期刊
JOURNAL OF CONTROLLED RELEASE
卷 328, 期 -, 页码 325-338出版社
ELSEVIER
DOI: 10.1016/j.jconrel.2020.08.062
关键词
Self-assembly; Photosensitizer; Size transformability; Synergistic nanoparticle; Chemo/photodynamic therapy
资金
- Zhejiang Province Preeminence Youth Fund [LR19H160002]
- Leading Talent of Ten Thousand Plan-National High-Level Talents Special Support Plan [2017RA4028]
- National Natural Science Foundation of China [81773193, 81571799]
- Fundamental Research Fund for the Central Universities [2019XZZX003-18]
- Jiaxing Key Laboratory of Oncological Photodynamic Therapy and Targeted Drug Research
Development of injectable nanoparticles for delivery of active anticancer compounds often requires complicated schemes that involve tedious synthetic protocols and nanoformulations. In particular, clinical translation of synergistic nanoparticles that can facilitate multimodal therapies remains a considerable challenge. Herein, we describe a self-assembling, small-molecule nanosystem with unique properties, including near-infrared (NIR) light-responsive drug activation, size transformability, combinatorial synergy, and substantially reduced toxicity. Ligation of anticancer cabazitaxel (CTX) drugs via a reactive oxygen species-activatable thioketal linkage generates a dimeric TKdC prodrug, and subsequent coassembly with a photosensitizer, chlorin e6 (Ce6), forms colloidal-stable nanoassemblies (termed psTKdC NAs). Upon NIR laser irradiation, psTKdC NAs are transformed into smaller size particles and facilitate production of pharmacologically active CTX. Importantly, reactive oxygen species yielded by coassembled Ce6 can synergize with chemotherapy to achieve potent combinatorial effects. In a preclinical orthotopic model of an aggressive, human melanoma patient-derived xenograft (PDX), we show that administration of psTKdC NAs followed by laser irradiation produced durable tumor regression, with the tumors being completely eradicated in three of six PDXs. Furthermore, low systemic toxicity of this smart, photo-activatable nanotherapy was observed in animals. The new self-deliverable combinatorial system addresses essential requirements for high efficacy, safety, and translational capacity and deserves further investigation.
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