College of Marine Life Science, Ocean University of China, Qingdao, China.
Department of Plastic Surgery, The Affiliated Hospital of Medical College Qingdao University, Qingdao, China.
Eur J Pharm Biopharm. 2014 May;87(1):197-207. doi: 10.1016/j.ejpb.2013.11.007. Epub 2013 Dec 4.
Chitosan/carboxymethyl chitosan nanogels (CS/CMCS-NGs) could enhance the oral bioavailability of doxorubicin hydrochloride (DOX). To identify the mechanisms that support this recent observation, different transport pathways of CS/CMCS-NGs through the small intestine were studied in this work. Transcellular mechanisms were investigated in the presence of different inhibitors of protein-mediated endocytosis. A reduction of 52.32±18% of drug transport was found when clathrin-mediated endocytosis was inhibited, which demonstrated that clathrin-mediated endocytosis played an important role in the transcellular transport of DOX:CS/CMCS-NGs. The paracellular transport results showed that CMCS in NGs could produce a transient and reversible enhancement of paracellular permeability by depriving Ca(2+) from adherens junctions, whose efficacy as an absorption enhancer was about 1.7-3.3 folds higher than CS in NGs in GI tract. Finally, in vivo experiment showed that the transport capacity of DOX:CS/CMCS-NGs was significantly inhibited by extra added Ca(2+), which confirmed that the higher capacity to binding Ca(2+) of CS/CMCS-NGs was beneficial for transport of DOX.
壳聚糖/羧甲基壳聚糖纳米凝胶（CS/CMCS-NGs）可以提高盐酸阿霉素（DOX）的口服生物利用度。为了确定支持这一最新观察结果的机制，本工作研究了 CS/CMCS-NGs 通过小肠的不同转运途径。在存在不同蛋白介导的内吞作用抑制剂的情况下，研究了细胞旁路转运机制。当抑制网格蛋白介导的内吞作用时，药物转运减少了 52.32±18%，这表明网格蛋白介导的内吞作用在 DOX:CS/CMCS-NGs 的细胞旁路转运中起重要作用。细胞旁路转运结果表明，NGs 中的 CMCS 可以通过剥夺黏着连接的 Ca(2+) 来产生瞬时和可逆的细胞旁路通透性增强，其作为吸收增强剂的功效比 NGs 中的 CS 高 1.7-3.3 倍。最后，体内实验表明，额外添加的 Ca(2+) 显著抑制了 DOX:CS/CMCS-NGs 的转运能力，这证实了 CS/CMCS-NGs 更高的结合 Ca(2+) 能力有利于 DOX 的转运。
