College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou 311121, China.
College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou 310003, China.
J Control Release. 2023 Sep;361:270-279. doi: 10.1016/j.jconrel.2023.07.062. Epub 2023 Aug 9.
Proteolysis-targeting chimera (PROTAC) is emerging as a new strategy to degrade target proteins in a precise way by taking advantage of the cellular ubiquitin-proteasome system. However, the potential cytotoxicity of PROTAC should be avoided to mitigate the off-target degradation of proteins in healthy tissues or cells. To address this issue, we herein present a strategy to cage a PROTAC with 4-(vinyloxy) benzyl carbonate (MZ1-O), which can be eliminated through a 3,6-dimethyl-1,2,4,5-tetrazine (Tz)-mediated inverse electron-demand Diels-Alder (iEDDA) reaction to generate a BRD4 (bromodomain-containing protein 4) degrader, MZ1. We further propose a dissolvable microneedle-assisted strategy for site-specific activation of MZ1-O that is delivered by a targeted delivery vector through systemic route in vivo, and demonstrate such a bioorthogonal strategy is efficient and precise for tumor treatment. Our study suggests that the bioorthogonal activation of PROTAC-based prodrug offers a highly specific and precise approach for cancer therapy.
蛋白水解靶向嵌合体（PROTAC）利用细胞内泛素-蛋白酶体系统，以精确的方式降解靶蛋白，作为一种新兴策略正在出现。然而，为了减轻 PROTAC 对健康组织或细胞中蛋白质的脱靶降解，应避免其潜在的细胞毒性。针对这一问题，我们提出了一种用 4-(乙烯氧基)苄基碳酸酯（MZ1-O）笼状包裹 PROTAC 的策略，通过 3,6-二甲基-1,2,4,5-四嗪（Tz）介导的逆电子需求 Diels-Alder（iEDDA）反应可以消除 MZ1-O，生成 BRD4（含溴结构域蛋白 4）降解剂 MZ1。我们进一步提出了一种可溶解的微针辅助策略，用于通过靶向递送载体经全身途径在体内进行 MZ1-O 的位点特异性激活，并证明这种生物正交策略在肿瘤治疗中是高效和精确的。我们的研究表明，基于 PROTAC 的前药的生物正交激活为癌症治疗提供了一种高度特异和精确的方法。
