Kulkarni Nishant S, Vaidya Bhuvaneshwar, Gupta Vivek
College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
School of Pharmacy, Keck Graduate Institute, Claremont, CA, USA.
Mater Sci Eng C Mater Biol Appl. 2021 Feb;121:111891. doi: 10.1016/j.msec.2021.111891. Epub 2021 Jan 15.
Non-small cell lung cancer (NSCLC), pre-dominant subtype of lung cancer, is a global disorder affecting millions worldwide. One of the early treatments for NSCLC was use of a first-generation tyrosine kinase inhibitor, Erlotinib (Erlo). However, chronic exposure to Erlo led to development of acquired drug resistance (ADR) in NSCLC, limiting the clinical use of Erlo. A potential approach to overcome development of ADR is a multi-drug therapy. It has been previously reported that Erlo and Quinacrine (QA), an anti-malarial drug, can work synergistically to inhibit tumor progression in NSCLC. However, the combination failed at clinical stages, citing lack of efficacy. In this study, an effort has been made to improve the efficacy of Erlo-QA combination via development of nanoformulations, known to enhance therapeutic efficacy of potent chemotherapies. Synergy between Erlo and QA was measured via estimating the combination indices (CI). It was seen that established combination of nanoformulations (CI: 0.25) had better synergy than plain drug solutions (CI: 0.85) in combination. Following extensive in-vitro testing, data were simulated in biologically relevant 3D tumor models. Two tumor models were developed for extensive in-vitro testing, 3D-Spheroids grown in ultra-low attachment culture plates for efficacy evaluation and a 5D-spheroid model in 5D-sphericalplate with capability of growing 750 spheroids/well for protein expression analysis. Extensive studies on these models revealed that combination of Erlo and QA nanoformulations overall had a better effect in terms of synergy enhancement as compared to plain drug combination. Further, effect of combinatorial therapy on molecular markers was evaluated on 5D-Sphericalplate leading to similar effects on synergy enhancement. Results from present study suggests that combination of nanoformulations can improve the synergy between Erlo and QA while reducing the overall therapeutic dose.
非小细胞肺癌（NSCLC）是肺癌的主要亚型，是一种影响全球数百万人的全球性疾病。NSCLC的早期治疗方法之一是使用第一代酪氨酸激酶抑制剂厄洛替尼（Erlo）。然而，长期接触Erlo会导致NSCLC产生获得性耐药（ADR），限制了Erlo的临床应用。克服ADR发展的一种潜在方法是多药联合治疗。此前有报道称，Erlo和抗疟药物奎纳克林（QA）可协同作用抑制NSCLC的肿瘤进展。然而，该联合用药在临床阶段失败，原因是缺乏疗效。在本研究中，人们致力于通过开发纳米制剂来提高Erlo-QA联合用药的疗效，已知纳米制剂可增强强效化疗药物的治疗效果。通过估计联合指数（CI）来测定Erlo和QA之间的协同作用。结果发现，已制备的纳米制剂组合（CI：0.25）比普通药物溶液组合（CI：0.85）具有更好的协同作用。经过广泛的体外测试后，在具有生物学相关性的3D肿瘤模型中对数据进行了模拟。开发了两种肿瘤模型用于广泛的体外测试，一种是在超低附着培养板中生长的用于疗效评估的3D球体，另一种是在5D球形板中能够每孔生长750个球体用于蛋白质表达分析的5D球体模型。对这些模型的广泛研究表明，与普通药物组合相比，Erlo和QA纳米制剂的组合在增强协同作用方面总体效果更好。此外，在5D球形板上评估了联合疗法对分子标志物的影响，结果显示对协同作用增强有类似效果。本研究结果表明，纳米制剂组合可以提高Erlo和QA之间的协同作用，同时降低总体治疗剂量。
