Department of Biochemistry and Molecular Biology, Mayo Clinic Florida, Jacksonville, FL 32224, USA.
Int J Nanomedicine. 2019 Jul 11;14:5109-5123. doi: 10.2147/IJN.S204221. eCollection 2019.
Renal cell carcinoma (RCC) is notorious for its resistance towards chemotherapy and radiation therapy in general. Combination therapy is often helpful in alleviating the resistance mechanisms by targeting multiple signaling pathways but is usually more toxic than monotherapy. Co-encapsulation of multiple therapeutic agents in a tumor-targeted drug delivery platform is a promising strategy to mitigate these limitations.
A tumor-targeted liposomal formulation was prepared using phospholipids, cholesterol, DSPE-(PEG)-OMe and a proprietary tumor-targeting-peptide (TTP)-conjugated lipopeptide. An efficient method was optimized to encapsulate everolimus and vinorelbine in this liposomal formulation. Single drug-loaded liposomes were also prepared for comparison. Finally, the drug-loaded liposomes were tested in vitro and in vivo in two different RCC cell lines.
The tumor-targeted liposomal formulation demonstrated excellent tumor-specific uptake. The dual drug-loaded liposomes exhibited significantly higher growth inhibition in vitro compared to the single drug-loaded liposomes in two different RCC cell lines. Similarly, the dual drug-loaded liposomes demonstrated significantly higher suppression of tumor growth compared to the single drug-loaded liposomes in two different subcutaneous RCC xenografts. In addition, the dual drug-loaded liposomes instigated significant reduction in lung metastasis in those experiments.
Taken together, this study demonstrates that co-delivery of everolimus and vinorelbine with a tumor-targeted liposomal formulation is an effective approach to achieve improved therapeutic outcome in RCC.
肾细胞癌（RCC）通常对化疗和放疗具有耐药性。联合治疗通常通过靶向多个信号通路有助于缓解耐药机制，但通常比单药治疗毒性更大。将多种治疗剂共同包封在肿瘤靶向药物递送平台中是减轻这些限制的一种有前途的策略。
使用磷脂、胆固醇、DSPE-（PEG）-OMe 和专有的肿瘤靶向肽（TTP）-缀合的脂肽制备肿瘤靶向脂质体制剂。优化了一种有效的方法将依维莫司和长春瑞滨包封在这种脂质体制剂中。也制备了单载药脂质体进行比较。最后，在两种不同的 RCC 细胞系中对载药脂质体进行了体外和体内测试。
肿瘤靶向脂质体制剂表现出优异的肿瘤特异性摄取。与两种不同的 RCC 细胞系中单载药脂质体相比，双载药脂质体在体外表现出更高的生长抑制作用。同样，与两种不同的皮下 RCC 异种移植中的单载药脂质体相比，双载药脂质体也表现出更高的肿瘤生长抑制作用。此外，双载药脂质体在这些实验中引发了肺转移的显著减少。
综上所述，这项研究表明，用肿瘤靶向脂质体制剂共同递送依维莫司和长春瑞滨是提高 RCC 治疗效果的有效方法。
