期刊
ACS APPLIED MATERIALS & INTERFACES
卷 9, 期 12, 页码 10567-10576出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsami.7b01938
关键词
cancer nanomedicine; prodrug cocktail; antiangiogenesis; combination; therapy; self-assembly
资金
- National Natural Science Foundation of China [81571799, 31671019, 21202147, 81421062, 91542205]
- Natural Science Foundation of Zhejiang Province [LY13H090013, LQ14B020003]
- Science and Technology Research Program of Jinhua City [2013-3-054]
The synergistic combination of two or more chemotherapeutics frequently requires packaging in single delivery vehicles for the sequential release of each substance in a predictable manner. Here, we demonstrate for the first time that the rational engineering of a prodrug cocktail into single polymeric nanoparticles (NPs) can enable the sequential release of chemotherapeutics in a controllable manner. Exploiting combretastatin-A4 (CA4, 1) as a model antiangiogenesis agent, two ester derivatives, 2 and 3, tethered with saturated fatty acids (butanoic and heptanoic acid for 2 and 3, respectively) were synthesized. 7-Ethyl-10-hydroxycamptothecin (SN38) derivative 4, esterified with a-linolenic acid, was used as a cytotoxic drug. Because of their augmented lipophilicity and miscibility, all constructed prodrugs readily assembled with clinically approved polymeric matrices. Results showed that altering the aliphatic chains of modifiers for CA4 chemical derivatization enabled the drug retention capacity within particle systems to be adjusted, leading to the ideritification of the prodrug cocktail of 2 and 4 as an optimal combination for subsequent preclinical studies. Furthermore; in vivo assessements indicated: that the resulting NPs simultaneously formulating 2 and 4 exhibited synergistic activities and outperformed NPs loaded with,individual prodrugs 2 or 4 in terms of therapeutic efficacy. These findings highlight a novel and versatile strategy for tailoring chemically disparate prodrug, cocktails for adaptation within a single nanoplatform as a potential modality for synergistic cancer therapy.
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