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Abstract：
Major obstacles in the development of nanoformulations as efficient drug delivery systems are the rapid clearance from blood circulation and lysosomal entrapment. To overcome these problems, a polysaccharide-based core-shell type charge-switchable nanoformulation (CS-LA-DMMA/CMCS/PAMAM@DOX) is constructed to improve antitumor efficacy of DOX. By applying carboxymethyl chitosan (CMCS) as bridge polymer and negatively charged chitosan-derivative as outer shell, the stability and pH-sensitivity of this nanoformulation is promisingly enhanced. Furthermore, the positively charged PAMAM@DOX could escape from lysosomes via \"proton sponge effect\" and \"cationic-anionic interaction with lysosome membranes\". Admirable cellular uptake and high apoptosis/necrosis rate were detected in this study. In vitro assays demonstrate that the CS-LA-DMMA/CMCS/PAMAM@DOX was internalized into HepG2 cells predominantly via the clathrin-mediated endocytosis pathway. Excitingly, in vivo studies showed that high accumulation of CS-LA-DMMA/CMCS/PAMAM@DOX in tumor tissue led to enhanced tumor inhibition. Compared with free DOX, the tumor inhibition rate of nanoformulation was improved up to 226%.
摘要：
发展纳米制剂作为有效药物递送系统的主要障碍是从血液循环和溶酶体截留的快速清除。为了克服这些问题,构建基于多糖的核-壳型电荷可转换纳米制剂(CS-LA-DMMA/CMCS/PAMAM@DOX)以提高DOX的抗肿瘤功效。通过应用羧甲基壳聚糖（CMCS）作为桥聚合物和带负电荷的壳聚糖衍生物作为外壳，该纳米制剂的稳定性和pH敏感性有望增强。此外，带正电荷的PAMAM@DOX可以通过“质子海绵效应”和“阳离子-阴离子与溶酶体膜的相互作用”从溶酶体中逸出。在这项研究中检测到令人钦佩的细胞摄取和高的凋亡/坏死率。体外测定表明CS-LA-DMMA/CMCS/PAMAM@DOX主要通过网格蛋白介导的内吞途径内化到HepG2细胞中。令人兴奋的是,体内研究表明，CS-LA-DMMA/CMCS/PAMAM@DOX在肿瘤组织中的高积累导致肿瘤抑制增强。与免费DOX相比，纳米制剂的抑瘤率提高到226%。
