College Pharmacy, Jiamusi University, 258 Xuefu Street, Jiamusi, Heilongjiang 154007, China.
Biomater Sci. 2021 May 4;9(9):3453-3464. doi: 10.1039/d1bm00331c.
The application of combination immune-chemotherapy makes up for the limitation of monotherapy and achieves superior antitumor activity against cancer. However, combinational therapy is always restricted by poor tumor targeted drug delivery efficacy. Herein, novel T cell membrane cloaking tumor microenvironment-responsive nanoparticles (PBA modified T cell membrane cloaking hyaluronic acid (HA)-disulfide bond-vitamin E succinate/curcumin, shortened as RCM@T) were developed. T cell membrane cloaking not only serves as a protection shell for sufficient drug delivery but also acts as a programmed cell death-1(PD-1) "antibody" to selectively bind the PD-L1 of tumor cells. When RCM@T is intravenously administrated into the blood stream, it accumulates at tumor sites and responds to an acidic pH to achieve a "membrane escape effect" and expose the HA residues of RCM for tumor targeted drug delivery. RCM accumulates in the cytoplasm via CD44 receptor mediated endocytosis and intracellularly releases antitumor drug in the intracellular redox microenvironment for tumor chemotherapy. T cell membrane debris targets the PD-L1of tumor cells for tumor immunotherapy, which not only directly kills tumor cells, but also improves the CD8+ T cell level and facilitates effector cytokine release. Taken together, the as-constructed RCM@T creates a new way for the rational design of a drug delivery system via the combination of stimuli-responsive drug release, chemotherapeutical agent delivery and cell membrane based immune checkpoint blockade immunotherapy.
联合免疫化疗的应用弥补了单药治疗的局限性,针对癌症实现了更优的抗肿瘤活性。然而,联合治疗总是受到肿瘤靶向药物递送效果差的限制。在此,开发了一种新型的 T 细胞膜伪装肿瘤微环境响应型纳米颗粒(PBA 修饰的 T 细胞膜伪装透明质酸(HA)-二硫键-维生素 E 琥珀酸/姜黄素,简称 RCM@T)。T 细胞膜伪装不仅作为充分药物递送的保护壳,还作为程序性细胞死亡-1(PD-1)“抗体”,选择性结合肿瘤细胞的 PD-L1。当 RCM@T 经静脉注射进入血流时,它在肿瘤部位聚集,并响应酸性 pH 值实现“膜逃逸效应”,暴露出 RCM 的 HA 残基以实现肿瘤靶向药物递送。RCM 通过 CD44 受体介导的内吞作用在细胞质中积累,并在细胞内氧化还原微环境中释放抗肿瘤药物进行肿瘤化疗。T 细胞膜碎片靶向肿瘤细胞的 PD-L1 进行肿瘤免疫治疗,不仅直接杀死肿瘤细胞,还提高 CD8+T 细胞水平并促进效应细胞因子释放。总之,所构建的 RCM@T 通过刺激响应性药物释放、化疗药物递送和基于细胞膜的免疫检查点阻断免疫治疗的结合,为药物递送系统的合理设计创造了一种新方法。
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