Pan Meichen, Yang Chunrong, Fu Zhongliang, Yang Yuchen, Zhuo Ying, Hou Hongwei, Li Jinghong
School of Biomedical Sciences, Hunan University, Changsha, Hunan, 410082, China.
Department of Chemistry, Center for BioAnalytical Chemistry, Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing, 100084, China.
Adv Sci (Weinh). 2025 Jun 29:e01384. doi: 10.1002/advs.202501384.
Proteolysis targeting chimera (PROTAC), as an emerging approach for target protein degradation based on the intracellular ubiquitin-protease system, is characterized by catalytic and reusability over traditional inhibitors. However, PROTACs are fraught with pharmacokinetic dangers due to poor water solubility and membrane permeability, further posing a huge challenge to the clinical potential. Herein, a nanodelivery system is developed that is elaborately decorated with prodrugs to improve the physicochemical properties and therapeutic efficacy of PROTAC. The nanodelivery, lipid nanodisk (LND), is readily assembled from three commercially available phospholipids, and shows high stability and long circulation time in vivo. The lipid-derived prodrug realizes prolonged retention and precise release of PROTACs at tumor sites under the endogenous stimulus. Collectively, the LND loaded with MZ1 prodrug (LND-MZ1) presents enhanced biocompatibility, improves intracellular accumulation, and superior tumor penetration capacity, enabling more potent and targeted PROTAC therapy with enhanced specificity in vivo. LND-MZ1 shows a more significant anti-tumor effect in the xenograft tumor model, even at a one-tenth dose of the parent PROTACs under the same therapeutic schedule. Overall, the LND-based nanomedicine paves the way for remodeling the physicochemical and pharmacokinetic properties of various drugs to expand the therapeutic scope.
蛋白酶靶向嵌合体（PROTAC）作为一种基于细胞内泛素-蛋白酶系统的新型靶向蛋白降解方法，具有优于传统抑制剂的催化性和可重复使用性。然而，由于水溶性和膜通透性差，PROTAC存在药代动力学风险，这对其临床应用潜力构成了巨大挑战。在此，我们开发了一种纳米递送系统，该系统用前药精心修饰，以改善PROTAC的理化性质和治疗效果。这种纳米递送载体，即脂质纳米盘（LND），由三种市售磷脂轻松组装而成，在体内表现出高稳定性和长循环时间。脂质衍生的前药可在内源刺激下实现PROTAC在肿瘤部位的延长保留和精确释放。总体而言，负载MZ1前药的LND（LND-MZ1）具有增强的生物相容性，改善了细胞内蓄积，并具有出色的肿瘤穿透能力，能够在体内实现更有效、更具靶向性的PROTAC治疗，且特异性增强。在相同治疗方案下，即使给予亲本PROTAC十分之一的剂量，LND-MZ1在异种移植肿瘤模型中也显示出更显著的抗肿瘤效果。总的来说，基于LND的纳米药物为重塑各种药物的理化性质和药代动力学性质以扩大治疗范围铺平了道路。
