 min NIR laser irradiation. (B) Tumor growth curves and (C) the survival rates of 4T1 tumor xenograft mice of different treatment groups. Adapted and modified with permission from ref 227. Copyright 2016 WILEY-VCH. In 2016, Shi and Qi et al. reported the first example of organic small molecule for mitochondriatargeted synchronous PTT-PDT.225 This heptamethine cyanine dyes derivative (PS 7) could target mitochondria via organic-anion transporting polypeptide mediation, and exhibited excellent mitochondrial retention capability owing to its lipophilic cationic feature. PS 7 exerted novel NIR


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fluorescent characteristics and synergistic PDT/PTT effects. In vitro tests revealed that A549 cells were completely killed during synchronous PDT/PTT, while 29.3% cell viability remained after PTT treatment alone and 67.4% remained in PDT treatment alone. Interestingly, in vivo results demonstrated that the tumor growth in the PS treated A549 and 4T1 xenograft models were completely inhibited without tumor recurrence (1.5 W/cm2, 5 min). The survival rate was 100%, suggesting the significant potential of the reported PS 7 and the great promise of synchronous PDT/PTT. By using spherical magnetite (Fe3O4) as the core, PDA as the inner shell and mesoporous silica (mSiO2) as the outer shell, mitochondria-targeted PTT-PDT nanosystem was constructed after loading indocyanine green (ICG) and further surface modification of polyethylene glycol (PEG), transferrin (Tf) and TPP.181 The multifunctional nanocomposites (MMCNs) could be used for NIR fluorescence imaging and MRI, and the synergistic effects between mitochondria-targeted PDT and PTT significantly reduced the demand of high laser power during cancer photo-therapy (0.5 W/cm2, 5 min). Lin’s group reported the Hf and Ru dual-metal contained nanoscale MOFs for mitochondriatargeted RT-radiodynamic therapy (RDT).184 The integration of Ru(bpy)32+ contained frameworks endowed the Hf-based nMOFs novel cationic UiO topology and excellent mitochondria localization capability. Upon ultralow dosage (1 Gy) X-ray irradiation, in situ ROS generation (•OH from the Hf6 SBUs and 1O2 from Ru based PSs) in the mitochondria significantly depolarized the mitochondrial membrane potential of MC38 cells and further activated the apoptosis pathways. In vivo experiments revealed the admirable colorectal tumor suppressing capacity of the nMOFs, and no significant side effects could be observed.


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The integration of multiple cancer treatment modality into one simple system has also emerged as a potential strategy for further boosting mitochondria-targeted cancer treatment, which could offer fascinating superadditive therapeutic effects and reduce unwanted side effects. In 2017, Shi et al. reported an indocyanine green analog (IR-DBI) for mitochondria-targeted multimodal therapy (Figure 19).227 IR-DBI possesses a series of properties, including cancer and mitochondriaspecific accumulation, NIR emission and chemo/PDT/PTT multimodal therapeutic activities. The IC50 values of IR-DBI toward a series of human and mouse cancer cell lines remained low. IRDBI was biocompatible to normal human cells after incorporated into human serum albumin (HSA). The nanosized complex exhibited enhanced characteristics for imaging guided multimodal cancer therapy. Interestingly, in vivo tests revealed that the tumor growth was significantly depressed after 24 h tail vein injection plus 808 nm laser irradiation (1.5 W/cm2, 5 min), and the survival rate of treated tumor-bearing mouse was 100% after 90 days (Figure 19A-C). 4. Lysosome-targeted therapy Lysosomes are the main digest components in cells and they contain tens of hydrolases for degradation, repair and recirculation of diverse biomolecules, which make them critical in autophagy, secretion and membrane repair.83 Therefore, lysosomes are responsible for the cancer resistance during diverse therapies. Lysosome-targeted therapy has caused increasing interest in the past decade. The acidic lysosomal microenvironments (pH≈5.0) have been frequently employed for controlled drug release as well as activation of diverse therapeutic agents.201,203,239246

