CAS Key Laboratory of Soft Matter Chemistry, Department of Polymer Science and Engineering, University of Science and Technology of China , Hefei 230026, Anhui, China.
Department of Pharmacology, Xinhua University of Anhui , Hefei 230088, China.
ACS Appl Mater Interfaces. 2017 Sep 6;9(35):29538-29546. doi: 10.1021/acsami.7b08347. Epub 2017 Aug 22.
The improved antioxidant system of cancer cells renders them well-adaptive to the intrinsic oxidative stress in tumor tissues. On the other hand, cancer cells are more sensitive to elevated tumor oxidative stress as compared with normal cells due to their deficient reactive oxygen species-eliminating systems. Oxidation therapy of cancers refers to the strategy of killing cancer cells through selectively increasing the oxidative stress in tumor tissues. In this article, to amplify the oxidation therapy, we develop integrated nanoparticles with the properties to elevate tumor oxidative stress and concurrently suppress the antioxidative capability of cancer cells. The amphiphilic block copolymer micelles of poly(ethylene glycol)-b-poly[2-((((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)carbonyl)oxy)ethyl methacrylate] (PEG-b-PBEMA) are integrated with palmitoyl ascorbate (PA) to form hybrid micelles (PA-Micelle). PA molecules at pharmacologic concentrations serve as a prooxidant to upregulate the hydrogen peroxide (HO) level in tumor sites and the PBEMA segment exhibits HO-triggered release of quinone methide for glutathione depletion to suppress the antioxidative capability of cancer cells, which synergistically and selectively kill cancer cells for tumor growth suppression. Given the significantly low side toxicity against normal tissues, this novel integrated nanoparticle design represents a novel class of nanomedicine systems for high-efficiency oxidation therapy with the potentials to be translated to clinical applications.
癌细胞改良的抗氧化系统使它们能够很好地适应肿瘤组织中的内在氧化应激。另一方面，由于癌细胞缺乏清除活性氧物质的系统，与正常细胞相比，它们对升高的肿瘤氧化应激更为敏感。癌症的氧化治疗是指通过选择性地增加肿瘤组织中的氧化应激来杀死癌细胞的策略。在本文中，为了放大氧化治疗的效果，我们开发了具有提高肿瘤氧化应激和同时抑制癌细胞抗氧化能力的综合纳米粒子。聚乙二醇-b-聚2-(((4-(4,4,5,5-四甲基-1,3,2-二恶硼烷-2-基)苄基)氧基)羰基)氧基)乙基甲基丙烯酸酯的两亲性嵌段共聚物胶束与棕榈酰抗坏血酸(PA)整合形成混合胶束(PA-胶束)。在药理浓度下，PA 分子作为一种促氧化剂，可上调肿瘤部位的过氧化氢(HO)水平，而 PBEMA 段则表现出 HO 触发的醌甲醚释放，以耗尽谷胱甘肽来抑制癌细胞的抗氧化能力，从而协同且选择性地杀死癌细胞，抑制肿瘤生长。鉴于对正常组织的毒性明显较低，这种新型的综合纳米粒子设计代表了一类新型的纳米医学系统，可用于高效氧化治疗，并有可能转化为临床应用。
