Beijing National Laboratory for Molecular Sciences, Radiochemistry and Radiation Chemistry Key Laboratory of Fundamental Science, NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China.
Changping Laboratory, Beijing, 102206, China.
Adv Mater. 2024 Feb;36(6):e2307818. doi: 10.1002/adma.202307818. Epub 2023 Dec 6.
Materials that can respond to multiple biomarkers simultaneously, acting as an "AND" gate, have the potential to enhance tumor-targeting for drug delivery. In this study, an "AND" logic-controlled release prodrug micelle is developed for codelivering the chemotherapeutic and the stimulator of interferon genes (STING) agonist, enabling precise combinatorial therapy. The drug release is programmed by tumor-enriched boramino acids (BAA) in the tumor microenvironment and intracellular reactive oxygen species (ROS), resulting in enhanced tumor targeting. STING agonist is successfully encapsulated into prodrug micelles through π-π stacking and hydrophobic interactions. These AND logic-gated prodrug micelles can achieve tumor-targeted delivery of STING agonist, leading to significantly enhanced immune activation and antitumor efficacy in vivo. It is expected that this clinically relevant nanoplatform will provide a rational design of an effective immunotherapy combination regimen to convert immunologically "cold" tumors to immunogenic "hot" tumors, addressing the major challenges faced by immunotherapies.
能够同时响应多种生物标志物、充当“与”门的材料有潜力增强药物输送的肿瘤靶向性。在这项研究中，开发了一种“与”逻辑控制释放前药胶束，用于共递送化疗药物和干扰素基因刺激物（STING）激动剂，实现精确的组合治疗。药物释放是由肿瘤中富含的硼氨基酸（BAA）和细胞内活性氧（ROS）在肿瘤微环境中编程的，从而增强了肿瘤靶向性。STING 激动剂通过π-π堆积和疏水相互作用成功地包裹在前药胶束中。这些“与”门控前药胶束可以实现 STING 激动剂的肿瘤靶向递送，从而显著增强体内的免疫激活和抗肿瘤疗效。预计这种具有临床相关性的纳米平台将为有效的免疫治疗联合方案提供合理设计，将免疫上“冷”的肿瘤转化为免疫原性“热”的肿瘤，解决免疫疗法面临的主要挑战。