Lysosomal membrane permeabilization (LMP) and subsequent lysosomal enzymes release

have been noticed to be an important cell death pathway: the released enzymes are capable of digesting the whole cell and activating caspase- or other cell death pathways. Therefore, lysosome-


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targeted/responsive toxins are another kind of therapeutic agents for enhanced cancer treatment.239242,247

There are many molecular/nano-formulations with lysosomal membrane disruption capability that are favorable for activation of LMP associated death pathways after entering cancer cells.105,248 Nanomaterials are rather attractive in lysosome targeting, because most ligand modified nanoformulations can finally reach lysosomes due to the lysosomal membrane fusion after entering cells via membrane receptor mediated internalization. And the nano-formulations can also be functionalized by lysosome targeting groups to improve the lysosomal accumulation and further enhancd the anticancer efficiency.240 Among the developed lysosomal membrane disruption strategies, alternating magnetic field (AMF) triggered LMP is highly admirable owing to the good controllability and non-invasive characteristics. The lysosomal membrane can be effectively broke by driving the nanomaterials via AMF after magnetic responsive nanomaterials reached the lysosomes, which could effectively trigger the leakage of lysosomal enzymes and subsequent cancer cell autolysis.248 Rinaldi’s group reported the activation of LMP death pathway by Epidermal Growth Factor (EGF) modified iron oxide magnetic nanoparticles (IO-MNPs). EGF receptor-mediated cell internalization resulted the MNPs located into lysosomes rapidly. After expose to AMF, the mechanic force caused the lysosomal contents release, and further triggered intracellular ROS production as well as protease cathepsin B activation, which significantly reduced the viability of cancer cells.249 This work suggested the potential application of remote control cancer cell fate via AMF. In addition to mechanistic force, ROS have also been employed for LMP activation. Other than the existence of multiple ROS scavenging enzymes in other places of cancer cells, the acidic and digestive lysosomal microenvironments restrict the activity of superoxide dismutase (SOD),


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peroxidase and so on, which make the local ROS concentration in lysosomes easier to be elevated.250-253 Therefore, lysosomal microenvironments are favorable for ROS induced apoptosis or LMP death pathway. Programmed ROS generation intra lysosomes of cancer cell should be another important point for enhanced cancer treatment.

Figure 20. (A) Schematic illustration of the mechanism of inducing and imaging LMP-dependent apoptosis in cancer cells by FITC-RR-Au-ZnO-RGD NPs. (B) TEM images of Au-ZnO hybrid NPs. (C) UV-Vis adsorption spectra of (a) Au NPs in hexane; (b) Au-ZnO NPs in hexane and (c) FITC-RR-Au-ZnO-RGD NPs in PBS. (D) The time-dependent confocal images of HepG2 cells after incubation with FITC-RR-Au-ZnO-RGD. The boxed areas are enlarged. Adapted and modified with permission from ref 106. Copyright 2014 Royal Society of Chemistry. Our group106 reported the Au-ZnO hybrid nanoparticles for lysosome-targeted LMP activation and real-time imaging (Figure 20A). FITC labeled protease cathepsin B substrate sequence ArgArg was grafted onto the Au NPs for selective tracing the activation of protease cathepsin B. RGD was modified onto ZnO to endowing the NPs with cancer targeting capacity (Figure 20B-C). The


