School of Studies in Pharmaceutical Sciences, Jiwaji University, Gwalior, MP, 474002, India; Divine International Group of Institutions, Gwalior, MP, India.
University Institute of Pharmaceutical Sciences, UGC Centre for Advanced Studies, Panjab University, CH, 160014, India.
Colloids Surf B Biointerfaces. 2021 Jul;203:111760. doi: 10.1016/j.colsurfb.2021.111760. Epub 2021 Apr 11.
The present study was designed to develop pH-sensitive lipid polymer hybrid nanoparticles (pHS-LPHNPs) for specific cytosolic-delivery of docetaxel (DTX). The pHS-LPHNPs-DTX formulation was prepared by self-assembled nano-precipitation technique and characterized for zeta potential, particle size, entrapment efficiency, polydispersity index (PDI), and in vitro drug release. In vitro cytotoxicity of pHS-LPHNPs-DTX was assessed on breast cancer cells (MDA-MB-231 and MCF-7) and compared with DTX-loaded conventional LPHNPs and bare DTX. In vitro cellular uptake in MDA-MB-231 cell lines showed better uptake of pHS-LPHNPs. Further, a significant reduction in the IC of pHS-LPHNPs-DTX against both breast cancer cells was observed. Flow cytometry results showed greater apoptosis in case of pHS-LPHNPs-DTX treated MDA-MB-231 cells. Breast cancer was experimentally induced in BALB/c female mice, and the in vivo efficacy of the developed pHS-LPHNPs formulation was assessed with respect to the pharmacokinetics, biodistribution in the vital organs (liver, kidney, heart, lungs, and spleen), percentage tumor burden, and survival of breast cancer-bearing animals. In vivo studies showed improved pharmacokinetic and target-specificity with minimum DTX circulation in the deep-seated organs in the case of pHS-LPHNPs-DTX compared to the LPHNPs-DTX and free DTX. Mice treated with pHS-LPHNPs-DTX exhibited a significantly lesser tumor burden than other treatment groups. Also, reduced distribution of DTX in the serum was evident for pHS-LPHNPs-DTX treated mice compared to the LPHNPs-DTX and free DTX. In essence, pHS-LPHNPs mediated delivery of DTX presents a viable platform for developing therapeutic-interventions against breast-cancer.
本研究旨在开发 pH 敏感的脂质聚合物杂化纳米粒（pHS-LPHNPs）用于特定的胞质内递送多西紫杉醇（DTX）。采用自组装纳米沉淀技术制备 pHS-LPHNPs-DTX 制剂，并对其进行 zeta 电位、粒径、包封效率、多分散指数（PDI）和体外药物释放进行表征。在乳腺癌细胞（MDA-MB-231 和 MCF-7）上评估 pHS-LPHNPs-DTX 的体外细胞毒性，并与载药常规 LPHNPs 和游离 DTX 进行比较。在 MDA-MB-231 细胞系中的体外细胞摄取显示出对 pHS-LPHNPs 的更好摄取。此外，观察到 pHS-LPHNPs-DTX 对两种乳腺癌细胞的 IC 显著降低。流式细胞术结果表明，pHS-LPHNPs-DTX 处理的 MDA-MB-231 细胞凋亡增加。在 BALB/c 雌性小鼠中实验性诱导乳腺癌，并评估所开发的 pHS-LPHNPs 制剂的体内疗效，包括药代动力学、在重要器官（肝、肾、心、肺和脾）中的分布、肿瘤负担百分比和荷瘤动物的生存情况。体内研究表明，与 LPHNPs-DTX 和游离 DTX 相比，pHS-LPHNPs-DTX 具有更好的药代动力学和靶向特异性，可减少 DTX 在深部器官中的循环。与其他治疗组相比，用 pHS-LPHNPs-DTX 治疗的小鼠肿瘤负担明显更小。此外，与 LPHNPs-DTX 和游离 DTX 相比，用 pHS-LPHNPs-DTX 治疗的小鼠血清中 DTX 的分布减少。总之，pHS-LPHNPs 介导的 DTX 递呈为开发针对乳腺癌的治疗干预提供了可行的平台。
