Photodynamic Chemotherapy Research Articles

Effect of gold nanocomposite treatment on male reproductive function

Recently, it has been proved that polymers with a dextran core and grafted polyacrylamide chains dextran–polyacrylamide are effective in photodynamic chemotherapy, which gives confidence in the prospect of drug nanosystem. However, further research is needed to determine the effect of the treatment on male reproductive function. Experiments have been conducted on 50 male and 50 females Albino white laboratory mice (25–30 g). Copolymer dextran-graft-polyacrylamide in nonionic (D-g-PAA) and anionic forms (D-g-PAA(PE) was used as a polymer matrix for in situ synthesis of gold nanoparticles (AuNPs). D-g-PAA consists of dextran core and five grafted PAA chains. The copolymer in anionic form was prepared by alkaline hydrolysis. Polymer/AuNP systems contain AuNPs of 2–11 nm in size and have spherical shape. The treatment of substances was carried out in the following way: D-g-PAA and D-g-PAA(PE) (10,00 mg/kg), D-g-PAA/AuNPs and D-g-PAA(PE)/AuNPs (9.78 mg/kg), saline solution was introduced intravenously (in the tail vein, in 0.3 mL) once a day, five times. For the first time, it has been shown that treatment with D-g-PAA, D-g-PAA(PE), and D-g-PAA/AuNPs did not affect reproductive function in male mice. Disorder of the male reproductive function occurs under conditions of treatment with D-g-PAA(PE)/AuNPs. Significant changes in the values of were established in: (1) pre- and post-implantation mortality of embryos; (2) the number of live newborns (pups); (3) sperm and abnormal sperm forms (%); (4) spermatocytes (primary) and spermatids (%); (5) living, apoptotic and necrotic cells in the testis (spermatocytes (primary)) and in the epididymis (spermatozoa).

Berberine-photodynamic therapy sensitizes melanoma cells to cisplatin-induced apoptosis through ROS-mediated P38 MAPK pathways

The clinical use of cisplatin are limited due to its drug resistance. Thus, it is urgent to find effective combination therapy that sensitizes tumor cells to this drug. The combined chemo-photodynamic therapy could increase anti-tumor efficacy while also reduce the side effects of cisplatin. Berberine is an isoquinoline alkaloid, which has been reported to show high photosensitizing activity.In this study, we have examined the effect of a combination of cisplatin and berberine-PDT in cisplatin-resistant melanoma cells. The cytotoxic effects of berberine-PDT alone or in combination with cisplatin were tested by MTT assays. We then examined the subcellular localization of berberine with confocal fluorescence microscopy. The percentage of apoptotic cells, the mitochondrial membrane potential (Δψm) and reactive oxygen species (ROS) generation assessed using flow cytometry analysis. Western blotting used in this study to determine the expression levels of MAPK signaling pathways and apoptosis-related proteins. Experimental data revealed that the mode of cell death is the caspase-dependent mitochondrial apoptotic pathways. Excessive accumulation of ROS played a key role in this process, which is confirmed by alleviation of cytotoxicity upon pretreatment with NAC. Furthermore, we found that the combined treatment activated MAPK signaling pathway. The inhibition of p38 MAPK by pretreating with SB203580 block the combined treatment-induced apoptotic cell death.In conclusion, berberine-PDT could be used as a chemo-sensitizer by promoting cell death through activation of a ROS/p38/caspase cascade.

Platinum-based photosensitizer with near-infrared aggregation-induced emission for synergistic photodynamic-chemo theranostics

Abstract Photodynamic therapy (PDT) is of great interest as an emerging paradigm towards cancer treatment, owing to its advantages of minimal invasiveness and low toxicity. In this work, we incorporated cisplatin into an AIE-based photosensitizer (BT) and achieved a highly efficient antitumor drug (BT-Pt). Possessing AIE characteristics, BT-Pt exhibited NIR fluorescence with large Stokes shift in cells, which can guide the location of the drug. More importantly, the ROS generation efficiency of BT-Pt has extremely been promoted with the fabrication of cisplatin, compared with BT. As a result, BT-Pt demonstrated favorable therapeutic efficacy with a half maximal inhibitory concentration (IC50) value of 1.54 μM for HeLa cells upon white light irradiation, attributed to its synergetic PDT and chemotherapy. The design strategy of such platinated photosensitizer showed great potential in developing multifunctional anticancer drugs with combinatorial photodynamic–chemotherapy, especially when ablating cisplatin resistant cancer cells and hypoxic tumors.

