Effective Enhancement of Hypoglycemic Effect of Insulin by Liver Targeted Nanoparticles Containing Cholic Acid-Modified Chitosan Derivative
Effective Enhancement of Hypoglycemic Effect of Insulin by Liver Targeted Nanoparticles Containing Cholic Acid-Modified Chitosan Derivative
复制标题
胆酸修饰壳聚糖衍生物肝靶向纳米粒有效增强胰岛素降血糖作用
DOI：
10.1021/acs.molpharmaceut.6b00188
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发表时间：
2016-07-01
影响因子：
4.9
通讯作者：
Yao, Ping
中科院分区：
文献类型：
--
作者：
Zhang, Zhe;Cai, Huanxin;Yao, Ping
肝脏负责血糖水平的平衡。本研究以胆酸和N-(2-羟基)-丙基-3-三甲基氯化铵修饰壳聚糖(HTCC-CA)作为胰岛素肝靶向给药载体。将胰岛素和HTCC-CA混合在50%乙醇和水的混合溶剂中，在pH=2的条件下，然后用pH 7.4的磷酸盐缓冲液进行透析，然后用水进行透析，从而有效地负载胰岛素。制备的胰岛素HTCC-CA纳米粒的平均粒径为86 nm，胰岛素的载药率为98.7%。由于HTCC-CA中疏水胆酸基团的随机分布，一些胆酸基团位于纳米粒子表面。与游离胰岛素相比，纳米粒在体外细胞对胰岛素的摄取增加到466%，并且皮下注射后纳米粒在肝脏中蓄积的时间更长。对糖尿病大鼠的治疗实验表明，该纳米粒可将胰岛素的药物生物利用度提高到游离胰岛素的475%，且其降血糖作用可维持24小时以上。本研究表明，表面含有胆酸基团的纳米粒具有肝脏靶向性，负载胰岛素的HTCC-CA纳米粒能有效地增强胰岛素的降血糖作用。
Liver is responsible for the balance of blood glucose level. In this study, cholic acid and N-(2-hydroxy)-propyl-3-trimethylammonium chloride modified chitosan (HTCC-CA) was used as a liver-targeted vehicle for insulin delivery. A novel approach was developed to effectively load insulin by mixing insulin and HTCC-CA in 50% ethanol and water mixed solvent at pH 2 and then dialysis against pH 7.4 phosphate buffer subsequently against water. The insulin-loaded HTCC-CA nanoparticles have an average diameter of 86 nm and insulin loading efficiency of 98.7%. Due to random distribution of the hydrophobic cholic acid groups in HTCC-CA, some of the cholic acid groups located on the nanoparticle surface. Compared with free insulin, the nanoparticles increased in vitro cellular uptake of insulin to 466%, and the nanoparticles accumulated in liver for more time after subcutaneous injection into mice. The therapy for diabetic rats displayed that the nanoparticles increased the pharmacological bioavailability of insulin to 475% relative to free insulin, and the nanoparticles could maintain the hypoglycemic effect for more than 24 h. This study demonstrates that the nanoparticles with cholic acid groups on their surface possess liver-targeted property and biocompatible insulin-loaded HTCC-CA nanoparticles can effectively enhance the hypoglycemic effect of insulin.