Liu Jinhu, Yang Han, Sang Xiao, Gao Tong, Zhang Zipeng, Fu Shunli, Yang Huizhen, Chang Lili, Liu Xiaoqing, Liang Shuang, Yuan Shijun, Wei Suyun, Yang Yuxin, Yan Xiaoxin, Zhang Xinke, Mu Weiwei, Liu Yongjun, Zhang Na
Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.
Acta Pharm Sin B. 2024 Nov;14(11):5053-5068. doi: 10.1016/j.apsb.2024.08.033. Epub 2024 Sep 12.
Cytopharmaceutical based on macrophages is a breakthrough in the field of targeted drug delivery. However, it remains a challenge to localize and control drug release while retaining macrophage activity and exerting its immunotherapeutic effect. Herein, a localized light-triggered release macrophage cytopharmaceutical (USIP@M) was proposed, which could utilize the tumor targeting and immunotherapy effects of macrophages to reverse the immune suppression of tumor microenvironment (TME). Amphiphilic block copolymers with ultraviolet (UV)-responsive -nitrobenzyl groups were synthesized and co-loaded with sorafenib (SF), IMD-0354 (IMD), and upconverting nanoparticles (UCNPs), which were then taken up by macrophages, and the targeted delivery of drugs was realized by using the tumor tropism of macrophages. UCNPs converted near-infrared light with strong penetrability and high safety into UV light, which promoted the photoresponsive depolymerization of block copolymers and production of exosomes from USIP@M, accelerated drug efflux and maintained the activity of macrophages. IMD simultaneously polarized carrier macrophages and tumor-associated macrophages to exert the antitumor effect of macrophages, enhance T cell immunity, and alleviate the immunosuppressive state of TME. Synergistically with the chemotherapeutic effect of SF, it could effectively kill tumors. In conclusion, based on the localized light-triggered release strategy, this study constructed a novel macrophage cytopharmaceutical that could localize and control drug release while retaining the activity of macrophages and exerting its immunotherapeutic effect, which could effectively treat solid tumors.
基于巨噬细胞的细胞药物是靶向给药领域的一项突破。然而，在保留巨噬细胞活性并发挥其免疫治疗作用的同时，实现药物的定位和控制释放仍然是一个挑战。在此，我们提出了一种局部光触发释放的巨噬细胞细胞药物（USIP@M），它可以利用巨噬细胞的肿瘤靶向和免疫治疗作用来逆转肿瘤微环境（TME）的免疫抑制。合成了具有紫外线（UV）响应性硝基苄基的两亲性嵌段共聚物，并将索拉非尼（SF）、IMD-0354（IMD）和上转换纳米颗粒（UCNPs）共负载，然后被巨噬细胞摄取，并利用巨噬细胞的肿瘤嗜性实现药物的靶向递送。UCNPs将具有强穿透性和高安全性的近红外光转换为紫外线，促进嵌段共聚物的光响应解聚和USIP@M中外泌体的产生，加速药物外排并维持巨噬细胞的活性。IMD同时使载体巨噬细胞和肿瘤相关巨噬细胞极化，以发挥巨噬细胞的抗肿瘤作用，增强T细胞免疫，并缓解TME的免疫抑制状态。与SF的化疗作用协同，它可以有效杀死肿瘤。总之，基于局部光触发释放策略，本研究构建了一种新型巨噬细胞细胞药物，该药物可以在保留巨噬细胞活性并发挥其免疫治疗作用的同时实现药物的定位和控制释放，从而有效治疗实体瘤。