Hyaluronic Acid-Functionalized Hollow Mesoporous Silica Nanoparticles as pH-Sensitive Nanocarriers for Cancer Chemo-Photodynamic Therapy.

Hollow mesoporous silica nanoparticles (HMSNs) served as nanocarriers for transporting doxorubicin hydrochloride (DOX) and indocyanine green (ICG) and were incorporated into a pH-sensitive targeted drug delivery system (DDS). Boronate ester bonds were employed to link HMSNs and dopamine-modified hyaluronic acid (DA-HA), which acted as both the "gatekeeper" and targeting agents (HMSNs-B-HA). Well-dispersed HMSNs-B-HA with a diameter of about 170 nm was successfully constructed. The conclusion was drawn from the in vitro drug release experiment that ICG and DOX (ID) co-loaded nanoparticles (ID@HMSNs-B-HA) with high drug loading efficiency could sustain drug release under acidic conditions. More importantly, in vitro cell experiments perfectly showed that ID@HMSNs-B-HA could well inhibit murine mammary carcinoma (4T1) cells via chemotherapy combined with photodynamic therapy and accurately target 4 T1 cells. In summary, all test results sufficiently demonstrated that the prepared ID@HMSNs-B-HA was a promising nano-DDS for cancer photodynamic combined with chemotherapy.

A review of advanced nanoformulations in phototherapy for cancer therapeutics.

Phototherapy has the potential to play a greater role in oncology. Phototherapy converts light energy into either chemical energy or thermal energy, which eventually destroys cancer cells after a series of biological reactions. With nanotechnology applications in cancer therapeutics, it has become possible to prepare smart drug carriers with multifunctional properties at the nanoscale level. These nanocarriers may be able to deliver the drug molecules to the target site more efficiently in the form of nanoparticles. Several intrinsic and extrinsic properties of these nanocarriers help target the tumor cells exclusively, and by utilizing these features, drug molecules can be delivered to the tumor cells specifically, which results in high tumor uptake and better therapeutic effects ultimately. Nanocarriers can also be designed to carry different drugs together to provide a platform for combination therapy like chemo-photodynamic therapy and chemo-photodynamic-photothermal therapy. In combination therapy, co-delivery of all different drugs is crucial to obtain their synergistic effects, and with the help of nanocarriers, it is possible to co-deliver these drugs by loading them together onto the nanocarriers.

Lipoparticles for Synergistic Chemo-Photodynamic Therapy to Ovarian Carcinoma Cells: In vitro and in vivo Assessments.

PurposeLipoparticles are the core-shell type lipid-polymer hybrid systems comprising polymeric nanoparticle core enveloped by single or multiple pegylated lipid layers (shell), thereby melding the biomimetic properties of long-circulating vesicles as well as the mechanical advantages of the nanoparticles. The present study was aimed at the development of such an integrated system, combining the photodynamic and chemotherapeutic approaches for the treatment of multidrug-resistant cancers.MethodsFor this rationale, two different sized Pirarubicin (THP) loaded poly lactic-co-glycolic acid (PLGA) nanoparticles were prepared by emulsion solvent evaporation technique, whereas liposomes containing Temoporfin (mTHPC) were prepared by lipid film hydration method. Physicochemical and morphological characterizations were done using dynamic light scattering, laser doppler anemometry, atomic force microscopy, and transmission electron microscopy. The quantitative assessment of cell damage was determined using MTT and reactive oxygen species (ROS) assay. The biocompatibility of the nanoformulations was evaluated with serum stability testing, haemocompatibility as well as acute in vivo toxicity using female albino (BALB/c) mice.Results and ConclusionThe mean hydrodynamic diameter of the formulations was found between 108.80 ± 2.10 to 405.70 ± 10.00 nm with the zeta (ζ) potential ranging from −12.70 ± 1.20 to 5.90 ± 1.10 mV. Based on the physicochemical evaluations, the selected THP nanoparticles were coated with mTHPC liposomes to produce lipid-coated nanoparticles (LCNPs). A significant (p< 0.001) cytotoxicity synergism was evident in LCNPs when irradiated at 652 nm, using an LED device. No incidence of genotoxicity was observed as seen with the comet assay. The LCNPs decreased the generalized in vivo toxicity as compared to the free drugs and was evident from the serum biochemical profile, visceral body index, liver function tests as well as renal function tests. The histopathological examinations of the vital organs revealed no significant evidence of toxicity suggesting the safety and efficacy of our lipid-polymer hybrid system.

