华东师范大学Zhi-ai Xu，南京中医药大学Xiao-hua Chen等人合作，近期取得重要工作进展。他们研究提出，肿瘤靶向PROTAC前药纳米平台实现精确的蛋白质降解和癌症联合治疗。相关研究成果2024年4月12日在线发表于《中国药理学报》杂志上。

据介绍，蛋白质水解靶向嵌合体（PROTAC）已成为降解致病蛋白质的革命性抗癌疗法。然而，PROTAC的抗癌性能往往因其生物利用度不足、肿瘤特异性不以及诱导获得性耐药性的能力而受损。

研究人员提出了一种聚合物偶联的PROTAC前药平台，用于最流行的基于von Hippel–Lindau（VHL）和小脑（CRBN）的PROTAC的肿瘤靶向递送，以及降解剂和常规小分子药物的精确共递送。自组装的PROTAC前药纳米颗粒（NP）可以特异性靶向肿瘤细胞并在肿瘤细胞内被激活，以释放游离的PROTAC，从而精确降解蛋白质。PROTAC前药NP通过降解含溴结构域蛋白4（BRD4）或细胞周期蛋白依赖性激酶9（CDK9），在小鼠模型中引起MDA-MB-231乳腺肿瘤的有效消退，同时降低全身毒性。

此外，研究人员证明了PROTAC前药NP可以作为一个多功能平台，用于PROTAC和化疗药物的共同递送，以提高抗癌效率和组合效益。

总之，这一研究为利用肿瘤靶向蛋白降解进行精确的抗癌治疗和复杂疾病的有效联合治疗提供了方案。

附：英文原文

Title: Tumor-targeted PROTAC prodrug nanoplatform enables precise protein degradation and combination cancer therapy

Author: Zou, Zhi-feng, Yang, Lei, Nie, Hui-jun, Gao, Jing, Lei, Shu-min, Lai, Yi, Zhang, Fan, Wagner, Ernst, Yu, Hai-jun, Chen, Xiao-hua, Xu, Zhi-ai

Issue&Volume: 2024-04-12

Abstract: Proteolysis targeting chimeras (PROTACs) have emerged as revolutionary anticancer therapeutics that degrade disease-causing proteins. However, the anticancer performance of PROTACs is often impaired by their insufficient bioavailability, unsatisfactory tumor specificity and ability to induce acquired drug resistance. Herein, we propose a polymer-conjugated PROTAC prodrug platform for the tumor-targeted delivery of the most prevalent von Hippel–Lindau (VHL)- and cereblon (CRBN)-based PROTACs, as well as for the precise codelivery of a degrader and conventional small-molecule drugs. The self-assembling PROTAC prodrug nanoparticles (NPs) can specifically target and be activated inside tumor cells to release the free PROTAC for precise protein degradation. The PROTAC prodrug NPs caused more efficient regression of MDA-MB-231 breast tumors in a mouse model by degrading bromodomain-containing protein 4 (BRD4) or cyclin-dependent kinase 9 (CDK9) with decreased systemic toxicity. In addition, we demonstrated that the PROTAC prodrug NPs can serve as a versatile platform for the codelivery of a PROTAC and chemotherapeutics for enhanced anticancer efficiency and combination benefits. This study paves the way for utilizing tumor-targeted protein degradation for precise anticancer therapy and the effective combination treatment of complex diseases.

DOI: 10.1038/s41401-024-01266-z

Source: https://www.nature.com/articles/s41401-024-01266-z