Bhattacharya Saswati, Khanam Jasmina, Sarkar Pradipta, Pal Tapan Kumar
Department of Pharmaceutical Technology, Jadavpur University Kolkata 700032 India
Bioequivalence Study Centre, Jadavpur University Kolkata-700032 India.
RSC Adv. 2019 Jan 2;9(1):240-254. doi: 10.1039/c8ra08924h. eCollection 2018 Dec 19.
Paclitaxel (PTX) is a major chemotherapeutic drug that is effective against a wide variety of cancers, particularly breast, ovarian and lung cancer. For a weakly basic chemotherapeutic drug such as PTX, the development of the acidic tumor microenvironment (Warburg effect) has a remarkable impact on therapeutic resistance. The present approach takes advantage of the acidic tumor microenvironment by incorporating lansoprazole (LAN), a proton pump inhibitor (PPI), with PTX as a potent therapeutic combination that is capable of reversing PTX resistance. To deliver optimal amounts of the drugs to neoplastic cells, a nano drug delivery system was selected. To design the nanoformulation process in a limited framework, typical formulation parameters were optimized and validated by the application of response surface methodology (RSM) using Box-Behnken design (BBD). On the basis of critical quality aspects, the experimental design helped to determine the optimal particle size (243.7 nm), zeta potential (-9.14 mV) and encapsulation efficiencies (88.91% and 80.35% for PTX and LAN respectively). The optimized formulation (PTX-LAN-PLGA-NPs) exhibited sustained release profiles over 384 hours for both the encapsulated drugs. The Korsmeyer-Peppas model was found to be the best fitted model for the release kinetics, where the release mechanism follows Fickian diffusion. In anti-tumor efficacy experiments using Michigan Cancer Foundation-7 (MCF-7) breast cancer cells, the PTX-LAN-PLGA-NPs exhibited a steep decrease in cell viability compared to the pure drugs. Taken together, the results strongly support that incorporation of PTX and LAN in nanoparticles (NPs) is a promising approach for cancer chemotherapy.
紫杉醇（PTX）是一种主要的化疗药物，对多种癌症有效，尤其是乳腺癌、卵巢癌和肺癌。对于PTX这种弱碱性化疗药物，酸性肿瘤微环境（瓦伯格效应）的形成对治疗耐药性有显著影响。目前的方法是利用酸性肿瘤微环境，将质子泵抑制剂（PPI）兰索拉唑（LAN）与PTX结合，形成一种有效的治疗组合，能够逆转PTX耐药性。为了将最佳剂量的药物递送至肿瘤细胞，选择了一种纳米药物递送系统。为了在有限的框架内设计纳米制剂工艺，采用Box-Behnken设计（BBD）的响应面方法（RSM）对典型的制剂参数进行了优化和验证。基于关键质量属性，实验设计有助于确定最佳粒径（243.7 nm）、zeta电位（-9.14 mV）以及包封率（PTX和LAN分别为88.91%和80.35%）。优化后的制剂（PTX-LAN-PLGA-NPs）对两种包封药物均表现出超过384小时的缓释特性。发现Korsmeyer-Peppas模型最适合该释放动力学，其释放机制遵循菲克扩散。在使用密歇根癌症基金会-7（MCF-7）乳腺癌细胞的抗肿瘤疗效实验中，与纯药物相比，PTX-LAN-PLGA-NPs使细胞活力急剧下降。综上所述，结果有力地支持了将PTX和LAN掺入纳米颗粒（NPs）是一种有前景的癌症化疗方法。