A two-fold interpenetration pillar-layered metal-organic frameworks based on BODIPY for chemo-photodynamic therapy

The combination of chemotherapy and photodynamic therapy has been proved to be a promising therapy for drug-resistant cancers. In this study, we report, for the first time, a novel two-fold interpenetration pillar-layered metal-organic frameworks (MOFs) material, using BODIPY-derivate bipyridine as linker and Photosensitizer (PS), named BBP-MOFs, was successfully synthesized to serve as a drug carrier and Photodynamic agent simultaneously. The BBP-MOFs could generate singlet oxygen (1O2) to perform PDT under 660 nm light irradiation, in the meantime, the anticancer drugs doxorubicin (DOX) could be loaded for chemotherapy. The results showed that BBP-MOFs exhibited a high drug loading content of 49.7% a controlled drug release and ideal biocompatibility. This DOX loaded BBP-MOFs was readily taken up by HeLa cells, and high levels of 1O2 were generated under light irradiation. This work provided strong evidence for BBP-MOFs as a promising new anticancer drug carrier and PDT candidate, the PDT and chemotherapy combined synergistic therapy revealed high therapeutic efficacy for cancer cells.

Self-Guiding Polymeric Prodrug Micelles with Two Aggregation-Induced Emission Photosensitizers for Enhanced Chemo-Photodynamic Therapy.

Nowadays, aggregation-induced emission luminogens (AIEgens) with reactive oxygen species (ROS) generating ability have been used as photosensitizers for imaging guided photodynamic therapy (PDT). To achieve enhanced antitumor outcomes, combining AIEgens-based PDT with chemotherapy is an efficient strategy. However, the therapeutic efficiency is hampered by the limited cellular uptake efficiency and the appropriate light irradiation occasion. In this paper, a self-guiding polymeric micelle (TB@PMPT) composed of two AIE photosensitizers and a reduction-sensitive paclitaxel prodrug (PTX-SS-N3) was established for enhanced chemo-photodynamic therapy by a dual-stage light irradiation strategy. When the micelles were accumulated in tumor tissues, the first light irradiation (L1, 6 min) was utilized to facilitate cellular uptake by "photochemical internalization" (PCI). Then, the intracellular glutathione (GSH) would induce the PTX release, micelles disassembly and the aggregation state change of AIEgens. The fluorescence signal change of two AIEgens-based ratiometric fluorescent probe could not only precisely guide the second light irradiation (L2, 18 min) for sufficient ROS production, but also monitor the nonfluorescent drug PTX release in turn. Both in vivo and in vitro studies demonstrated that the dual-stage light irradiation strategy employed for TB@PMPT micelles exhibited a superior therapeutic effect over only 24 min continuous light irradiation.

Self-assembled Camptothecin derivatives – Curcuminoids conjugate for combinatorial chemo-photodynamic therapy to enhance anti-tumor efficacy

Camptothecin (CPT), an alkaloid, was first discovered from plants and has potent anti-tumor activity. Since then, CPT analogs (namely Irinotecan and Topotecan) have been approved by the FDA for cancer treatments. Curcumin, on the other hand, is a widely used photosensitizer in photodynamic therapy (PDT) treatment. In our previous work, we have reported a straightforward strategy to construct a drug self-delivery system in which two-molecular species Irinotecan and Curcumin can self-assembly into a complex of ion pairs, namely ICN, through intermolecular non-covalent interactions. We found that ICN has slightly better chemotherapy efficacy than its individual components with much fewer side effects. In this paper, we aim to combine the chemotherapy and the PDT of ICN to further improve its anti-tumor performance. The efficient cellular uptake of ICNs was observed by confocal microscopy. Dichloro-dihydro-fluorescein diacetate (DCFH-DA) assay was used to detect the generation of singlet oxygen species. We found that the cell viability was 9% with both chemotherapy and PDT, and 31% with chemotherapy alone for the case with an ICN concentration of 10 μM, which demonstrated that the anti-tumor efficacy against the HT-29 cancer cell line was enhanced substantially with the combination therapy strategy. The study with an in vivo mouse model has further verified that the chemo-PDT dual therapy can inhibit tumor growth by 84% and 18.8% comparing with the control group and the chemotherapy group, respectively. Our results demonstrated that the new strategy using self-assembly and carrier-free nanoparticles with their chemo-PDT dual therapy may provide new opportunities to develop future combinatorial therapy methods in treating cancer.

