Department of Pharmaceutics, School of Pharmacy, China Medical University, Shenyang, Liaoning, 110122, PR China; Laboratory of Nano- and Translational Medicine, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Laboratory of Nano- and Translational Medicine, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; UNC/NCSU Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Biomaterials. 2018 Jul;169:1-10. doi: 10.1016/j.biomaterials.2018.03.055. Epub 2018 Mar 31.
Most ovarian cancer patients respond well to initial platinum-based chemotherapy. However, within a year, many patients experience disease recurrence with a platinum resistant phenotype that responds poorly to second line chemotherapies. As a result, new strategies to address platinum resistant ovarian cancer (PROC) are needed. Herein, we report that NP co-delivery of cisplatin (CP) and wortmannin (Wtmn), a DNA repair inhibitor, synergistically enhances chemoradiotherapy (CRT) and reverses CP resistance in PROC. We encapsulated this regimen in FDA approved poly(lactic-co-glycolic acid)-poly(ethylene glycol) (PLGA-PEG) NPs to reduce systemic side effects, enhance cellular CP uptake, improve Wtmn stability, and increase therapeutic efficacy. Treatment of platinum-sensitive ovarian cancer (PSOC) and PROC murine models with these dual-drug loaded NPs (DNPs) significantly reduced tumor burden versus treatment with combinations of free drugs or single-drug loaded NPs (SNPs). These results support further investigation of this NP-based, synergistic drug regimen as a means to combat PROC in the clinic.
大多数卵巢癌患者对初始基于铂类的化疗反应良好。然而，在一年内，许多患者出现铂耐药表型的疾病复发，对二线化疗反应不佳。因此，需要新的策略来解决铂耐药卵巢癌（PROC）。在此，我们报告顺铂（CP）和wortmannin（Wtmn），一种 DNA 修复抑制剂的 NP 共递药，协同增强化学放射治疗（CRT）并逆转 PROC 中的 CP 耐药性。我们将该方案封装在 FDA 批准的聚（乳酸-共-羟基乙酸）-聚乙二醇（PLGA-PEG）NP 中，以减少全身副作用，增强细胞 CP 摄取，提高 Wtmn 稳定性，并提高治疗效果。用这些双药物负载 NP（DNP）治疗铂敏感卵巢癌（PSOC）和 PROC 小鼠模型，与用游离药物或单药物负载 NP（SNP）的组合治疗相比，显著降低了肿瘤负担。这些结果支持进一步研究这种基于 NP 的协同药物方案，作为在临床上对抗 PROC 的一种手段。
