A tumor-specific cleavable nanosystem of PEG-modified C60@Au hybrid aggregates for radio frequency-controlled release, hyperthermia, photodynamic therapy and X-ray imaging.

Taking advantages of fullerene (C60) and gold nanoparticles (AuNPs) for potentials in photodynamic therapy (PDT), drug delivery and radio frequency thermal therapy (RTT), a C60@Au hybrid nanocomposite was synthesized by chemical deposition of Au nanoparticles onto C60, and functionalized by PEG5000 via a pH cleavable hydrazone bond, making C60@Au-PEG keep the PEG on the surface of drug delivery system during circulation but dissociate PEG from the system after accumulation in tumor tissue, then doxorubicin (DOX) was loaded onto C60@Au-PEG with a very high drug loading efficiency. The release profiles of DOX from C60@Au-PEG/DOX showed strong dependences on radio frequency (RF). For the drug delivery, C60@Au-PEG/DOX afforded much higher antitumor efficacy owing to 8.6-fold higher DOX uptake of tumor than DOX. Besides, in this work, C60@Au-PEG/DOX not only served as a powerful RTT agent for RF-thermal ablation of tumor and a strong photosensitizer (PS) for PDT, but also as an X-ray contrast agent for tumor diagnosis. In the in vitro and in vivo studies, C60@Au-PEG/DOX showed excellent chemo-RF thermal-photodynamic therapeutic efficacy, RF-controlled drug releasing function, tumor targeting property, tumoral acid PEG dissociating character and X-ray imaging ability, demonstrating that there is a great potential of C60@Au-PEG/DOX for simultaneous diagnosis and therapy in cancer treatment. A significant challenge in cancer therapy is to maximize the therapeutic efficacy and minimize the side effects. In the past decade, a lot of nanoparticles have been used as the carriers for efficient drug delivery. However, the design of drug delivery system (DDS) with stimuli-responsive controlled-release property, simultaneous diagnosis and therapy functions is still a challenge. Herein, we developed a new drug delivery system (C60@Au-PEG/DOX), and explored its applications in tumor therapy. The in vitro and in vivo results showed C60@Au-PEG/DOX could significantly improve the therapeutic efficacy and reduce the systemic toxicity through X-ray imaging guided locatable DOX release, photodynamic and photothermal therapies. These results are of interest as they demonstrate a multi-functional DDS for tumor theranostic applications.

Shi J ，Chen Z ，Wang L ，Wang B ，Xu L ，Hou L ，Zhang Z ... -  《-》

PEGylated hydrazided gold nanorods for pH-triggered chemo/photodynamic/photothermal triple therapy of breast cancer.

Integration of multimodal therapies into one nanoplatform holds great promise to overcome the drawbacks of conventional single-modal therapy and pursues enhanced anticancer efficacy. Herein, we developed a PEGylated gold nanorods (GNRs)-based nanoplatform (GNRs-MPH-ALA/DOX-PEG) with pH-responsive drug release property for triple-combined chemotherapy (CT), photodynamic therapy (PDT) and photothermal therapy (PTT) of breast cancer. GNRs were first decorated with mercaptopropionylhydrazide (MPH) and thiol-terminated monomethoxyl poly(ethylene glycol) (mPEG-SH) via Au-thiol linkage, and subsequently conjugated with chemotherapeutant doxorubicin (DOX) and pro-photosensitizer 5-aminolevulinic acid (ALA) through acid-liable hydrazone bonds between drugs and MPH molecules. The resulting nanoplatform GNRs-MPH-ALA/DOX-PEG exhibited excellent stability in physiological solutions and pH-responsive DOX and ALA release behaviors. In vitro studies showed that GNRs-MPH-ALA/DOX-PEG could efficiently enter human breast cancer MCF-7 cells and release DOX and ALA into cytoplasm. Furthermore, DOX could locate in the cell nucleus and ALA was productively metabolized into protoporphyrin IX (PpIX). Upon near-infrared (NIR) irradiation, PpIX produced enough reactive oxygen species for PDT and meanwhile GNRs could efficiently induce hyperthermia for PTT. Compared with single CT and dual-modal CT/PDT or CT/PTT treatment, the triple-combined CT/PDT/PTT treatment could more efficiently kill MCF-7 cells via a superadditive antitumor effect. Furthermore, the circulation half-life of GNRs-MPH-ALA/DOX-PEG in the blood was as long as approximately 52 min and it exhibited a tumor accumulation of 3.3%. The triple-combined CT/PDT/PTT treatment could completely suppress tumor growth without obvious systemic toxicity. Our study paves a new avenue for multimodal therapy of breast cancer. STATEMENT OF SIGNIFICANCE: The development of a simple but effective strategy to construct a versatile nanoplatform for multi-combined therapy still remains an enormous challenge. In this work, we developed a novel and simple nanoplatform GNRs-MPH-ALA/DOX-PEG with pH-responsive drug release for triple-combined chemotherapy (CT), photodynamic therapy (PDT) and photothermal therapy (PTT) of breast cancer. The nanoplatform could be efficiently internalized by MCF-7 cells. The intracellular GNRs-MPH-ALA/DOX-PEG could release DOX for CT, induce hyperthermia for PTT and generate high levels of ROS for PTT. Compared with single CT and dual-modal CT/PDT or CT/PTT treatments, the triple-combined CT/PDT/PTT treatment could more efficiently kill MCF-7 cells via a superadditive antitumor effect. Furthermore, upon triple-combined CT/PDT/PTT treatment, the tumor growth was completely suppressed without obvious systemic toxicity.

