Department of Pharmaceutics, PSG College of Pharmacy, Coimbatore, Tamil Nadu, India.
Faculty of Pharmacy and Pharmaceutical Sciences, Katz Group Centre for Pharmacy and Health Research, University of Alberta, Edmonton, Alberta, Canada.
Eur J Pharm Sci. 2021 Oct 1;165:105938. doi: 10.1016/j.ejps.2021.105938. Epub 2021 Jul 10.
The pH-stimuli release behavior of nanoformulations may enhance the success rate of chemotherapeutic drugs in cancers by site-specific delivery of drugs to cancer tissues. The aim of the present study was to prepare chitosan (CS) nanoparticles (NPs) with previously synthesized folic acid (FA) capped silver nanoparticles (AgNPs) loaded with the anti-cancer drug gemcitabine (GEM) (FA-GEM-AgNPs). The CS-FA-GEM-AgNPs (CS-NPs) were characterized with dynamic light scattering (DLS), transmission electron microscopy (TEM), energy dispersive x-ray analysis (EDAX), selected area electron diffraction (SAED), and differential scanning calorimetric (DSC) analyses. The in-vitro drug release of GEM was evaluated in media of different pH. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was carried out to determine the cytotoxic effects of the prepared nanoformulations in media with various pH. The time- and pH-dependent apoptotic cell death induced by CS-NPs with MDA-MB-453 human breast cancer cell line was observed using acridine orange (AO)/ethidium bromide (EtBr) staining. The pharmacokinetic parameters were studied with high-performance liquid chromatography (HPLC) and atomic absorption spectroscopy (AAS). Two batches of CS-NPs formulations were prepared, one with AgNPs of particle size 143 nm and the other with 244 nm. The particle size for CS-NPs-I (FA-GEM-AgNPs-143 nm) and CS-NPs-II (FA-GEM-AgNPs-244 nm) was found to be 425 and 545 nm, respectively. The zeta potential was found to be 36.1 and 37.5 mV for CS-NPs-I and CS-NPs-II, respectively. CS-NPs-I and CS-NPs-II showed a polydispersity index (PDI) of 0.240 and 0.261, respectively. A TEM study confirmed the spherical nature of the NPs. The nanoformulations exerted pH-dependant effect against MDA-MB-453 cells with relatively higher cytotoxicity at the lower pH than at higher pH levels. The pharmacokinetic profile and tissue distribution of CS-NPs in rats exerted drug release in a pH-dependent manner with enhanced excretion of Ag. An optimized nanoformulation for pH-stimuli responsive release of GEM was successfully developed for future therapeutic exploration.
纳米制剂的 pH 刺激释放行为可以通过将药物递送到癌症组织中的特定部位来提高化疗药物在癌症中的成功率。本研究的目的是制备壳聚糖 (CS) 纳米粒子 (NPs)，其中负载有抗癌药物吉西他滨 (GEM) 的先前合成的叶酸 (FA) 封端的银纳米粒子 (AgNPs) (FA-GEM-AgNPs)。CS-FA-GEM-AgNPs (CS-NPs) 用动态光散射 (DLS)、透射电子显微镜 (TEM)、能量色散 X 射线分析 (EDAX)、选区电子衍射 (SAED) 和差示扫描量热法 (DSC) 分析进行了表征。在不同 pH 值的介质中评估了 GEM 的体外药物释放。在不同 pH 值的介质中进行了 3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑溴化盐 (MTT) 测定，以确定制备的纳米制剂的细胞毒性。用吖啶橙 (AO)/溴化乙锭 (EtBr) 染色观察 CS-NPs 诱导 MDA-MB-453 人乳腺癌细胞系时间和 pH 依赖性细胞凋亡。用高效液相色谱法 (HPLC) 和原子吸收光谱法 (AAS) 研究了药代动力学参数。用两种批次的 CS-NPs 制剂进行了制备，一种是粒径为 143nm 的 AgNPs，另一种是粒径为 244nm 的 AgNPs。CS-NPs-I (FA-GEM-AgNPs-143nm) 和 CS-NPs-II (FA-GEM-AgNPs-244nm) 的粒径分别为 425nm 和 545nm。CS-NPs-I 和 CS-NPs-II 的 Zeta 电位分别为 36.1mV 和 37.5mV。CS-NPs-I 和 CS-NPs-II 的多分散指数 (PDI) 分别为 0.240 和 0.261。TEM 研究证实了 NPs 的球形性质。纳米制剂对 MDA-MB-453 细胞具有 pH 依赖性作用，在较低 pH 值下比在较高 pH 值下具有更高的细胞毒性。CS-NPs 在大鼠中的药代动力学特征和组织分布以 pH 依赖性方式释放药物，Ag 的排泄增加。成功开发了用于 pH 刺激响应释放 GEM 的优化纳米制剂，用于未来的治疗探索。
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