期刊
ADVANCED MATERIALS
卷 30, 期 21, 页码 -出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/adma.201706307
关键词
combination chemotherapy; gated crosslinked vesicles; permeabilization; polyprodrug amphiphiles; therapeutic activation
类别
资金
- National Natural Science Foundation of China (NNSFC) [51690150, 51690154, 21674103, 21674040, 21504087]
- Natural Science Foundation for Distinguished Young Scholars of Guangdong Province [2016A030306013]
- Guangdong Program for Support of Top-notch Young Professionals [2015TQ01R604]
- Scientific Research Projects of Guangzhou [201607010328]
- International S&T Cooperation Program of China (ISTCP) of Ministry of Science and Technology of the People's Republic of China [2016YFE0129700]
Combination chemotherapy with both hydrophobic and hydrophilic therapeutic drugs is clinically vital toward the treatment of persistent cancers. Though conventional liposomes and polymeric vesicles possessing hydrophobic bilayers and aqueous interiors can serve as codelivery nanocarriers, it remains a considerable challenge to achieve synchronized release of both types of drugs due to distinct encapsulation mechanisms; premature release of water-soluble cargos from unstable liposomes and ruptured vesicles is also a major concern. Herein, the fabrication of physiologically stable polyprodrug-gated crosslinked vesicles (GCVs) via the self-assembly of camptothecin (CPT) polyprodrug amphiphiles and in situ bilayer crosslinking through traceless sol-gel reaction is reported. Polyprodrug-GCVs possess high CPT loading (>30 wt%) and minimized leakage of encapsulated hydrophilic doxorubicin (DOX) hydrochloride due to the suppressed permeability of crosslinked membrane, exhibiting extended blood circulation (t(1/2) > 13 h) with caged cytotoxicity in physiological circulation. Upon cellular uptake by cancer cells, cytosolic reductive milieu-triggered CPT unplugging from vesicle bilayers is demonstrated to generate hydrophilic mesh channels and make the membrane highly permeable. Concurrently, it will promote DOX corelease from hydrophilic lumen (approximate to 36-fold increase). The reduction-activated combination chemotherapeutic potency based on polyprodrug-GCVs is confirmed by both in vitro and in vivo explorations.
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