N-(2-羟丙基)甲基丙烯酰胺聚合物米托蒽醌接合物荷瘤小鼠体内分布的研究

Biodistribution of N-(2-hydroxypropyl) Methacrylamide Copolymer-bound Mitoxantrone in Mice Bearing Ehrlich Solid Tumor

本实验成功合成N (2 羟丙基 )甲基丙烯酰胺聚合物 (N (2 hydroxypropyl)methacrylamide ,HPMA) 米托蒽醌接合物。以小鼠皮下接种艾氏癌实体型作为肿瘤模型 ,考察游离药物与接合物在动物体内分布及药代动力学行为。研究结果表明 ,接合物较之游离药物在荷瘤小鼠体内的分布明显不同 ,表现为具有较长的血浆半衰期及较强的肿瘤趋向性 ,证实了HPMA聚合物对实体瘤具有“增强的透过及滞留效应”。同时 ,接合物在心脏中的分布明显减少 ,降低了原药的毒副作用。从而更进一步说明 ,将具有仲氨基的米托蒽醌连接于HPMA聚合物 ,较原药而言 ,可提高肿瘤组织的分布 ,用于临床实体瘤治疗 ,具有一定的潜力。

N-(2-hydroxypropyl) methacrylamide (HPMA) copolyme r -Mitoxantrone conjugates was successf- ully synthesized and characterized a s an anti-cancer drug for solid tumors. The biodistribution and pharmacokinetic s of the conjugates were examined in mice bearing Ehrlich solid tumor. The biodi stribution of the HPMA copolymer-bound Mitoxantrone in tumor-bearing mice was significantly different from that of the free drug. It appeared that the circula tion life times of the conjugates were three times more than those of the drugs in the free form. The concentrations of HPMA copolymer-bound Mitoxantrone in tu mor reached maximum levels 24 h post injection. AUC is three times higher th an that of free drug. The P- Mitoxantrone level in heart was five times lower t han that of free drug. This reduces the possibility of toxicity to heart. In par ticular, HPMA copolymer-bound Mitoxantrone accumulated at higher levels in tumo r tissues. This may be explained by “Enhanced Permeability and Retention effect ”(EPR effect). These results show the possibility of targeting anticancer drug - Mitoxantrone with secondary amino residue to the tumor tissue by HPMA copolym er as carrier.