State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Biological Science and Medical Engineering, Donghua University, Shanghai, 201620, China.
School of Pharmacy, Second Military Medical University, Shanghai, 200433, China.
Small. 2024 Feb;20(8):e2306378. doi: 10.1002/smll.202306378. Epub 2023 Oct 10.
Proteolysis-targeting chimeras (PROTACs) can provide promising opportunities for cancer treatment, while precise regulation of their activities remains challenging to achieve effective and safe therapeutic outcomes. A semiconducting polymer nanoPROTAC (SPN ) is reported that can achieve ultrasound (US) and tumor microenvironment dual-programmable PROTAC activity for deep-tissue sonodynamic-ferroptosis activatable immunotherapy. SPN is formed through a nano-precipitation of a sonodynamic semiconducting polymer, a ferroptosis inducer, and a newly synthesized PROTAC molecule. The semiconducting polymers work as sonosensitizers to produce singlet oxygen ( O ) via sonodynamic effect under US irradiation, and ferroptosis inducers react with intratumoral hydrogen peroxide (H O ) to generate hydroxyl radical (·OH). Such a dual-programmable reactive oxygen species (ROS) generation not only triggers ferroptosis and immunogenic cell death (ICD), but also induces on-demand activatable delivery of PROTAC molecules into tumor sites. The effectively activated nanoPROTACs degrade nicotinamide phosphoribosyl transferase (NAMPT) to suppress tumor infiltration of myeloid-derived suppressive cells (MDSCs), thus promoting antitumor immunity. In such a way, SPN mediates sonodynamic-ferroptosis activatable immunotherapy for entirely inhibiting tumor growths in both subcutaneous and 2-cm tissue-covered deep tumor mouse models. This study presents a dual-programmable activatable strategy based on PROTACs for effective and precise cancer combinational therapy.
蛋白水解靶向嵌合体（PROTACs）可为癌症治疗提供有前景的机会，而精确调控其活性对于实现有效和安全的治疗效果仍然具有挑战性。本文报道了一种半导体聚合物纳米 PROTAC（SPN），它可以实现超声（US）和肿瘤微环境的双重可编程 PROTAC 活性，用于深组织声动力学-铁死亡激活免疫治疗。SPN 通过超声处理下的声敏半导体聚合物、铁死亡诱导剂和新合成的 PROTAC 分子的纳米沉淀形成。半导体聚合物作为声敏剂，通过声动力学效应产生单线态氧（1 O 2 ），铁死亡诱导剂与肿瘤内的过氧化氢（H 2 O 2 ）反应生成羟基自由基（·OH）。这种双重可编程活性氧（ROS）的产生不仅触发铁死亡和免疫原性细胞死亡（ICD），还能按需将 PROTAC 分子递送到肿瘤部位。有效激活的纳米 PROTAC 降解烟酰胺磷酸核糖转移酶（NAMPT），抑制髓系来源抑制细胞（MDSCs）浸润肿瘤，从而促进抗肿瘤免疫。通过这种方式，SPN 介导了声动力学-铁死亡激活免疫治疗，完全抑制了皮下和 2cm 组织覆盖的深部肿瘤小鼠模型中的肿瘤生长。本研究提出了一种基于 PROTAC 的双重可编程激活策略，用于有效的癌症联合治疗。
