State Key Laboratory of Natural Medicines, Key Laboratory of Drug Quality Control and Pharmacovigilance, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
J Mater Chem B. 2024 Mar 27;12(13):3240-3248. doi: 10.1039/d3tb03046f.
Proteolysis targeting chimeras (PROTACs) is a promising strategy for cancer therapy. However, the always-on bioactivity of PROTACs may lead to non-target toxicity, which restricts their antitumor performance. Here, we developed an X-ray radiation responsive PROTAC nanomicelle (RCNprotac) by covalently conjugating a reported small molecule PROTAC (MZ1) to hydrophilic PEG a diselenide bond-containing carbon chain, which then self-assembled into a 141.80 ± 5.66 nm nanomicelle. The RCNprotac displayed no bioactivity during circulation due to the occupation of the hydroxyl group on the E3 ubiquitin ligand component and could effectively accumulate at the tumor site owing to the enhanced permeability and retention effect. Upon exposure to X-ray radiation, the radiation-sensitive diselenide bonds were broken to specifically release MZ1 for tumor BRD4 protein degradation. Furthermore, the reduction in the BRD4 protein level could increase the tumor's sensitivity to radiation. RCNprotac showed a synergistic enhancement of antitumor effects both and . We believe that this X-ray-responsive PROTAC nanomicelle could provide a new strategy for the X-ray-activated spatiotemporally controlled protein degradation and for the BRD4 proteolysis enhanced tumor radiosensitivity.
蛋白水解靶向嵌合体（PROTAC）是癌症治疗的一种很有前途的策略。然而，PROTAC 的始终保持的生物活性可能导致非靶向毒性，从而限制了它们的抗肿瘤性能。在这里，我们通过将报道的小分子 PROTAC（MZ1）共价连接到亲水性 PEG 二硒键含碳链上，开发了一种 X 射线辐射响应的 PROTAC 纳米胶束（RCNprotac），然后自组装成 141.80 ± 5.66nm 的纳米胶束。由于 E3 泛素连接酶配体成分上的羟基被占据，RCNprotac 在循环过程中没有生物活性，并且由于增强的渗透性和保留效应，能够有效地聚集在肿瘤部位。在 X 射线辐射下，辐射敏感的二硒键被破坏，以特异性释放 MZ1 用于肿瘤 BRD4 蛋白降解。此外，BRD4 蛋白水平的降低可以增加肿瘤对辐射的敏感性。RCNprotac 表现出协同增强的抗肿瘤作用。我们相信，这种 X 射线响应的 PROTAC 纳米胶束可为 X 射线激活的时空可控蛋白降解以及 BRD4 蛋白水解增强肿瘤放射敏感性提供一种新策略。
