Department of Chemistry, Dyal Singh College, University of Delhi, Lodhi Road, New Delhi, 110003, India.
Dr. B. R. Ambedkar Center for Biomedical Research, University of Delhi, New Delhi, 110007, India.
AAPS PharmSciTech. 2018 Feb;19(2):634-647. doi: 10.1208/s12249-017-0863-5. Epub 2017 Sep 25.
Treatment regimens for cancer patients using single chemotherapeutic agents often lead to undesirable toxicity, drug resistance, reduced uptake etc. Combination of two or more drugs is therefore becoming an imperative strategy to overcome these limitations. A step forward can be taken through delivery of the drugs used in combination via nanoparticles. Co-administration of chemotherapeutic drugs encapsulated in nanoparticles has been shown to result in synergistic effects and enhanced therapeutic efficacy. In present study, we explored the combination treatment of histone deacetylase inhibitor vorinostat (VOR) and topoisomerase II inhibitor etoposide (ETOP). The concurrent combination treatment of VOR and ETOP resulted in synergistic effect on human cervical HeLa cancer cells. VOR and ETOP were encapsulated into poly(ethylene glycol) monomethacrylate (POEOMA)-based disulfide cross-linked nanogels. The nanogels were synthesized using atom transfer radical polymerization (ATRP) via cyclohexane/water inverse mini-emulsion and were degradable in presence of intracellular glutathione (GSH) concentration. Both the drugs were loaded into the nanogels by physical encapsulation method and characterized by Fourier transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM), X-ray diffraction (XRD), dynamic light scattering (DLS), and differential scanning calorimetry (DSC). Both VOR- and ETOP-loaded nanogels showed sustained release profile. Furthermore, combination treatment drugs encapsulated of POEOMA nanogel demonstrated enhanced synergistic cytotoxic effect compared with combination of free drugs. Enhanced synergistic cell killing efficiency of drug-loaded POEOMA nanogels was due to increased apoptosis via caspase 3/7 activation. Therefore, combination of VOR- and ETOP-loaded PEG-based biodegradable nanogels may provide a promising therapy with enhanced anticancer effect.
癌症患者使用单一化疗药物的治疗方案常常导致不良毒性、耐药性、摄取减少等问题。因此，联合使用两种或多种药物成为克服这些限制的必要策略。通过纳米粒子递送来联合使用药物可以向前迈出一步。研究表明，将纳米粒子包封的化疗药物联合给药可产生协同作用并提高治疗效果。在本研究中，我们探索了组蛋白去乙酰化酶抑制剂伏立诺他（VOR）和拓扑异构酶 II 抑制剂依托泊苷（ETOP）的联合治疗。VOR 和 ETOP 的同时联合治疗对人宫颈 HeLa 癌细胞产生协同作用。VOR 和 ETOP 被包封在聚乙二醇单甲醚（POEOMA）-基二硫键交联纳米凝胶中。纳米凝胶是通过环己烷/水反相微乳液中的原子转移自由基聚合（ATRP）合成的，并且在存在细胞内谷胱甘肽（GSH）浓度的情况下可降解。两种药物均通过物理包封法载入纳米凝胶，并通过傅里叶变换红外光谱（FTIR）、透射电子显微镜（TEM）、X 射线衍射（XRD）、动态光散射（DLS）和差示扫描量热法（DSC）进行表征。VOR 和 ETOP 负载的纳米凝胶均表现出持续释放的特性。此外，与游离药物组合相比，POEOMA 纳米凝胶包封的联合治疗药物表现出增强的协同细胞毒性作用。载药 POEOMA 纳米凝胶增强的协同细胞杀伤效率归因于通过 caspase 3/7 激活增加的细胞凋亡。因此，VOR 和 ETOP 负载的基于 PEG 的可生物降解纳米凝胶的组合可能提供一种具有增强的抗癌效果的有前途的治疗方法。