Ultra-thin metal-organic framework nanosheets for chemo-photodynamic synergistic therapy.

Synergistic therapies, such as chemo-photodynamic therapy, have been growing fast because of their efficacy against cancers. Although metal-organic frameworks have been widely studied in the field of drug delivery, the metal-organic frameworks (MOFs) with a two-dimensional (2D) structure integrated by photosensitizers are rarely reported. However, chemo-photodynamic therapy still has limitations such as the inhibitory effect from intracellular glutathione (GSH). In this work, a simple bottom-up synthesis method was used to synthesize a pH-responsive drug delivery system with a 2D MOF structure. In particular, tetracarboxyporphyrin (TCPP) derivatives were coordinated with bivalent copper ions as organic bridging molecules in a polyvinylpyrrolidone (PVP) solution, and copper porphyrin MOFs (Cu-TCPP nanosheets) were synthesized by a hydrothermal method from bottom to top. DOX was loaded onto Cu-TCPP nanosheets by π-π stacking with a high drug loading rate of 33%. DOX@Cu-TCPP nanosheets showed pH-responsive DOX releasing behaviour and significant GSH scavenging ability. In addition, the evaluation of in vitro and in vivo treatment showed that DOX@Cu-TCPP nanosheets had high anti-tumor activity and excellent biocompatibility. Therefore, this study opens a new idea for the application of MOF nanosheets in tumor therapy and provides a supporting basis for the treatment of cancers by chemo-photodynamic synergistic therapy.

Photosensitizer-driven nanoassemblies of homodimeric prodrug for self-enhancing activation and synergistic chemo-photodynamic therapy.

Carrier-free prodrug-nanoassemblies have emerged as promising nanomedicines. In particular, the self-assembled nanoparticles (NPs) composed of homodimeric prodrugs with ultrahigh drug loading have attracted broad attention. However, most homodimeric prodrugs show poor self-assembly ability due to their symmetric structures. Herein, we developed photosensitizer-driven nanoassemblies of homodimeric prodrug for self-enhancing activation and chemo-photodynamic synergistic therapy.Methods: In this work, a pyropheophorbide a (PPa)-driven nanoassemblies of an oxidation-responsive cabazitaxel homodimer (CTX-S-CTX) was fabricated (pCTX-S-CTX/PPa NPs). The assembly mechanisms, aggregation-caused quenching (ACQ) effect alleviation, singlet oxygen generation, self-enhancing prodrug activation, cellular uptake, intracellular reactive oxygen species (ROS) generation and synergistic cytotoxicity of pCTX-S-CTX/PPa NPs were investigated in vitro. Moreover, the pharmacokinetics, ex vivo biodistribution and in vivo therapeutic efficacy of pCTX-S-CTX/PPa NPs were studied in mice bearing 4T1 tumor.Results: Interestingly, PPa was found to drive the assembly of CTX-S-CTX, which cannot self-assemble into stable NPs alone. Multiple intermolecular forces were found to be involved in the assembly process. Notably, the nanostructure was destroyed in the presence of endogenous ROS, significantly relieving the ACQ effect of PPa. In turn, ROS generated by PPa under laser irradiation together with the endogenous ROS synergistically promoted prodrug activation. As expected, the nanoassemblies demonstrated potent antitumor activity in a 4T1 breast cancer BALB/c mice xenograft model.Conclusion: Our findings offer a simple strategy to facilitate the assembly of homodimeric prodrugs and provide an efficient nanoplatform for chemo-photodynamic therapy.

An albumin-binding dimeric prodrug nanoparticle with long blood circulation and light-triggered drug release for chemo-photodynamic combination therapy against hypoxia-induced metastasis of lung cancer.

