Sun Suhui, Tang Qingshuang, Wang Yuan, Zhang Lulu, Chen Jing, Xu Menghong, Sun Lihong, Cui Ligang, Liang Xiaolong
Department of Ultrasound, Peking University Third Hospital, Beijing 100191, China.
ACS Appl Mater Interfaces. 2022 Jun 3. doi: 10.1021/acsami.2c02490.
The immune checkpoint blockade (ICB) therapy based on monoclonal antibodies still suffers from a lower immune response rate and severe immune-related side effects, which greatly compromise its therapeutic benefits. Herein, ultrasound (US) microbubbles (MBs) that locally delivered the camptothecin-floxuridine (CF) drug combination and anti-PD-L1 blocking antibody (αPD-L1) to tumors were developed to improve ICB therapy. The resulting αPCF MBs exhibited good stability, allowing their use as US imaging contrast agents to trace the drug delivery . Furthermore, the combination of αPCF MBs treatment and disrupted US irradiation triggered tumor conversion of αPCF MBs to αPCF NPs while promoting higher tumor cell uptake and deeper tumor penetration as confirmed by the US/fluorescence bimodal imaging. Camptothecin (CPT) and floxuridine (FUDR) were further released at a fixed 1:1 molar ratio within the tumor microenvironment (TME) to synergistically elicit an immunogenic tumor phenotype and sensitize tumors to αPD-L1-mediated ICB therapy, while the local simultaneous delivery of immunotherapeutic αPD-L1 further reversed the immunosuppressive tumor microenvironment and promoted the infiltration of cytotoxic T lymphocytes (CTLs), thus achieving a synergistic therapeutic effect of chemotherapy and immunotherapy in the CT26 tumor-bearing mice. Thus, αPCF MBs + US mediated local co-delivering of the drug combination and αPD-L1 well augmented the ICB therapy while effectively minimizing the off-target side effects, providing a safe and universal therapeutic strategy for tumor immunotherapy.
基于单克隆抗体的免疫检查点阻断（ICB）疗法仍然存在免疫应答率较低和严重免疫相关副作用的问题，这极大地损害了其治疗效果。在此，我们开发了一种超声（US）微泡（MBs），其可将喜树碱-氟尿苷（CF）药物组合和抗PD-L1阻断抗体（αPD-L1）局部递送至肿瘤，以改善ICB疗法。所得的αPCF MBs表现出良好的稳定性，使其能够用作US成像造影剂来追踪药物递送。此外，αPCF MBs治疗与间断US照射相结合，触发了αPCF MBs向αPCF NPs的肿瘤转化，同时促进了更高的肿瘤细胞摄取和更深的肿瘤渗透，这一点通过US/荧光双模态成像得到了证实。喜树碱（CPT）和氟尿苷（FUDR）在肿瘤微环境（TME）中以固定的1:1摩尔比进一步释放，以协同引发免疫原性肿瘤表型，并使肿瘤对αPD-L1介导的ICB疗法敏感，而免疫治疗性αPD-L1的局部同步递送进一步逆转了免疫抑制性肿瘤微环境，并促进了细胞毒性T淋巴细胞（CTL）的浸润，从而在荷CT26肿瘤小鼠中实现了化疗和免疫治疗的协同治疗效果。因此，αPCF MBs + US介导的药物组合和αPD-L1的局部共递送很好地增强了ICB疗法，同时有效地将脱靶副作用降至最低，为肿瘤免疫治疗提供了一种安全且通用的治疗策略。
