Zhou Qidong, Ding Weihong, Qian Zhiyu, Zhu Quangang, Sun Chuanyu, Yu Qin, Tai Zongguang, Xu Ke
Department of Urology, Huashan Hospital, Fudan University, Shanghai 200040, China.
Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai 200040, China.
Mol Pharm. 2021 Nov 1;18(11):4015-4028. doi: 10.1021/acs.molpharmaceut.1c00448. Epub 2021 Oct 14.
Combination immunotherapy is a promising strategy to remove the inhibitory effect of the tumor microenvironment on immune effector cells, improving the efficacy of immune checkpoint inhibitor treatment in bladder cancer. However, it is challenging to deliver multiple drugs to the tumor tissue effectively and simultaneously to ensure optimal therapeutic effects. Macrophage-derived exosome-mimetic nanovesicles (EMVs) were designed and validated as a nanoplatform for coloading and delivery of the CD73 inhibitor (AB680) and the monoclonal antibody to programmed cell death ligand 1 (aPDL1). The tumor-targeting, biosafety, and therapeutic effects of these nanocomplexes (AB680@EMVs-aPDL1), as a combined immunotherapy strategy for bladder cancer, were assessed and . Our results indicate that the nanodrug system was highly stable, provided adequate biosafety, and enhanced tumor targeting in a mouse model of bladder cancer. Moreover, the CD73 inhibitor reduced extracellular adenosine production, and the combination therapy significantly promoted the activation and infiltration of cytotoxic T-lymphocytes, which helped to optimally suppress tumor growth and extend median survival . Therefore, using EMVs to deliver a combination of aPDL1 and the CD73 inhibitor may be a useful combined immunotherapy strategy for treating bladder cancer.
联合免疫疗法是一种很有前景的策略，可消除肿瘤微环境对免疫效应细胞的抑制作用，提高免疫检查点抑制剂治疗膀胱癌的疗效。然而，有效且同时向肿瘤组织递送多种药物以确保最佳治疗效果具有挑战性。巨噬细胞衍生的外泌体模拟纳米囊泡（EMVs）被设计并验证为一种用于共负载和递送CD73抑制剂（AB680）和程序性细胞死亡配体1单克隆抗体（aPDL1）的纳米平台。评估了这些纳米复合物（AB680@EMVs-aPDL1）作为膀胱癌联合免疫治疗策略的肿瘤靶向性、生物安全性和治疗效果。我们的结果表明，该纳米药物系统高度稳定，具有足够的生物安全性，并在膀胱癌小鼠模型中增强了肿瘤靶向性。此外，CD73抑制剂减少了细胞外腺苷的产生，联合治疗显著促进了细胞毒性T淋巴细胞的活化和浸润，有助于最佳地抑制肿瘤生长并延长中位生存期。因此，利用EMVs递送aPDL1和CD73抑制剂的组合可能是一种治疗膀胱癌的有用联合免疫治疗策略。
