蛋白水解靶向嵌合体(PROTACs)通过诱导肿瘤过度表达的致癌蛋白的降解而迅速成为癌症治疗的潜在治疗策略。它们可以通过募集E3连接酶并利用泛素-蛋白酶体途径特异性催化目标致癌蛋白的降解。由于他们的行动方式是普遍的,不可逆转的,可回收,持久的,适用于“不可食用的”蛋白质,PROTACs正在逐渐取代常规小分子抑制剂的作用。此外,它们的应用领域正在扩展到癌症免疫疗法,作为参与免疫抑制肿瘤微环境的各种类型的致癌蛋白。然而,不良的水溶性和低的细胞渗透性极大地限制了药代动力学(PK)性质,这就需要使用适当的递送系统进行癌症免疫疗法。在这次审查中,一般特征,发展状况,首先简要介绍PROTACs的PK。接下来,介绍了最近对各种类型的被动或主动靶向递送系统在PROTACs中的应用的研究,描述了它们对PROTACs的PK和肿瘤靶向能力的影响。最后,综述了近年来用于肿瘤免疫治疗的PROTACs给药系统。采用适当的PROTAC递送系统有望加速PROTAC的临床翻译,以及提高其对癌症治疗的疗效。
Proteolysis-targeting chimeras (PROTACs) are rapidly emerging as a potential therapeutic strategy for cancer therapy by inducing the degradation of tumor-overexpressing oncogenic proteins. They can specifically catalyze the degradation of target oncogenic proteins by recruiting E3 ligases and utilizing the ubiquitin-proteasome pathway. Since their mode of action is universal, irreversible, recyclable, long-lasting, and applicable to \'undruggable\' proteins, PROTACs are gradually replacing the role of conventional small molecular inhibitors. Moreover, their application areas are being expanded to cancer immunotherapy as various types of oncogenic proteins that are involved in immunosuppressive tumor microenvironments. However, poor water solubility and low cell permeability considerably restrict the pharmacokinetic (PK) property, which necessitates the use of appropriate delivery systems for cancer immunotherapy. In this review, the general characteristics, developmental status, and PK of PROTACs are first briefly covered. Next, recent studies on the application of various types of passive or active targeting delivery systems for PROTACs are introduced, and their effects on the PK and tumor-targeting ability of PROTACs are described. Finally, recent drug delivery systems of PROTACs for cancer immunotherapy are summarized. The adoption of an adequate delivery system for PROTAC is expected to accelerate the clinical translation of PROTACs, as well as improve its efficacy for cancer therapy.