Photodynamic therapy (PDT) has been widely used in cancer therapy, but its therapeutic effect is reduced by the aggravating hypoxic microenvironment via upregulating hypoxia-associated proteins and promoting tumor metastasis. To mitigate these issues, we designed an albumin-binding and light-triggered core-shell dimeric prodrug nanoparticle to inhibit hypoxia-induced tumor metastasis and enhance the PDT efficacy. The prodrug nanoparticles, Ce6&DHA-S-DHA@CMN NPs (CDC NPs), were prepared using a single thioether-linked dihydroartemisinin (DHA) dimer co-encapsulated with Chlorin e6 (Ce6) and stabilized by albumin-capturing maleimide- and hypoxia-sensitive 2-nitroimidazole-modified carboxymethyl chitosan (CMCTS-MAL&NI, CMN for short). Upon laser irradiation, Ce6 could generate reactive oxygen species (ROS), which not only exerted the effect of the PDT but also broke the ROS-sensitive single thioether bridge in the dimeric prodrug DHA-S-DHA, thus accelerating the disassembly of the nanoparticles. DHA-S-DHA served as both an ROS-responsive carrier for Ce6 and a chemotherapeutic drug, synergizing with PDT and inhibiting tumor metastasis by downregulating hypoxia-inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF). Polyethylene glycol (PEG) modification has been widely used to stabilize hydrophobic prodrug nanoparticles and prolong the circulation time, but the PEGylated nanoparticles always suffer from accelerated blood clearance (ABC), a phenomenon which restricts their application severely. In this study, PEG was replaced by an amphipathic micelle, CMN, which could specifically capture albumin in the blood, conferring the nanoparticles long circulation and no ABC phenomenon. Under the aggravating hypoxic condition during PDT, the conversion of 2-nitroimidazole groups to 2-aminoimidazole groups in CMN could destabilize the structure of the shell and accelerate drug release. Results showed that the novel CDC NPs exhibited unique advantages in chemo-photodynamic combination therapy, such as long systemic circulation, high tumor accumulation, light-triggered drug release, HIF-1α/VEGF downregulation, and anti-metastasis efficacy, which provided a new route to overcome the ABC phenomenon of the PEGylated prodrug nanoparticles and reverse the hypoxia-induced metastasis simultaneously.

Designer exosomes for targeted and efficient ferroptosis induction in cancer via chemo-photodynamic therapy.

Background: Efficient and specific induction of cell death in liver cancer is urgently needed. In this study, we aimed to design an exosome-based platform to deliver ferroptosis inducer (Erastin, Er) and photosensitizer (Rose Bengal, RB) into tumor tissues with high specificity.Methods: Exosome donor cells (HEK293T) were transfected with control or CD47-overexpressing plasmid. Exosomes were isolated and loaded with Er and RB via sonication method. Hepa1-6 cell xenograft C57BL/6 model was injected with control and engineered exosomes via tail vein. In vivo distribution of the injected exosomes was analyzed via tracking the fluorescence labeled exosomes. Photodynamic therapy was conducted by 532 nm laser irradiation. The therapeutic effects on hepatocellular carcinoma and toxic side-effects were systemically analyzed.Results: CD47 was efficiently loaded on the exosomes from the donor cells when CD47 was forced expressed by transfection. CD47 surface functionalization (ExosCD47) made the exosomes effectively escape the phagocytosis of mononuclear phagocyte system (MPS), and thus increased the distribution in tumor tissues. Erastin and RB could be effectively encapsulated into exosomes after sonication, and the drug-loaded exosomes (Er/RB@ExosCD47) strongly induced ferroptosis both in vitro and in vivo in tumor cells after irradiation of 532 nm laser. Moreover, compared with the control exosomes (Er/RB@ExosCtrl), Er/RB@ExosCD47 displayed much lower toxicity in liver.Conclusion: The engineered exosomes composed of CD47, Erastin, and Rose Bengal, induce obvious ferroptosis in hepatocellular carcinoma (HCC) with minimized toxicity in liver and kidney. The proposed exosomes would provide a promising strategy to treat types of malignant tumors.

Polymyxin B-functionalized phthalocyanine for chemo-photodynamic antibacterial therapy in enhanced wound healing

The rapid healing of bacteria-infected wounds was achieved via synergistic photodynamic antimicrobial therapy and chemotherapy using polymyxin B-functionalized phthalocyanine.

