Self-Strengthened Oxidation-Responsive Bioactivating Prodrug Nanosystem with Sequential and Synergistically Facilitated Drug Release for Treatment of Breast Cancer
Self-Strengthened Oxidation-Responsive Bioactivating Prodrug Nanosystem with Sequential and Synergistically Facilitated Drug Release for Treatment of Breast Cancer
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用于治疗乳腺癌的具有顺序和协同促进药物释放的自强化氧化响应生物活化前药纳米系统
DOI：
10.1021/acsami.9b03056
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发表时间：
2019-05-29
影响因子：
9.5
通讯作者：
Sun, Jin
中科院分区：
文献类型：
--
作者：
Wang, Kaiyuan;Yang, Bin;Sun, Jin
尽管环境敏感的前药纳米粒发展迅速，但由于肿瘤的异质性，许多前药纳米粒对母体药物的选择性和生物激活效率仍然很差。本文中，通过将氧化响应性硫醚连接的亚油酸紫杉醇缀合物（PTX-S-LA）和β-拉帕酮（LPC）共包封到聚合物胶束（PM）中来制造基于自增强生物活化前药的NP。在细胞摄取后，PM首先释放LPC，通过NAD（P）H：醌氧化还原酶-1（NQO 1）催化显著提高活性氧化物质（ROS）水平。然后，NQO 1产生的ROS与肿瘤细胞中内源性高ROS水平的组合可以协同促进PTX-S-LA释放活性细胞毒性剂PTX。这种新型的前药纳米系统表现出自增强的前药生物活化、超选择性释放、癌细胞和正常细胞之间的细胞毒性、延长的循环时间和增强的肿瘤蓄积，导致高抗肿瘤效率和上级生物安全性。我们的研究结果为合理设计氧化响应性前药纳米粒用于高效癌症化疗铺平了新的道路。
Although environment-sensitive prodrug-based nanoparticles (NPs) have developed rapidly, lots of prodrug NPs still show poor selectivity and efficiency of parent drug bioactivation because of tumor heterogeneity. Herein, self-strengthened bioactivating prodrug-based NPs are fabricated via co-encapsulation of oxidation-responsive thioether-linked linoleic acidpaclitaxel conjugates (PTX-S-LA) and beta-lapachone (LPC) into polymeric micelles (PMs). Following cellular uptake, PMs first release LPC to significantly elevate the reactive oxidative species (ROS) level through NAD(P)H: quinone oxidoreductase-1 (NQO1) catalysis. Then, NQO1-generated ROS in combination with endogenous high ROS levels in tumor cells could synergistically facilitate PTX-S-LA to release the active cytotoxic agent PTX. Such a novel prodrug nanosystem exhibits self strengthened prodrug bioactivation, ultraselective release, and cytotoxicity between cancer and normal cells, prolonged circulation time, and enhanced tumor accumulation, leading to high antitumor efficiency and superior biosafety. Our findings pave the new way for the rational design of oxidation-responsive prodrug NPs for high-efficacy cancer chemotherapy.