米托蒽醌-胰岛素偶联物体内分布和体外药效学评价

Investigation on Biodistribution of Mitoxantrone-Insulin Conjugates in vivo and Pharmacodynamics in vitro

目的考察本实验室合成的米托蒽醌-胰岛素偶联物(MIT-INS)的肿瘤主动靶向性及药效。方法对比考察合成偶联物与原药米托蒽醌(MIT)在荷瘤小鼠体内的分布情况,并采用噻唑蓝比色法(MTT)考察了两者对肝癌细胞株SMMC-7721的体外抑瘤效果。结果体内分布实验结果显示,在肿瘤组织中MIT-INS较MIT半衰期(t1／2)延长75％,药-时曲线下面积(AUC)增大 67％,初始浓度提高近1倍,相对靶向效率(RTE)为1．67,药物在其他脏器特别是心脏中浓度显著降低;体外实验显示,MIT-INS 与MIT有相同肿瘤细胞抑制率。结论初步证明了胰岛素作为米托蒽醌的载体,能提高药物的肿瘤靶向性,降低不良反应, 并保持药物疗效,为肿瘤主动靶向生物大分子载体设计提供了新的思路。

OBJECTIVE To investigate the initiative target efficiency of newly conjugated mltoxantrone-insulin （MIT-INS） on tumor in vivo and in vitro. METHODS The drug biodistributions of mitoxantrone （MIT） and MIT-INS in vivo were examined in tumor-bearing mice, while MTT assays were employed to evaluate the depression efficiencies of MIT-INS and MIT on SMMC-7721 hepatocareinoma cells in vitro. RESULTS It was proved in vivo that, compared with MIT, the half-life of MIT-INS was prolonged by 75 % ; the area under the concentration-time curve （AUC） of MIT-INS was enlarged by 67% ; the initial concentration of MIT-INS was increased by almost 1130% ; the relative target efficiency （RTE） of MIT-INS was 1.67; and MIT concentrations of MIT-INS were much lower in all examined organs, especially in heart. Moreover, the inhibition rate （IR） of MIT-INS, proved/n vitro, was similar to that of the free drug. CONCLUSION MIT-INS has tumor-targeting property with enough anti-tumor activity, and insulin, as the vector of anti-tumor drugs, can improve target effect with low side effect.