Zheng Jun, Huang Ju, Zhang Liang, Wang Mengna, Xu Lihong, Dou Xiaoyun, Leng Xiaojing, Fang Mingxiao, Sun Yang, Wang Zhigang
State Key Laboratory of Ultrasound in Medicine and Engineering, Institute of Ultrasound Imaging, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, People's Republic of China.
Ultrasound Department, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400042, People's Republic of China.
Biomater Res. 2023 Feb 9;27(1):9. doi: 10.1186/s40824-023-00350-5.
Although programmed cell death protein 1 (PD-1)/ programmed cell death-ligand protein 1 (PD-L1) checkpoint blockade immunotherapy demonstrates great promise in cancer treatment, poor infiltration of T cells resulted from tumor immunosuppressive microenvironment (TIME) and insufficient accumulation of anti-PD-L1 (αPD-L1) in tumor sites diminish the immune response. Herein, we reported a drug-loaded microbubble delivery system to overcome these obstacles and enhance PD-L1 blockade immunotherapy.
Docetaxel (DTX) and imiquimod (R837)-loaded microbubbles (RD@MBs) were synthesized via a typical rotary evaporation method combined with mechanical oscillation. The targeted release of drugs was achieved by using the directional "bursting" capability of ultrasound-targeted microbubble destruction (UTMD) technology. The antitumor immune response by RD@MBs combining αPD-L1 were evaluated on 4T1 and CT26 tumor models.
The dying tumor cells induced by DTX release tumor-associated antigens (TAAs), together with R837, promoted the activation, proliferation and recruitment of T cells. Besides, UTMD technology and DTX enhanced the accumulation of αPD-L1 in tumor sites. Moreover, RD@MBs remolded TIME, including the polarization of M2-phenotype tumor-associated macrophages (TAMs) to M1-phenotype, and reduction of myeloid-derived suppressor cells (MDSCs). The RD@MBs + αPD-L1 synergistic therapy not only effectively inhibited the growth of primary tumors, but also significantly inhibited the mimic distant tumors as well as lung metastases.
PD-L1 blockade immunotherapy was enhanced by RD@MBs delivery system.
尽管程序性细胞死亡蛋白1（PD-1）/程序性细胞死亡配体蛋白1（PD-L1）检查点阻断免疫疗法在癌症治疗中显示出巨大潜力，但肿瘤免疫抑制微环境（TIME）导致的T细胞浸润不足以及肿瘤部位抗PD-L1（αPD-L1）的积累不足削弱了免疫反应。在此，我们报道了一种载药微泡递送系统，以克服这些障碍并增强PD-L1阻断免疫疗法。
通过典型的旋转蒸发法结合机械振荡合成了载有多西他赛（DTX）和咪喹莫特（R837）的微泡（RD@MBs）。利用超声靶向微泡破坏（UTMD）技术的定向“爆破”能力实现药物的靶向释放。在4T1和CT26肿瘤模型上评估了RD@MBs联合αPD-L1的抗肿瘤免疫反应。
DTX释放诱导的肿瘤细胞死亡释放肿瘤相关抗原（TAAs），与R837一起促进T细胞的激活、增殖和募集。此外，UTMD技术和DTX增强了αPD-L1在肿瘤部位的积累。此外，RD@MBs重塑了TIME，包括将M2表型肿瘤相关巨噬细胞（TAM）极化为M1表型，以及减少髓源性抑制细胞（MDSC）。RD@MBs + αPD-L1联合疗法不仅有效抑制了原发性肿瘤的生长，还显著抑制了模拟远处肿瘤以及肺转移。
RD@MBs递送系统增强了PD-L1阻断免疫疗法。