Xu W ，Qian J ，Hou G ，Wang Y ，Wang J ，Sun T ，Ji L ，Suo A ，Yao Y ... -  《-》

Fullerene (C60)-based tumor-targeting nanoparticles with "off-on" state for enhanced treatment of cancer.

The traditional drug delivery systems always suffer from the unexpected drug release during circulation and the sluggish release of drug in target site. To address the problem, an "off-on" type drug delivery system with precise control was developed in this study. Doxorubicin (DOX) was covalently conjugated to fullerene (C60) nanoaggregates via a reactive oxygen species (ROS)-sensitive thioketal linker (C60-DOX NPs), and then the hydrophilic shell (Distearoyl-sn-glycero-3-phosphoethanolamine-PEG-CNGRCK2HK3HK11, DSPE-PEG-NGR) was attached to the outer surface of C60-DOX, giving it (C60-DOX-NGR NP) excellent stability in physiological solutions and active tumor-targeting capacity. C60-DOX-NGR NPs were able to entrap DOX efficiently even at acidic environment (pH5.5) when they were "off" state. In sharp contrast, when the NPs were "on" state, a large number of ROS were generated by C60, leading to the breaking of ROS-sensitive linker, thereby enabling the burst release of DOX. The "off" or "on" state of C60-DOX-NGR NPs could be precisely remote-controlled by a 532nm laser (at a low power density) with a high spatial/temporal resolution. In the in vivo and in vitro studies, the C60-based drug delivery system with "off-on" state exhibited a high antitumor efficacy and a low toxicity to normal tissues due to its tumor-targeting ability, remote-controlled drug release property and combined therapeutic effect (photodynamic therapy combined with chemotherapy).

Shi J ，Wang B ，Wang L ，Lu T ，Fu Y ，Zhang H ，Zhang Z ... -  《-》

A Multi-Functional Tumor Theranostic Nanoplatform for MRI Guided Photothermal-Chemotherapy.

Shi J ，Wang B ，Chen Z ，Liu W ，Pan J ，Hou L ，Zhang Z ... -  《-》

A tumoral acidic pH-responsive drug delivery system based on a novel photosensitizer (fullerene) for in vitro and in vivo chemo-photodynamic therapy.

Fullerene has shown great potential both in drug delivery and photodynamic therapy. Herein, we developed a doxorubicin (DOX)-loaded poly(ethyleneimine) (PEI) derivatized fullerene (C60-PEI-DOX) to facilitate combined chemotherapy and photodynamic therapy in one system, and DOX was covalently conjugated onto C60-PEI by the pH-sensitive hydrazone linkage. The release profiles of DOX from C60-PEI-DOX showed a strong dependence on the environmental pH value. The biodistributions of C60-PEI-DOX were investigated by injecting CdSe/ZnS (Qds) labeled conjugates (C60-PEI-DOX/Qds) into tumor-bearing mice. C60-PEI-DOX/Qds showed a higher tumor targeting efficiency compared with Qds alone. Compared with free DOX in an in vivo murine tumor model, C60-PEI-DOX afforded higher antitumor efficacy without obvious toxic effects to normal organs owing to its good tumor targeting efficacy and the 2.4-fold greater amount of DOX released in the tumor than in the normal tissues. C60-PEI-DOX also showed high antitumor efficacy during photodynamic therapy. The ability of C60-PEI-DOX nanoparticles to combine local specific chemotherapy with external photodynamic therapy significantly improved the therapeutic efficacy of the cancer treatment, the combined treatment demonstrating a synergistic effect. These results suggest that C60-PEI-DOX may be promising for high treatment efficacy with minimal side effects in future therapy.

Shi J ，Liu Y ，Wang L ，Gao J ，Zhang J ，Yu X ，Ma R ，Liu R ，Zhang Z ... -  《-》