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resulting FITC-RR-Au-ZnO-RGD heterojunction structured NPs have high affinity to HepG2 cells and specifically localized to the lysosomes after entering cancer cells. ZnO NPs effectively catalyzed the ROS generation in the acidic lysosomal environments and successfully increased the permeability of lysosomal membrane, further resulting LMP-dependent apoptosis pathway activation in cancer cells (Figure 20D). This work demonstrated Au-ZnO as a promising platform for lysosome-targeted cancer cell treatment. In 2016, lysosomal activatable bis-styryl BODIPY based nanoparticles (BODIPY NPs) were reported by Huang and co-workers (Figure 21A).254 The nanoprecipitation method prepared BODIPY NPs possessed good water dispersibility, photostability and biocompatibility. The strong NIR adsorption of BODIPY NPs allowed them as the contrast agents for photoacoustic imaging, and the pH responsive feature made the NPs capable for lysosome-targeted PDT (200 mW/cm2, 10 min). Lan et al. reported the polythiophene nanoparticles (PT NPs) for lysosome-targeted twophoton excited (TPE) imaging and PDT.255 The energy dependent, clathrin- and caveolaindependent endocytic was found to be the main pathway for PT NPs endocytosis, diethylenediamine group endowed the PT NPs lysosome-targeting capacity. Under TPE, significant 1O2 generation in lysosomes was realized due to the ultra large TPA cross section (~3420 GM). PT NPs were also demonstrated for deep penetration (1300 μm) PDT and fluorescence imaging. Lysosome-targeted synergistic therapy was realized in the recent work of Mao and co-workers (Figure 21B).224 Reduced graphene oxide (rGO) was selected as the vehicle and PTT agent owing to the photothermal conversion efficiency as well as large surface area. The PEGylated Ru(II) based PS (Ru-PEG) was facile loaded onto rGO via π-π staking and hydrophobic interaction. The PDT effect of Ru-PEG was initially switched off due to the quenching effect of rGO, but would


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be switched on in the acidic lysosomal environments plus 808 nm laser irradiation, based on the photothermal enhanced PSs release in acidic microenvironments (Figure 21C). Thus, lysosometargeted combined PDT and PTT was realized under 808 nm (0.5 W/cm2, 5 min) and 450 nm (20 mW/cm2, 2 min) laser irradiation. With this system, significant synergistic effect was realized during in vitro and in vivo cancer treatment (Figure 21D-F).

Figure 21. (A) Schematic illustration of the construction of lysosome-targeted BODIPY NPs and their applications in lysosomal PAI and pH-activated PDT. Adapted and modified with permission from ref 254. Copyright 2016 American Chemical Society. (B) Schematic illustration of the construction of rGO-Ru-PEG. (C) Colocalization of rGO-Ru-PEG with lysosomes and mitochondria. (D) IR thermal images of A549 tumor-bearing mice under 808 nm laser irradiation. (E) Tumor growth curves of different groups of A549 tumor-bearing mice. (F) Photos of mice after various treatments taken at day 15. Adapted and modified with permission from ref 224. Copyright


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2017 American Chemical Society. (G) TEM image of PTX@PAsp-g-(PEG-ICG) micelles, scale bar is 500 nm. (H) Statistical data of PAsp-g-(PEG-ICG) micelles’ diameter in (G). Cell viability of U-87 MG cells at (I) 48 h and (J) 72 h incubated with Taxol and PTX@PAsp-g-(PEG-ICG) micelles with/without laser irradiation. Adapted and modified with permission from ref 256. Copyright 2018 Royal Society of Chemistry. Although with promising application, lysosome-targeted therapeutics have not received as much interest as nucleus- or mitochondria-targeted modalities, mostly because many kinds of therapeutic agents including proteins and peptides are intolerant to the digestive acidic lysosomal microenvironments. Therefore, more investigations on lysosome-targeted therapy are desired. More importantly, it makes sense to devote more efforts to explore their working mechanisms and enhance the controllability as well as therapeutic efficiency of related therapeutic agents, because it should be beneficial for future personal medicines without resistance. 5. Endoplasmic reticulum/ Golgi apparatus-targeted therapy Endoplasmic reticulum (ER) and Golgi apparatus are closely related with protein/lipids synthesis and transfer, and they also play critical roles in tumor growth, drug resistance, cancer metastasis and immune escape.86 Specific therapeutic drugs accumulation in ER as well as Golgi apparatus may hamper the protein folding and result in stress signal, which will further cause cancer cell apoptosis. ER stress has been regarded as an important signal pathway to trigger cancer death, which makes ER another important target toward enhanced cancer treatment.257-260 In 2014, Chakravarty et al. reported an ER-targeted oxovanadium(IV) vitamin-B6 complex, [VO(HL)(acdppz)]Cl, for cancer PDT.261 By virtue of the over-expressed VB6 transporting membrane carrier (VTC) in cancer cells,


