Center of Gene Sequencing, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan 030032, China.
Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan 030032, China.
Mol Pharm. 2024 Oct 7;21(10):5126-5137. doi: 10.1021/acs.molpharmaceut.4c00514. Epub 2024 Sep 16.
As a first-line chemotherapeutic agent, albumin-bound paclitaxel (PA) has a considerable effect on the treatment of various cancers. However, in chemotherapy for hepatocarcinoma, the sensitivity to PA is low owing to the innate resistance of hepatocarcinoma cells; the toxicity and side effects are severe, and the clinical treatment impact is poor. In this study, we present a unique nanodrug delivery system. The ultraviolet (UV)-induced tumor-cell-derived extracellular vesicles (EVs) were isolated and purified by differential centrifugation. Then, PA was loaded by coextrusion to create a vesicle drug delivery system (EVPA). By employing the EV-dependent enhanced retention effect and specific homing effect, EVPA would passively and actively target tumor tissues, activate the immune response to release PA, and achieve the combination therapeutic effect of chemo-immunotherapy on hepatocarcinoma. We demonstrated that the tumor-killing effect of EVPA is superior to that of PA, both in vivo and in vitro and that EVPA can be effectively taken up by hepatocarcinoma and dendritic cells, activate the body's specific immune response, promote the infiltration of CD4+ and CD8+ T cells in tumor tissues, and exert a precise killing effect on hepatocarcinoma cells via chemo-immunotherapy.
白蛋白结合紫杉醇（PA）作为一线化疗药物，对多种癌症的治疗具有显著效果。然而，在肝癌的化疗中，由于肝癌细胞的固有耐药性，PA 的敏感性较低，毒性和副作用严重，临床治疗效果较差。在本研究中，我们提出了一种独特的纳米药物递送系统。采用差速离心法分离和纯化紫外（UV）诱导的肿瘤细胞衍生的细胞外囊泡（EVs）。然后，通过共挤出将 PA 加载到囊泡中，构建囊泡药物递送系统（EVPA）。通过利用 EV 依赖性增强的滞留效应和特异性归巢效应，EVPA 可以被动和主动靶向肿瘤组织，激活免疫反应释放 PA，实现肝癌的化疗免疫联合治疗效果。我们证明了 EVPA 的肿瘤杀伤效果优于 PA，无论是在体内还是体外，并且 EVPA 可以被肝癌细胞和树突状细胞有效摄取，激活机体的特异性免疫反应，促进 CD4+和 CD8+T 细胞在肿瘤组织中的浸润，并通过化疗免疫联合治疗对肝癌细胞发挥精确杀伤作用。
