Syahputra Endry Wahyu, Lee Hyunji, Cho Hyukjun, Park Hyun Jin, Park Kwang-Su, Hwang Duhyeong
College of Pharmacy, Keimyung University, Daegu 42601, Republic of Korea.
College of Pharmacy, Kyungsung University, Busan 48434, Republic of Korea.
Pharmaceutics. 2025 Apr 9;17(4):501. doi: 10.3390/pharmaceutics17040501.
Proteolysis targeting chimeras (PROTACs), heterobifunctional molecules that hijack the ubiquitin-proteasome system (UPS) to degrade specific proteins, hold great promise in treating diseases driven by traditionally "undruggable" targets. However, their large molecular weight, high hydrophobicity, and other physicochemical hurdles contribute to their limited bioavailability, suboptimal pharmacokinetics, and attenuated therapeutic efficacy. Consequently, diverse formulation innovations have been investigated to optimize PROTAC delivery. This review examines current challenges and advances in specialized drug delivery approaches designed to bolster PROTAC pharmacological performance. We first outline the fundamental limitations of PROTACs-their low aqueous solubility, poor cell permeability, rapid clearance, and concentration-dependent "hook effect". We then discuss how various enabling formulations address these issues, including polymeric micelles, emulsions, amorphous solid dispersions, lipid-based nanoparticles, liposomes, and exosomes. Collectively, these delivery technologies substantially improve the therapeutic outcomes of PROTACs in preclinical cancer models. Future applications may extend beyond oncology to address other complex diseases using newly emerging heterobifunctional molecules. By integrating advanced formulation science with innovative degrader design, the field stands poised to unlock the clinical potential of PROTACs for protein degradation therapies.
蛋白酶靶向嵌合体（PROTACs）是一类异双功能分子，可利用泛素-蛋白酶体系统（UPS）降解特定蛋白质，在治疗由传统上“不可成药”靶点驱动的疾病方面具有巨大潜力。然而，它们的大分子量、高疏水性和其他物理化学障碍导致其生物利用度有限、药代动力学不理想以及治疗效果减弱。因此，人们研究了多种制剂创新方法以优化PROTAC的递送。本综述探讨了旨在增强PROTAC药理性能的特殊药物递送方法的当前挑战和进展。我们首先概述了PROTAC的基本局限性——它们的低水溶性、差的细胞通透性、快速清除以及浓度依赖性“钩效应”。然后我们讨论了各种辅助制剂如何解决这些问题，包括聚合物胶束、乳液、无定形固体分散体、脂质纳米颗粒、脂质体和外泌体。总体而言，这些递送技术在临床前癌症模型中显著改善了PROTAC的治疗效果。未来的应用可能会超越肿瘤学领域，利用新出现的异双功能分子来解决其他复杂疾病。通过将先进的制剂科学与创新的降解剂设计相结合，该领域有望释放PROTAC在蛋白质降解疗法方面的临床潜力。
