去甲斑蝥二羧酸壳聚糖络合物的制备及药理活性研究

目的:制备去甲斑蝥二羧酸壳聚糖络合物(NCTD络合物),降低去甲斑蝥素的毒性,增强抗肿瘤活性。方法:应用间歇式碱性水解得到的高脱乙酰度(DD)壳聚糖与去甲斑蝥二羧酸制备络合物,通过小鼠尾静脉、灌胃方式分别观察络合物与去甲斑蝥素的急性毒性,计算半数致死量(median lethal dose,LD_(50));建立小鼠移植性H_(22)肝癌肿瘤模型,观察NCTD络合物对肿瘤生长的抑制作用。结果:NCTD络合物能降低去甲斑蝥素的毒性;络合物的低、中、高剂量组均抑制小鼠的肿瘤生长,抑瘤率分别达26.60%、31.69%、44.38%,呈量效关系。结论:去甲斑蝥二羧酸与壳聚糖所成的络合物增加了水溶性,降低了毒性,提高了疗效。

Studies on Preparation of Dicarboxylic Acid of Norcantharidin & Chitosan Complex and Its PharmacologicalActivities in Tumor Animal Model

Objective： To prepare dicarboxylic acid of norcantharidin（NCTD）＆ chitosan complex, in order to reduce the toxicity of NCTD and to enhance its anti-tumor activity. Methods： The chitosan samples with high degree of deacetylation and low molecular weight were prepared by an intermittent alkaline hydrolysis and H2O2 degradation and the dicarboxylic acid of NCTD was prepared by the hydrolysis. Subsequently, the negatively charged dicarboxylic acid of NCTD at acidic pH values allowed the formation of complex with the polycationic character of chitosan molecules. The acute toxicities of mice treated with vena caudalis and lavage for the dicarboxylic acid of NCTD/chitosan complex and the NCTD were observed. The median lethal dose （LD50） was calculated by Bliss software, furthermore the antineoplastic effect of the complex was investigated using the H22 hepatoma carcinoma model of mouse. Results： The initial experiment of anti-tumor activity has validated that the complex has abated the toxicity of the NCTD and can inhibit the growth of tumors in mice. The biggest inhibitory rate was 44.38%, with a linear relationship between the effect of anti-tumor and concentrations. Conclusion： The dicarboxylic acid of NCTD/chitosan complex could enhance the anti-cancer activity and curative effect, and reduce the toxicity of of NCTD.