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[VO(HL)(acdppz)]Cl was specifically internalized by the MCF-7 cells and localized in the ER, while the internalization rate for normal counterparts of MCF-10A cells was slow. The ERtargeted [VO(HL)(acdppz)]Cl was biocompatible under dark but induced 1O2 production as well as ER stress under white light irradiation (2.4 mW/cm2, 1 h). Therefore, [VO(HL)(acdppz)]Cl was a potential candidate for ER stress activation and this work demonstrated ER as a potential target for highly efficient and specific cancer treatment. In 2016, Kwon and co-workers synthesized four Ir(III)-based complexes (TIr1-4). TIr1-4 with different energy levels exhibited TPA characteristics and ER location capabilities.262 TIr3 and TIr4 have high quantum yields for 1O2 and phosphorescence due to their well-matched energy levels. TIr3 could effectively induce cell apoptosis under hypoxia condition even under low density TPlaser irradiation (100 mW/cm2, 10 s). They further proved that the potential mechanism of ERtargeted PDT was the arbitrary protein oxidation and crosslinking via protein mass spectrometry analysis. This work offered a new idea for cancer therapy targeting the protein dysfunction associated cell death pathways. Very recently, Wang’s group developed an ER targeted comblike polymer, PAsp-g-(PEG-ICG), for enhanced chemotherapy (Figure 21G-H).256 Azido-modified PEG and ICG were grafted onto the alkynyl-functionalized poly(aspartic acid) (PAsp) through the 1,2,3-triazole connected click reaction. Owing to the rich carboxyl groups in PAsp, the PAsp-g-(PEG-ICG) effectively accumulated into the ER of SK-OV-3 cancer cells based on the coordination interaction with Ca2+ of ER lumen. PTX loaded nano micelles (PTX@PAsp-g-(PEG-ICG)) exhibited significant synergistic effect for enhanced in vivo cancer treatment owing to the ER targeted ROS production under laser irradiation (2 W/cm2, 5 min), which further proved the potential application of ERtargeting for enhanced cancer treatment (Figure 21I-J).


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Yi’s group reported a pH responsive cyanine based photothermal agent (pH-PTT) for Golgi apparatus-targeted PTT.263 pH-PTT could be converted into conjugated structure with strong 808 nm adsorption under acidic microenvironments, and it was used for preparing nano anticancer agent after assembled with bovine serum albumin (BSA-pH-PTT). Interestingly, owing to the hypertrophic morphology of Golgi apparatus in cancer cells, the obtained BSA-pH-PTT exhibited cancer cell Golgi apparatus selectivity and could be activated by the local acidic microenvironment. Upon 808 nm laser irradiation (1.45 Wcm2, 10 min), BSA-pH-PTT significantly inhibited tumor growth due to the induction of Golgi apparatus hyperthermia. In contrast, lysosome-, ER- and Golgi apparatus-targeted nanodrugs have not receive as much interest as nucleus- and mitochondria-targeted therapeutics. Mostly because the targeting mechanisms are still unclear and development of related nanomaterials remains challengeable. (Table 3) Table 3. Typical nanomaterials for lysosome-, ER- and Golgi apparatus-targeted therapy. Organelles

Therapy modality

Nanomaterials

Targeting ligands


Cell type

Tumor model


Treatment times

Treatment period

Refs

Lysosome

Catalytic therapy

Au-ZnO

RGD

Endocytic pathway mediated targeting

HepG2









106

PDT

Polythiophene NPs

Triethylen ediamine

Protonation induced targeting

HeLa









255

Synergistic therapy

rGO



Endocytic pathway mediated targeting

A549

A549

i.t.

1

15

224

Endoplasmic reticulum

Synergistic therapy

Comblike polymer NPs

Carboxyl group

Carboxyl-Ca(II) coordination induced targeting

U-87 MG

U-87 MG

i.v.

