Velpurisiva Praveena, Rai Prakash
Department of Biomedical Engineering and Biotechnology, University of Massachusetts Lowell, Lowell, MA 01854, USA.
Department of Chemical Engineering, University of Massachusetts Lowell, Lowell, MA 01854, USA.
J Clin Med. 2019 Mar 15;8(3):367. doi: 10.3390/jcm8030367.
Glioblastoma Multiforme is a deadly cancer of glial cells with very low survival rates. Current treatment options are invasive and have serious side effects. Single drug treatments make the tumor refractory after a certain period. Combination therapies have shown improvements in treatment responses against aggressive forms of cancer and are becoming a mainstay in the management of cancer. The purpose of this study is to design a combinatorial treatment regimen by engineering desired ratios of two different small molecule drugs (gefitinib and GSK461364A) in a single carrier that can reduce off-target effects and increase their bioavailability. Synergistic effects were observed with our formulation when optimal ratios of gefitinib and GSK461364A were loaded in poly (lactic-co-glycolic) acid and polyethylene glycol (PLGA-PEG) nanoparticles and tested for efficacy in U87-malignant glioma (U87-MG) cells. Combination nanoparticles proved to be more effective compared to single drug encapsulated nanoparticles, free drug combinations, and the mixture of two single loaded nanoparticles, with statistically significant values at certain ratios and drug concentrations. We also observed drastically reduced clonogenic potential of the cells that were treated with free drugs and nanoparticle combinations in a colony forming assay. From our findings, we conclude that the combination of GSK461364A and higher concentrations of gefitinib when encapsulated in nanoparticles yield synergistic killing of glioma cells. This study could form the basis for designing new combination treatments using nanoparticles to deliver multiple drugs to cancer cells for synergistic effects.
多形性胶质母细胞瘤是一种致命的胶质细胞癌，生存率极低。目前的治疗方法具有侵入性且有严重的副作用。单一药物治疗在一定时期后会使肿瘤产生耐药性。联合疗法在治疗侵袭性癌症方面已显示出疗效改善，正成为癌症治疗的主要手段。本研究的目的是通过在单一载体中设计两种不同小分子药物（吉非替尼和GSK461364A）的理想比例来设计一种联合治疗方案，以减少脱靶效应并提高其生物利用度。当吉非替尼和GSK461364A的最佳比例负载于聚（乳酸-乙醇酸）和聚乙二醇（PLGA-PEG）纳米颗粒中，并在U87恶性胶质瘤（U87-MG）细胞中测试疗效时，我们的制剂观察到了协同效应。与单药包封纳米颗粒、游离药物组合以及两种单载纳米颗粒的混合物相比，联合纳米颗粒被证明更有效，在某些比例和药物浓度下具有统计学显著值。在集落形成试验中，我们还观察到用游离药物和纳米颗粒组合处理的细胞的克隆形成潜力大幅降低。根据我们的研究结果，我们得出结论，当GSK461364A与更高浓度的吉非替尼封装在纳米颗粒中时，可产生协同杀死胶质瘤细胞的效果。本研究可为设计新的联合治疗方案奠定基础，该方案利用纳米颗粒将多种药物递送至癌细胞以产生协同效应。
