College of Chemical and Environment Protection, Southwest Minzu University, First Ring Road, 4th Section No.16, Chengdu, Sichuan 610041, China.
College of Chemical and Environment Protection, Southwest Minzu University, First Ring Road, 4th Section No.16, Chengdu, Sichuan 610041, China.
Colloids Surf B Biointerfaces. 2018 Oct 1;170:373-381. doi: 10.1016/j.colsurfb.2018.06.015. Epub 2018 Jun 18.
The high toxicity, poor stability, premature drug release, and lack of intracellular stimuli responsibility of current polymeric micelles still hinder them for potential clinical applications. To address these challenges, a novel type of multi-stimuli responsive, core cross-linked polypeptide hybrid micelles (CCMs) was developed for triggered anticancer drug delivery in tumor microenvironment. The CCMs was prepared via free radical copolymerization by using N,N'-methylene-bis-acylamide (BACy) as the cross-linking agent, 2,2-azobisisobutyronitrile (AIBN) as the initiator, where poly (γ-benzyl-L-glutamate) (PBLG) and N-isopropylacrylamide (NIPPAM) as comonomers. The doxorubicin (DOX) was then introduced into the CCMs by hydrazone bond to prepare the drug-incorporated core cross-linked micelles (CCMs-DOX). By the experimental results, the CCMs showed reduction responsibility due to the degradable disulfide bond in the polymer network. The hydrazone bond can be broken under acidic condition causing a controllable drug release for CCMs-DOX. Compared to only 7.7% DOX release under pH 7.4 at 37°C, a much higher DOX release rate up to 85.3% was observed under 10 mM GSH (pH 5.0, 42°C). In vitro cell assays showed that the blank CCMs showed almost no toxicity against HUVEC cells while the CCMS-DOX exhibited significant cancer cell killing effect. These experimental results suggested that the prepared multi-stimuli responsive polymeric micelles could serve as a smart and promising drug delivery candidate for anti-cancer therapy.
当前的聚合物胶束仍然存在毒性高、稳定性差、药物提前释放以及缺乏细胞内刺激响应等问题，这限制了它们在潜在临床应用中的发展。为了解决这些挑战，开发了一种新型的多刺激响应的核交联多肽杂化胶束（CCMs），用于在肿瘤微环境中触发抗癌药物的递送。通过自由基共聚反应，使用 N,N'-亚甲基双丙烯酰胺（BACy）作为交联剂，2,2-偶氮二异丁腈（AIBN）作为引发剂，聚（γ-苄基-L-谷氨酸）（PBLG）和 N-异丙基丙烯酰胺（NIPPAM）作为共聚单体来制备 CCMs。然后通过腙键将阿霉素（DOX）引入 CCMs 中，制备载药的核交联胶束（CCMs-DOX）。实验结果表明，由于聚合物网络中的可降解二硫键，CCMs 具有还原响应性。腙键在酸性条件下可以断裂，从而使 CCMs-DOX 能够进行可控的药物释放。与在 pH 7.4、37°C 下仅 7.7%的 DOX 释放相比，在 pH 5.0、42°C 下 10 mM GSH 条件下，DOX 的释放率高达 85.3%。体外细胞实验表明，空白 CCMs 对 HUVEC 细胞几乎没有毒性，而 CCMs-DOX 则表现出显著的癌细胞杀伤作用。这些实验结果表明，所制备的多刺激响应性聚合物胶束可以作为一种智能且有前途的抗癌治疗药物递送载体。