1

21

256

Golgi apparatus

PTT

BSA-Cyanine

BSA

Cancer cell Golgi apparatus hypertrophic resulted BSA accumulation

HepG-2









263

6. Summary and Perspectives


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Organelles are critical components for cancer cell survival and proliferation. Owing to the specific destruction of tumor cell structures and activation of certain cell apoptosis pathways, therapeutic nanomaterials capable of targeting specific organelles have shown significant advantages over traditional drugs: they are rather favorable for reducing the drug dosage, boosting therapeutic index, avoiding multidrug resistance, recurrence, and detouring side effects. Organelletargeted chemotherapy, PDT, PTT, RT, gene therapy etc. have been widely investigated in recent years. These agents can be regarded as the new generation of therapeutics for cancer treatment and hold promise for clinical translation. Despite significant advances have been made, it still should be noteworthy that there are several barriers to be broke before preclinical studies: (a) current strategies for nanomaterials fabrication are still hard to fulfill the requirements of controlled and high-dosage preparation of well-defined nanostructures, while the pharmacokinetics behaviors and toxicity effects of nanomaterials are highly dependent on their morphology and size264,265; (b) targeting ligands on the surface of nanomaterials is another critical factor determining targeting efficiency, few efforts have been devoted into the optimization of the surface charge and ligand density of organelle-targeted nanomaterials; (c) there are multiple biological barriers to be overcome for i.v. administrated drugs reaching the organelles of interest, which depends on different and even opposite material properties, the available systems still cannot fulfill this demand; (d) nano-formulations that are capable of highly efficient cargo encapsulation and controlled release are desired for safe and efficient drug delivery, but the developed organelle-targeted nano-systems are still far from this objective; (e) the biodegradability as well as long-term toxicity of most employed nanomaterials have not been fully evaluated, biocompatible nanomaterials should be better candidates for clinical anticancer application;266-271 (f) multifunctional theranostic platforms are promising candidates for


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precise cancer treatment, multiple imaging functions integrated organelle-targeted therapeutic systems have not been well investigated up to now; (g) nucleus and mitochondria-targeted therapy have attracted significant research interests, while much less attention have been devoted into the lysosome, ER, Golgi apparatus and other organelles, though they are also important targets for enhanced cancer treatment; (h) it is hard to compare the treatment potentials of different nanomaterials, due to the absence of standard methods for evaluating the therapeutic efficiency between different works. On the basis of the described challenges, we propose future works should focus on the following aspects: i) developing standard procedures for precise control of the size distribution and morphologies of nano-formulations, to ensure the repeatability of nano-drugs; ii) exploring more feasible cancer cell/organelle targeting ligands to enhance the subcellular location capability of nano-drugs; iii) designing smart platforms to overcome the multiple biological barriers in living systems, to further realize cancer cell subcellular structure-specific drug accumulation; iv) developing novel drug encapsulation as well as controlled release strategies for boosting the therapeutic index and avoiding the side effects; v) designing more therapeutic systems based on nontoxic/biodegradable nanomaterials, thoroughly evaluate their pharmacokinetics as well as clinical translation potential; vi) developing imaging guided theranostic systems for precise cancer treatment and even future personalized medicine; vii) paying more efforts to the therapeutic mechanisms of organelle-targeted nano-drugs, evaluating their immune effect, finding out the best recipes for specific cancer; viii) establishing universal evaluation protocols for comparing the therapeutic efficiency of different therapeutics, to further guide the design and synthesis of advanced organelle-targeted nano-drugs.


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Overall, this review described the latest achievements of advanced organelle-targeted nanomaterials for boosting cancer therapy. Because it is still at the early stage, some molecular drugs were also included to highlight the significance and advantages of driving drugs into specific organelles. A list of recently published papers is provided for interested readers to further get to know the state of the art of this field.272-293 We believe this review will offer valuable information for the researchers to design better organelle-targeted nanomaterials, and more encouraging news can be brought to this field in the near future under the joint efforts from chemist to pharmaceutical scientists and clinical doctors. AUTHOR INFORMATION Corresponding Authors [email protected]; [email protected] ORCID Peng Gao: 0000-0002-3839-3167 Wei Pan: 0000-0002-2281-8749 Na Li: 0000-0002-0392-6672 Bo Tang: 0000-0002-8712-7025 Notes The authors declare no competing financial interests. ACKNOWLEDGMENT


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