Cisplatin-Induced Formation of Biocompatible and Biodegradable Polypeptide-Based Vesicles for Targeted Anticancer Drug Delivery

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• 作者：Steven J. Shirbin ; Katharina Ladewig ; Qiang Fu ; Molly Klimak ; Xiaoqing Zhang ; Wei Duan ; Greg G. Qiao
• 刊名：Biomacromolecules
• 出版年：2015
• 出版时间：August 10, 2015
• 年：2015
• 卷：16
• 期：8
• 页码：2463-2474
• 全文大小：685K
• ISSN：1526-4602

文摘

Novel cisplatin (CDDP)-loaded, polypeptide-based vesicles for the targeted delivery of cisplatin to cancer cells have been prepared. These vesicles were formed from biocompatible and biodegradable maleimide-poly(ethylene oxide)₁₁₄-b-poly(_L-glutamic acid)₁₂ (Mal-PEG₁₁₄-b-PLG₁₂) block copolymers upon conjugation with the drug itself. CDDP conjugation forms a short, rigid, cross-linked, drug-loaded, hydrophobic block in the copolymer, and subsequently induces self-assembly into hollow vesicle structures with average hydrodynamic diameters (D_h) of 鈭?70 nm. CDDP conjugation is critical to the formation of the vesicles. The reactive maleimide-PEG moieties that form the corona and inner layer of the vesicles were protected via formation of a reversible Diels鈥揂lder (DA) adduct throughout the block copolymer synthesis so as to maintain their integrity. Drug release studies demonstrated a low and sustained drug release profile in systemic conditions (pH = 7.4, [Cl^{鈥?/sup>] = 140 mM) with a higher 鈥渂urst-like鈥?release rate being observed under late endosomal/lysosomal conditions (pH = 5.2, [Cl鈥?/sup>] = 35 mM). Further, the peripheral maleimide functionalities on the vesicle corona were conjugated to thiol-functionalized folic acid (FA) (via in situ reduction of a novel bis-FA disulfide, FA-SS-FA) to form an active targeting drug delivery system. These targeting vesicles exhibited significantly higher cellular binding/uptake into and dose-dependent cytotoxicity toward cancer cells (HeLa) compared to noncancerous cells (NIH-3T3), which show high and low folic acid receptor (FR) expression, respectively. This work thus demonstrates a novel approach to polypeptide-based vesicle assembly and a promising strategy for targeted, effective CDDP anticancer drug delivery.}