Liu Yan, Hao Yu, Lv Xiang, Zhang Yefei, Chen Jiahui, Tian Jia, Ma Xinxing, Zhou Yehui, Feng Liangzhu
Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Cancer Institute, Department of Biochemistry, College of Life Science, Nanjing Normal University, Nanjing 210023, China.
Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou 215123, China.
Fundam Res. 2023 Jun 19;5(3):1288-1297. doi: 10.1016/j.fmre.2023.05.016. eCollection 2025 May.
Irregular vasculature of solid tumors has proven to be a pivotal factor restricting their response to chimeric antigen receptor-T (CAR-T) cell therapy because it is tightly associated with hypoxia and other biological barriers. Herein, an injectable hydrogel composed of poly (ethylene glycol) dimethacrylate (PEGDMA) and ferrous chloride (FeCl) responding to endogenous hydrogen peroxides (HO) is developed to enable sustained intratumoral release of Chinese herbal extracts tetramethylpyrazine (TMP). TMP is selected due to its potency in activating vascular endothelial growth factor (VEGF) expression and the endothelial nitric oxide synthase/nitric oxide (eNOS/NO) axis inside vascular endothelial cells. Upon being fixed inside tumors with the PEGDMA based hydrogel, TMP can remodel tumor vasculature by simultaneously promoting angiogenesis and dilating tumor vasculature and thus attenuate tumor hypoxia in two murine xenografts bearing human triple negative breast cancer (TNBC). Resultantly, treatment with TMP fixation potentiates the tumor suppression effect of intravenously injected epidermal growth factor receptor expressing CAR-T (HER1-CAR-T) cells toward two TNBC tumor xenografts by promoting their tumor infiltration, survival, and effector function. This study highlights a concise yet effective approach to reinforce the therapeutic potency of CAR-T cells towards targeted solid tumors by simply remodeling tumor vasculature.
实体瘤的不规则血管结构已被证明是限制其对嵌合抗原受体 T 细胞（CAR-T）疗法反应的关键因素，因为它与缺氧和其他生物屏障密切相关。在此，开发了一种由聚乙二醇二甲基丙烯酸酯（PEGDMA）和氯化亚铁（FeCl）组成的可注射水凝胶，其可对内源性过氧化氢（H₂O₂）作出反应，以实现中药提取物川芎嗪（TMP）在肿瘤内的持续释放。选择 TMP 是因为它能够激活血管内皮细胞内的血管内皮生长因子（VEGF）表达以及内皮型一氧化氮合酶/一氧化氮（eNOS/NO）轴。在用基于 PEGDMA 的水凝胶固定在肿瘤内部后，TMP 可以通过同时促进血管生成和扩张肿瘤血管来重塑肿瘤血管结构，从而减轻两种携带人三阴性乳腺癌（TNBC）的小鼠异种移植瘤中的肿瘤缺氧情况。结果，通过促进静脉注射的表达表皮生长因子受体的 CAR-T（HER1-CAR-T）细胞的肿瘤浸润、存活和效应功能，TMP 固定处理增强了其对两种 TNBC 肿瘤异种移植瘤的肿瘤抑制作用。这项研究强调了一种简洁而有效的方法，即通过简单地重塑肿瘤血管结构来增强 CAR-T 细胞对靶向实体瘤的治疗效力。
