Khare Vaibhav, Singh Amarinder, Mahajan Girish, Alam Noor, Kour Smit, Gupta Mehak, Kumar Ajay, Singh Gurdarshan, Singh Shashank K, Saxena Ajit K, Mondhe Dilip M, Gupta Prem N
Formulation & Drug Delivery Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.
PK-PD-Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.
Eur J Pharm Sci. 2016 Sep 20;92:183-93. doi: 10.1016/j.ejps.2016.07.007. Epub 2016 Jul 9.
The anticancer potential of gemcitabine, a nucleoside analog, is compromised due to the enzymatic degradation into inactive form leading to the short half-life in systemic circulation. Novel delivery strategies are required to improve therapeutic efficacy of this potential drug. Monomethoxy polyethylene glycol amine-polylactide-co-glycolide (mPEG-PLGA) co-polymer was synthesized and characterized by FTIR and (1)H NMR. Gemcitabine loaded mPEG-PLGA nanoparticles (NPs) were developed and investigated for pharmacokinetic profile and in vivo anticancer activity. The mPEG-PLGA NPs (size: 267±10nm, zeta potential: -17.5±0.2mV) exhibited sustained drug release profile and were found to be compatible with blood. The mPEG-PLGA NPs were able to evade the uptake by macrophages (i.e. THP-1 and J774A) by reducing the adsorption of proteins on the surface of NPs. The enhanced cellular uptake and cell cytotoxicity was observed by mPEG-PLGA NPs in MiaPaCa-2 and MCF-7 cells. The half-life of gemcitabine in mPEG-PLGA NPs was remarkably enhanced (19 folds) than native gemcitabine. Further, the pharmacokinetic modulation of gemcitabine using mPEG-PLGA-NPs was translated in improved anticancer efficacy as compared to native gemcitabine in Ehrlich ascites bearing Balb-c mice. The results demonstrated the potential of long-circulatory nanoparticles in improving the pharmacokinetic profile and in-turn the anticancer efficacy of gemcitabine.
吉西他滨是一种核苷类似物，其抗癌潜力因酶促降解为无活性形式而受到影响，导致其在体循环中的半衰期较短。需要新的给药策略来提高这种潜在药物的治疗效果。合成了单甲氧基聚乙二醇胺-聚乳酸-共-乙醇酸（mPEG-PLGA）共聚物，并通过傅里叶变换红外光谱（FTIR）和核磁共振氢谱（¹H NMR）对其进行了表征。制备了负载吉西他滨的mPEG-PLGA纳米颗粒（NPs），并研究了其药代动力学特征和体内抗癌活性。mPEG-PLGA NPs（尺寸：267±10nm，zeta电位：-17.5±0.2mV）呈现出药物缓释特征，且被发现与血液相容。mPEG-PLGA NPs能够通过减少蛋白质在NPs表面的吸附来逃避巨噬细胞（即THP-1和J774A）的摄取。在MiaPaCa-2和MCF-7细胞中观察到mPEG-PLGA NPs增强了细胞摄取和细胞毒性。与天然吉西他滨相比，吉西他滨在mPEG-PLGA NPs中的半衰期显著延长（19倍）。此外，与天然吉西他滨相比，在携带艾氏腹水瘤的Balb-c小鼠中，使用mPEG-PLGA-NPs对吉西他滨进行药代动力学调节转化为提高的抗癌疗效。结果证明了长循环纳米颗粒在改善药代动力学特征进而提高吉西他滨抗癌疗效方面的潜力。
