PD-L1-targeted microbubbles loaded with docetaxel produce a synergistic effect for the treatment of lung cancer under ultrasound irradiation
PD-L1-targeted microbubbles loaded with docetaxel produce a synergistic effect for the treatment of lung cancer under ultrasound irradiation
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负载多西紫杉醇的PD-L1靶向微泡在超声照射下对肺癌治疗产生协同作用
DOI：
10.1039/c9bm01575b
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Jinhe Guo
中科院分区：
文献类型：
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作者：
Tiankuan Li;Zhongqian Hu;Chao Wang;Jian Yang;Chuhui Zeng;Rui Fan1;Jinhe Guo
免疫疗法在癌症治疗中逐渐变得与传统疗法一样重要，但药物不良反应限制了患者从治疗非小细胞肺癌（NSCLC）的PD1/PD-L1检查点抑制剂药物中获益。作为非小细胞肺癌的化疗药物，多西他赛（DTX）可以与PD1/PD-L1检查点抑制剂协同作用，但会增加血液毒性和神经毒性。本文研究了抗pd - l1单克隆抗体（mAb）偶联和多西他赛负载的多功能脂壳微泡（PDMs），该微泡采用生物安全的磷脂设计，产生协同抗肿瘤作用，减少了副作用的发生率，提高了超声（US）照射下的治疗效果。通过声振法制备pdm，并与抗pd - l1单抗偶联。研究了微泡的材料特性及其细胞毒性、细胞凋亡和细胞周期抑制作用。建立皮下肿瘤模型，测试pdm联合US照射的药物浓度依赖性和抗肿瘤作用，同时建立正位肺肿瘤模型，证实这种协同治疗的抗肿瘤作用。与游离DTX相比，pdm获得了更高的细胞摄取，特别是当与US照射联合使用时。pdm联合US照射还诱导癌细胞细胞凋亡率升高，G2-M阻滞率升高，与PD-L1表达呈正相关。一项体内研究表明，协同治疗对肿瘤生长有较强的抑制作用，延长了生存时间，降低了不良反应发生率。我们的研究可能为免疫治疗和化疗提供了一个良好的控制设计，并在非小细胞肺癌治疗中具有良好的临床应用潜力。
Immunotherapy is gradually becoming as important as traditional therapy in the treatment of cancer, but adverse drug reactions limit patient benefits from PD1/PD-L1 checkpoint inhibitor drugs in the treatment of non-small cell lung cancer (NSCLC). As a chemotherapeutic drug for NSCLC, docetaxel (DTX) can synergize with PD1/PD-L1 checkpoint inhibitors but increase haematoxicity and neurotoxicity. Herein, anti-PD-L1 monoclonal antibody (mAb)-conjugated and docetaxel-loaded multifunctional lipid-shelled microbubbles (PDMs), which were designed with biologically safe phospholipids to produce synergistic antitumour effects, reduced the incidence of side effects and promoted therapeutic effects under ultrasound (US) irradiation. The PDMs were prepared by the acoustic-vibration method and then conjugated with an anti-PD-L1 mAb. The material features of the microbubbles and their cytotoxic effects, cellular apoptosis and cell cycle inhibition were studied. A subcutaneous tumour model was established to test the drug concentration-dependent and antitumour effects of the PDMs combined with US irradiation, and an orthotopic lung tumour model simultaneously confirmed the antitumour effect of this synergistic treatment. The PDMs achieved higher cellular uptake than free DTX, especially when combined with US irradiation. The PDMs combined with US irradiation also induced an increased rate of cellular apoptosis and an elevated G2-M arrest rate in cancer cells, which was positively correlated with PD-L1 expression. An in vivo study showed that synergistic treatment had relatively strong effects on tumour growth inhibition, increased survival time and decreased adverse effect rates. Our study possibly provides a well-controlled design for immunotherapy and chemotherapy and has promising potential for clinical application in NSCLC treatment.