Drug-loaded microbubble delivery system to enhance PD-L1 blockade immunotherapy with remodeling immune microenvironment.

IF 11.3 1区 医学 Q1 Medicine
Jun Zheng, Ju Huang, Liang Zhang, Mengna Wang, Lihong Xu, Xiaoyun Dou, Xiaojing Leng, Mingxiao Fang, Yang Sun, Zhigang Wang
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引用次数: 7

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: PD-L1 blockade immunotherapy was enhanced by RD@MBs delivery system.

Abstract Image

Abstract Image

Abstract Image

通过重塑免疫微环境增强PD-L1阻断免疫治疗的载药微泡递送系统。
背景: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的前景,但由于肿瘤免疫抑制微环境(TIME)导致T细胞浸润不良和抗PD-L1 (αPD-L1)在肿瘤部位的积累不足,降低了免疫应答。在此,我们报道了一种载药微泡递送系统来克服这些障碍并增强PD-L1阻断免疫治疗。方法:采用典型的旋转蒸发法结合机械振荡合成多西他赛(DTX)和咪喹莫德(R837)负载微泡(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。观察RD@MBs联合αPD-L1对4T1和CT26肿瘤模型的抗肿瘤免疫反应。结果:DTX诱导垂死的肿瘤细胞释放肿瘤相关抗原(tumor associated antigens, TAAs),与R837共同促进T细胞的活化、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m2表型肿瘤相关巨噬细胞(tam)向m1表型的极化,以及髓源性抑制细胞(MDSCs)的减少。RD@MBs + αPD-L1协同治疗不仅能有效抑制原发肿瘤的生长,还能显著抑制模拟远处肿瘤及肺转移。结论:RD@MBs给药系统对PD-L1阻断免疫治疗有增强作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Biomaterials Research
Biomaterials Research Medicine-Medicine (miscellaneous)
CiteScore
10.20
自引率
3.50%
发文量
63
审稿时长
30 days
期刊介绍: Biomaterials Research, the official journal of the Korean Society for Biomaterials, is an open-access interdisciplinary publication that focuses on all aspects of biomaterials research. The journal covers a wide range of topics including novel biomaterials, advanced techniques for biomaterial synthesis and fabrication, and their application in biomedical fields. Specific areas of interest include functional biomaterials, drug and gene delivery systems, tissue engineering, nanomedicine, nano/micro-biotechnology, bio-imaging, regenerative medicine, medical devices, 3D printing, and stem cell research. By exploring these research areas, Biomaterials Research aims to provide valuable insights and promote advancements in the biomaterials field.
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