Vivek Raju, Thangam Ramar, NipunBabu Varukattu, Rejeeth Chandrababu, Sivasubramanian Srinivasan, Gunasekaran Palani, Muthuchelian Krishnasamy, Kannan Soundarapandian
Proteomics & Molecular Cell Physiology Laboratory, Department of Zoology, School of Life Sciences, Bharathiar University , Coimbatore 641 046, Tamilnadu, India.
ACS Appl Mater Interfaces. 2014 May 14;6(9):6469-80. doi: 10.1021/am406012g. Epub 2014 Apr 29.
Nanotechnology-based medical approaches have made tremendous potential for enhancing the treatment efficacy with minimal doses of chemotherapeutic drugs against cancer. In this study, using tamoxifen (Tam), biodegradable antibody conjugated polymeric nanoparticles (NPs) was developed to achieve targeted delivery as well as sustained release of the drug against breast cancer cells. Poly(D,L-lactic-co-glycolic acid) (PLGA) NPs were stabilized by coating with poly(vinyl alcohol) (PVA), and copolymer polyvinyl-pyrrolidone (PVP) was used to conjugate herceptin (antibody) with PLGA NPs for promoting the site-specific intracellular delivery of Tam against HER2 receptor overexpressed breast cancer (MCF-7) cells. The Tam-loaded PVP-PLGA NPs and herceptin-conjugated Tam-loaded PVP-PLGA NPs were characterized in terms of morphology, size, surface charge, and structural chemistry by dynamic light scattering (DLS), Transmission electron microscopy (TEM), ζ potential analysis, 1H nuclear magnetic resonance (NMR), and Fourier transform infrared (FT-IR) spectroscopy. pH-based drug release property and the anticancer activity (in vitro and in vivo models) of the herceptin conjugated polymeric NPs were evaluated by flow cytometry and confocal image analysis. Besides, the extent of cellular uptake of drug via HER2 receptor-mediated endocytosis by herceptin-conjugated Tam-loaded PVP-PLGA NPs was examined. Furthermore, the possible signaling pathway of apoptotic induction in MCF-7 cells was explored by Western blotting, and it was demonstrated that drug-loaded PLGA NPs were capable of inducing apoptosis in a caspase-dependent manner. Hence, this nanocarrier drug delivery system (DDS) not only actively targets a multidrug-resistance (MDR) associated phenotype (HER2 receptor overexpression) but also improves therapeutic efficiency by enhancing the cancer cell targeted delivery and sustained release of therapeutic agents.
基于纳米技术的医学方法在使用最小剂量的化疗药物提高癌症治疗效果方面具有巨大潜力。在本研究中，使用他莫昔芬（Tam）开发了可生物降解的抗体偶联聚合物纳米颗粒（NPs），以实现对乳腺癌细胞的靶向递送以及药物的持续释放。聚（D，L-乳酸-乙醇酸共聚物）（PLGA）纳米颗粒通过用聚乙烯醇（PVA）包被来稳定，并且使用共聚物聚乙烯基吡咯烷酮（PVP）将赫赛汀（抗体）与PLGA纳米颗粒偶联，以促进Tam针对过表达HER2受体的乳腺癌（MCF-7）细胞的位点特异性细胞内递送。通过动态光散射（DLS）、透射电子显微镜（TEM）、ζ电位分析、1H核磁共振（NMR）和傅里叶变换红外（FT-IR）光谱对负载Tam的PVP-PLGA纳米颗粒和偶联赫赛汀的负载Tam的PVP-PLGA纳米颗粒进行了形态、大小、表面电荷和结构化学方面的表征。通过流式细胞术和共聚焦图像分析评估了偶联赫赛汀的聚合物纳米颗粒的基于pH的药物释放特性和抗癌活性（体外和体内模型）。此外，还研究了偶联赫赛汀的负载Tam的PVP-PLGA纳米颗粒通过HER2受体介导的内吞作用对药物细胞摄取的程度。此外，通过蛋白质印迹法探索了MCF-7细胞中凋亡诱导的可能信号通路，结果表明负载药物的PLGA纳米颗粒能够以半胱天冬酶依赖性方式诱导凋亡。因此，这种纳米载体药物递送系统（DDS）不仅能主动靶向与多药耐药（MDR）相关的表型（HER2受体过表达），还能通过增强癌细胞靶向递送和治疗剂的持续释放来提高治疗效率。
