Department of Ultrasound, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China.
J Nanobiotechnology. 2023 Jan 30;21(1):35. doi: 10.1186/s12951-023-01776-8.
Immunotherapy had demonstrated inspiring effects in tumor treatment, but only a minority of people could benefit owing to the hypoxic and immune-suppressed tumor microenvironment (TME). Therefore, there was an urgent need for a strategy that could relieve hypoxia and increase infiltration of tumor lymphocytes simultaneously. In this study, a novel acidity-responsive nanoscale ultrasound contrast agent (L-Arg@PTX nanodroplets) was constructed to co-deliver paclitaxel (PTX) and L-arginine (L-Arg) using the homogenization/emulsification method. The L-Arg@PTX nanodroplets with uniform size of about 300 nm and high drug loading efficiency displayed good ultrasound diagnostic imaging capability, improved tumor aggregation and achieved ultrasound-triggered drug release, which could prevent the premature leakage of drugs and thus improve biosafety. More critically, L-Arg@PTX nanodroplets in combination with ultrasound targeted microbubble destruction (UTMD) could increase cellular reactive oxygen species (ROS), which exerted an oxidizing effect that converted L-Arg into nitric oxide (NO), thus alleviating hypoxia, sensitizing chemotherapy and increasing the CD8 + cytotoxic T lymphocytes (CTLs) infiltration. Combined with the chemotherapeutic drug PTX-induced immunogenic cell death (ICD), this promising strategy could enhance immunotherapy synergistically and realize powerful tumor treatment effect. Taken together, L-Arg@PTX nanodroplets was a very hopeful vehicle that integrated drug delivery, diagnostic imaging, and chemoimmunotherapy.
免疫疗法在肿瘤治疗中显示出了令人鼓舞的效果，但由于肿瘤微环境（TME）缺氧和免疫抑制，只有少数人能从中受益。因此，迫切需要一种既能缓解缺氧又能同时增加肿瘤淋巴细胞浸润的策略。在本研究中，构建了一种新型的酸响应纳米级超声造影剂（L-Arg@PTX 纳米液滴），采用匀化/乳化法共载紫杉醇（PTX）和 L-精氨酸（L-Arg）。粒径约为 300nm 的 L-Arg@PTX 纳米液滴具有均匀的尺寸和高载药效率，显示出良好的超声诊断成像能力，增强了肿瘤聚集，并实现了超声触发的药物释放，可防止药物过早泄漏，从而提高生物安全性。更重要的是，L-Arg@PTX 纳米液滴联合超声靶向微泡破坏（UTMD）可增加细胞内活性氧（ROS），发挥氧化作用，将 L-Arg 转化为一氧化氮（NO），从而缓解缺氧，增敏化疗，增加 CD8+细胞毒性 T 淋巴细胞（CTL）浸润。与化疗药物 PTX 诱导的免疫原性细胞死亡（ICD）相结合，这种有前途的策略可以协同增强免疫治疗，实现强大的肿瘤治疗效果。综上所述，L-Arg@PTX 纳米液滴是一种很有前途的药物载体，集药物输送、诊断成像和化疗免疫治疗于一体。
