Dual-Sensitive Charge-Conversional Polymeric Prodrug for Efficient Codelivery of Demethylcantharidin and Doxorubicin

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• 作者：Yanjuan Wu ; Dongfang Zhou ; Qingfei Zhang ; Zhigang Xie ; Xuesi Chen ; Xiabin Jing ; Yubin Huang
• 刊名：Biomacromolecules
• 出版年：2016
• 出版时间：August 8, 2016
• 年：2016
• 卷：17
• 期：8
• 页码：2650-2661
• 全文大小：909K
• 年卷期：0
• ISSN：1526-4602

文摘

A tumor is a complicated system, and tumor cells are typically heterogeneous in many aspects. Polymeric drug delivery nanocarriers sensitive to a single type of biosignals may not release cargos effectively in all tumor cells, leading to low therapeutic efficacy. To address the challenges, here, we demonstrated a pH/reduction dual-sensitive charge-conversional polymeric prodrug strategy for efficient codelivery. Reduction-sensitive disulfide group and acid-labile anticancer drug (demethylcantharidin, DMC)-conjugated β-carboxylic amide group were repeatedly and regularly introduced into copolymer chain simultaneously via facile CuAAC click polymerization. The obtained multifunctional polymeric prodrug P(DMC), mPEG-b-poly(disulfide-alt-demethylcantharidin)-b-mPEG was further utilized for DOX encapsulation. Under tumor tissue/cell microenvironments (pH 6.5 and 10 mM GSH), the DOX-loaded polymeric prodrug nanoparticles (P(DMC)@DOX NPs) performed surface negative-to-positive charge conversion and accelerated/sufficient release of DMC and DOX. The remarkably enhanced cellular internalization and cytotoxicity in vitro, especially against DOX-resistant SMMC-7721 cells, were demonstrated. P(DMC)@DOX NPs in vivo also exhibited higher tumor accumulation and improved antitumor efficiency compared to P(SA)@DOX NPs with one drug and without charge-conversion ability. The desired multifunctional polymeric prodrug strategy brings a new opportunity for cancer chemotherapy.