Quantitative self-assembly of photoactivatable small molecular prodrug cocktails for safe and potent cancer chemo-photodynamic therapy. (February 2021)

• Record Type: Journal Article
• Authors: Huang, Lingling; Wan, Jianqin; Wu, Honghui; Chen, Xiaona; Bian, Qiong; Shi, Linlin; Jiang, Xinchi; Yuan, Anran; Gao, Jianqing; Wang, Hangxiang
• Is Part Of: Nano today. Volume 36(2021)
• Publication Date: 2021-02
• Subjects: Prodrug -- Self-assembly -- Combination therapy -- Size transformability -- Photodynamic therapy; Nanotechnology -- Periodicals; Nanosciences -- Périodiques; 620.505
• DOI: 10.1016/j.nantod.2020.101030
• Languages: English
• ISSNs: 1748-0132

Abstract

Graphical abstract: Highlights: PUFAylation of small-molecule therapeutics enabled self-assembly of the prodrugs into injectable cocktail nanoparticles. Near-infrared light illumination produced photocytotoxicity in synchrony with a cascade reaction for drug activation. Quantitative encapsulation efficiency (>98 %) and high drug loading (∼65 %) were achieved. Nanoassemblies potentiated synergistic chemo/photodynamic efficacy in vivo . High efficacy and low toxicity were validated against multiple cell-derived and patient-derived xenograft models. Abstract: 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.