De‐novo Design of Structure‐tunable Multivalent Chimeras for Tumor‐Targeted PD‐L1 Degradation and Potentiated Cancer Immunotherapy

IF 16.1 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Huiling Zhou, Bo Hou, Yiming Shan, Lujia Huang, Fangmin Chen, Siyuan Ren, Shunan Zhang, Jiaxing Pan, Yijing Dang, Haijun Yu, Zhiai Xu
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引用次数: 0

Abstract

Targeted protein degradation (TPD) technology holds significant potential for modulating protein homeostasis and treating diseases. However, current methods for degrading membrane protein highly depend on the lysosome‐targeting ligands or membrane receptors. In this study, we present a set of multivalent targeting chimeras (multi‐TACs) for tumor‐specific degradation of programmed death ligand 1 (PD‐L1) on the surface of tumor cell membrane. The multi‐TACs are synthesized by copolymerization of small molecule PD‐L1 inhibitor BMS‐1 with acid‐responsive monomers. The chemical structures of the multi‐TACs are optimized by investigating the correlation between PD‐L1 degradation efficacy and the key parameters including acid‐sensitive moieties, BMS‐1 valences and spacer lengths. Mechanistic study reveals that the multi‐TACs highly efficiently degrade PD‐L1 on the surface of tumor cells via the adsorption‐mediated endocytosis and lysosomal degradation pathways, which differ significantly from the reported strategies for membrane protein degradation. The outperformed multi‐TAC GG56 with tumor extracellular acidity and enzyme‐sensitivity dramatically reduces PD‐L1 levels and suppresses tumor growth in mouse models of B16‐F10 melanoma and 4T1 breast tumors. Furthermore, GG56 serves as a versatile nanoplatform for combinatory chemo‐immunotherapy and radio‐immunotherapy of 4T1 breast tumor by co‐delivery of chemotherapeutic and radio‐sensitizer, respectively.
用于肿瘤靶向PD - L1降解和增强癌症免疫治疗的结构可调多价嵌合体从头设计
靶向蛋白降解(TPD)技术在调节蛋白质稳态和治疗疾病方面具有重要的潜力。然而,目前的膜蛋白降解方法高度依赖于溶酶体靶向配体或膜受体。在这项研究中,我们提出了一组多价靶向嵌合体(multi - tac),用于肿瘤细胞膜表面程序性死亡配体1 (PD - L1)的肿瘤特异性降解。多tac是由小分子PD‐L1抑制剂BMS‐1与酸响应单体共聚合成的。通过研究PD - L1降解效果与酸敏感基团、BMS - 1价和间隔长度等关键参数的关系,优化了多tac的化学结构。机制研究表明,多tac通过吸附介导的内吞作用和溶酶体降解途径高效地降解肿瘤细胞表面的PD‐L1,这与报道的膜蛋白降解策略有很大不同。在B16‐F10黑色素瘤和4T1乳腺肿瘤小鼠模型中,具有肿瘤细胞外酸性和酶敏感性的多TAC GG56显著降低PD‐L1水平,抑制肿瘤生长。此外,GG56作为一种多功能纳米平台,分别通过联合递送化疗药物和放射增敏剂,对4T1乳腺肿瘤进行联合化疗免疫治疗和放射免疫治疗。
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来源期刊
CiteScore
26.60
自引率
6.60%
发文量
3549
审稿时长
1.5 months
期刊介绍: Angewandte Chemie, a journal of the German Chemical Society (GDCh), maintains a leading position among scholarly journals in general chemistry with an impressive Impact Factor of 16.6 (2022 Journal Citation Reports, Clarivate, 2023). Published weekly in a reader-friendly format, it features new articles almost every day. Established in 1887, Angewandte Chemie is a prominent chemistry journal, offering a dynamic blend of Review-type articles, Highlights, Communications, and Research Articles on a weekly basis, making it unique in the field.
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