Polyamino acid calcified nanohybrids induce immunogenic cell death for augmented chemotherapy and chemo-photodynamic synergistic therapy.

Background: Monotherapy for cancer treatment is limited by unstable efficacy and uncontrollable toxic side effects, while the multifunctional nanoplatform with complex preparation process cannot avoid the potential toxicity of each functional component.Methods: We exploited tumor-specific activated polyamino acid calcified nanoparticles (CHC NPs) as new-type oxidative stress amplification of anticancer drugs via building a safe and biodegradable multifunctional nanoplatform. Giving priority to chemotherapy, and synergizing chemodynamic therapy (CDT) with photodynamic therapy (PDT), this strategy was to achieve enhanced chemotherapy, simultaneously inducing immunogenic cell death and inhibiting tumor cell invasion.Results: Based on amorphous calcium carbonate, pH-responsive nanocarrier was prepared with classical chemotherapeutic drug 10-hydroxycamplothecin (HCPT) and photosensitizer Chlorin e6 (Ce6) to realize multifunctional nanotheranostics.Conclusion: Inventive calcified nanohybrids, where topoisomerase inhibited by HCPT to prevent DNA synthesis, the generation of •OH induced via Fenton reaction, along with a large amount of 1O2 produced by Ce6, might be a promising strategy for anti-tumor combination therapy in clinical translation.

Cyclo-γ-polyglutamic acid-coated dual-responsive nanomicelles loaded with doxorubicin for synergistic chemo-photodynamic therapy.

Nanodrug delivery systems have been used extensively to improve the tumor-targeting ability and reduce the side effects of anticancer drugs. In this study, nanomicelles responsive to dual stimuli were designed and developed as drug carriers for delivering doxorubicin (DOX). The hydrophobic group of the nanomicelles was composed of the photosensitizer protoporphyrin IX (PpIX) and the disulfide bond-containing alpha-lipoic acid (LA); the hydrophilic group was made up of the nuclear localization signal (NLS, CGGGPKKKRKVGG) peptide with a lysine linker. Furthermore, anionic cyclo-γ-polyglutamic acid (cyclo-γ-PGA) was coated on the surface of the cationic micelles to construct a multifunctional drug delivery system (NLS-LA-PpIX-DOX@cyclo-γ-PGA). Cyclo-γ-PGA, as a biological coating material, notably improved the stability of the cationic micelles by reducing nonspecific reactions with anionic groups. Additionally, the cyclo-γ-PGA coating mediated active tumor targeting and enhanced the cellular uptake of micelles via the γ-glutamyl transpeptidase (GGT) pathway. The integrated micelles not only achieved photochemical internalization (PCI) and photodynamic therapy (PDT) via light-activated reactive oxygen species (ROS) but also realized controlled intracellular drug release via the glutathione (GSH)-responsive disulfide-bond cleavage. As a result, NLS-LA-PpIX-DOX@cyclo-γ-PGA exhibited excellent synergistic chemo-photodynamic antitumor activity and fewer side effects than other therapies both in vitro and in vivo. In conclusion, this new dual-responsive drug delivery system (NLS-LA-PpIX-DOX@cyclo-γ-PGA) with improved stability and enhanced tumor-targeting ability may facilitate the development of high-efficiency and low-toxicity nanotherapeutic approaches.

Red blood cell membrane-coated biomimetic upconversion nanoarchitectures for synergistic chemo-photodynamic therapy

The red blood cell (RBC) membrane camouflaged core–shell upconversion/mesoporous silica nanoparticles (UCNPs@mSiO2 NPs) were constructed for synergistic chemo-photodynamic therapy.

A multifunctional nanoplatform based on graphitic carbon nitride quantum dots for imaging-guided and tumor-targeted chemo-photodynamic combination therapy

