Prodrug self-nanoassemblies have many advantages for anticancer drug delivery, including high drug loading rate, resistance to recrystallization, and on-demand drug release. However, few studies have focused on their protein corona, which is inevitably formed after entering the blood and determines their subsequent fates in vivo. To actively tune the protein corona of prodrug nanoassemblies, three maleimide-paclitaxel prodrugs were synthesized via different redox-sensitive linkers (ester bond, thioether bond and disulfide bond). After incubation with rat plasma, the surface maleimide groups effectively captured albumins, resulting in albumin-enriched protein corona. The recruited albumin corona enabled enhanced tumor accumulation and facilitated cellular uptake, ensuring the high-efficiency delivery of nanoassemblies to tumor cells. Surprisingly, we found that the traditionally reduction-sensitive disulfide bond could also be triggered by reactive oxygen species (ROS). Such a redox dual-responsive drug release property of the disulfide bond-containing prodrug nanoassemblies further increased the selectivity in cytotoxicity between normal and tumor cells. Moreover, the disulfide bond-containing prodrug nanoassemblies exhibited the highest antitumor efficacy in vivo compared to marketed Abraxane® and other prodrug nanoassemblies. Thus, the fabrication of the maleimide-decorated disulfide bond bridged prodrug nanoassembly, integrating a tunable protein corona and on-demand drug release, is a promising strategy for improved cancer chemotherapy.

中文翻译：

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氧化还原双敏感紫杉醇前药制造的基于前药的纳米组件的体内定制蛋白电晕，用于乳腺癌的超选择性治疗†

前药自组装具有抗癌药物输送的许多优点，包括高载药率，抗重结晶和按需释放药物。然而，很少有研究集中在它们的蛋白质电晕上，这种蛋白质电晕是在进入血液后不可避免地形成的，并决定了它们随后在体内的命运。为了积极调整前药纳米组件的蛋白质电晕，通过以下方法合成了三种马来酰亚胺-紫杉醇前药：不同的氧化还原敏感接头（酯键，硫醚键和二硫键）。与大鼠血浆一起温育后，表面的马来酰亚胺基团有效捕获了白蛋白，从而产生了富含白蛋白的蛋白质电晕。募集的白蛋白电晕能够增强肿瘤的积累并促进细胞摄取，从而确保将纳米组件高效递送至肿瘤细胞。令人惊讶的是，我们发现传统上还原敏感的二硫键也可能由活性氧（ROS）触发。含二硫键的前药纳米组件的这种氧化还原双重响应药物释放特性进一步提高了正常细胞与肿瘤细胞之间细胞毒性的选择性。此外，含二硫键的前药纳米组装体在体内表现出最高的抗肿瘤功效与市售的Abraxane®和其他前药纳米组件相比。因此，马来酰亚胺修饰的二硫键桥接的前药纳米组装体的制备，整合了可调的蛋白电晕和按需释放的药物，是改善癌症化学疗法的有前途的策略。