Graphitic carbon nitride quantum dots (g-CNQDs) have shown great potential in imaging, drug delivery and photodynamic therapy (PDT). However, relevant research on g-CNQDs for PDT or drug delivery has been conducted separately. Herein, we develop a g-CNQDs-based nanoplatform (g-CPFD) to achieve simultaneously imaging and chemo-photodynamic combination therapy in one system. A g-CNQDs-based nanocarrier (g-CPF) is first prepared by successively introducing carboxyamino-terminated oligomeric polyethylene glycol and folic acid onto the surface of g-CNQDs via two-step amidation. The resultant g-CPF possesses good physiological stability, strong blue fluorescence, desirable biocompatibility, and visible light-stimulated reactive oxygen species generating ability. Further non-covalently loaded doxorubicin enables the system with chemotherapy function. Compared with free doxorubicin, g-CPFD expresses more efficient chemotherapy to HeLa cells due to improved folate receptor-mediated cellular uptake and intracellular pH-triggered drug release. Furthermore, g-CPFD under visible light irradiation shows enhanced inhibition on the growth of cancer cells compared to sole chemotherapy or PDT. Thus, g-CPFD exhibits exceptional anti-tumor efficiency due to folate receptor-mediated targeting ability, intracellular pH-triggered drug release and a combined treatment effect arising from PDT and chemotherapy. Moreover, this nanoplatform benefits imaging-guided drug delivery because of inherent fluorescent properties of doxorubicin and g-CPF, hence achieving the goal of imaging-guided chemo-photodynamic combination treatments.

Reactive Oxygen Species Self-Sufficient Multifunctional Nanoplatform for Synergistic Chemo-Photodynamic Therapy with Red/Near-Infrared Dual-Imaging.

Developing multifunctional nanoplatforms that combine controlled drug release, therapy, and real-time monitoring of intracellular distribution of therapeutic agents can provide a solution for practical precision cancer therapy. Herein, a daylight activatable and red to near-infrared (NIR) dual-imaging guided multifunctional anticancer nanoplatform based on diselenium-conjugated and aggregation-induced emission fluorogen (AIEgen)-cross-linked oligoethylenimine polymer loaded with cisplatin (Pt) and biscyclometalated iridium(III) (Ir(III)) complex (Pt&Ir@P NPs) is reported. Upon short-time daylight irradiation, the nanoplatform generates reactive oxygen species (ROS), which help them to escape from endo/lysosomes via enhanced lysosomal membrane permeability. Meanwhile, the chemotherapeutic drug cisplatin and the photosensitizer (PS) Ir(III) complex are released via breaking the ROS-labile diselenium bond. The released PS, together with AIEgen, respond to the continuous long-time daylight irradiation and produce more ROS, inducing photodynamic therapy (PDT) and damaging the nucleus. Along with PDT, selenium liberates cisplatin and exerts chemotherapy in the presence of endogenous spermine. In addition, the red/NIR emitting Ir(III) complex and the engineered AIEgen act as dual-imaging agents for real-time monitoring the distribution of PS and polymer. This daylight responsive multifunctional nanoplatform for efficient anticancer therapy and imaging could provide an intriguing strategy for developing theranostic antitumor platforms.

Quantitative self-assembly of photoactivatable small molecular prodrug cocktails for safe and potent cancer chemo-photodynamic therapy

Cancer nanomedicines that integrate multimodal therapies have been remarkably successful in numerous preclinical models, yet have achieved variable levels of success in the clinic because of tedious and complex manufacturing schemes. Here, we present a facile and versatile strategy to construct photoactivatable self-assembling prodrug cocktail (PSPC) nanoparticles for specific drug activation and cancer chemo-photodynamic therapy. Our strategy involves the PUFAylation of a cytotoxic agent using a polyunsaturated fatty acid (PUFA) via a self-immolation thioketal linkage and a photosensitizer via noncleavable linker. Both PUFAylated prodrugs self-assemble into PSPC therapeutic nanoassemblies without any exogenous excipients. Upon near-infrared (NIR) photoirradiation, the neighboring photosensitizer generates reactive oxygen species (ROS), which spontaneously degrades the thioketal bond to activate the cytotoxic drug cabazitaxel. Consequently, light illumination produces phototoxicity in synchrony with a tumor-specific cascade reaction to accelerate the release of cabazitaxel for potentiating therapeutic synergistic effects on cancer. In multiple mouse models of melanoma xenografts, one of which is a patient-derived xenograft, PSPC nanoassemblies exert a synergistic effect to effectively eradicate tumors. More importantly, the tumor-selective nanotherapy exhibits substantially low systemic toxicity in animals. We propose that the PSPC nanotherapies created using self-assembling small-molecule prodrugs have great therapeutic potential because they enable the spatiotemporal activation of drugs in tumors while alleviating systemic drug exposure and associated toxicities.