FATE OF N-(2-HYDROXYPROPYL)METHACRYLAMIDE COPOLYMERS WITH PENDENT GALACTOSAMINE RESIDUES AFTER INTRAVENOUS ADMINISTRATION TO RATS
FATE OF N-(2-HYDROXYPROPYL)METHACRYLAMIDE COPOLYMERS WITH PENDENT GALACTOSAMINE RESIDUES AFTER INTRAVENOUS ADMINISTRATION TO RATS
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DOI：
10.1016/0304-4165(86)90120-0
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发表时间：
1986-01-15
期刊：
影响因子：
--
通讯作者：
KOPECEK, J
中科院分区：
文献类型：
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作者：
DUNCAN, R;SEYMOUR, LCW;KOPECEK, J
对大鼠静脉内给药后，带有半乳糖胺残基的N-（2-羟丙基）甲基丙烯酰胺（HPMA）共聚物在肝脏中积累（邓肯，R.，Kopecek，J.，Rejkova，P. and Lloyd，J. B.（1983）Biochim. Biophys. Acta 755，518-521）。在这项研究中，HPMA共聚物轴承侧半乳糖胺残基（1.0-11.6摩尔%）静脉注射到大鼠和他们的血液清除率和肝脏蓄积的测量。发现4摩尔%的取代水平足以在给药后30分钟在肝脏中引起大量沉积。最高度取代的聚合物（11.6摩尔%）被迅速导向肝脏，80-90%在给药后10分钟内被回收。肝脏分离成肝细胞和非实质细胞表明，聚合物主要与肝细胞相关，给药后不同时间的肝脏密度梯度亚细胞分级证实，聚合物被肝细胞内化，并随时间推移转运至次级溶酶体。使用分离的大鼠肝细胞的实验表明，HPMA共聚物与高半乳糖胺和另外的甘氨酰甘氨酰酪氨酸酰胺侧链被用来证明释放的药物类似物穿过溶酶体膜。这些聚合物被放射性碘标记，在静脉内给药大鼠后，分离肝溶酶体并在37 ℃温育。C在0.25M蔗糖中。放射性从溶酶体中释放的速度快于溶酶体酶芳基硫酸酯酶，这一观察结果表明共聚物侧链在溶酶体内水解，随后低分子量降解产物穿过溶酶体膜。
N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymers bearing galactosamine residues accumulate in the liver after intravenous administration to rats (Duncan, R., Kopecek, J., Rejmanova, P. and Lloyd, J. B. (1983) Biochim. Biophys. Acta 755, 518-521). In this study HPMA copolymers bearing pendent galactosamine residues (1.0-11.6 mol%) were injected intravenously into rats and their rates of blood clearance and liver accumulation were measured. A level of substitution of 4 mol% was found to be sufficient to cause substantial deposition in the liver 30 min after administration. The most highly substituted polymer (11.6 mol%) was directed rapidly to the liver, 80-90% being recovered there less than 10 min after administration. Separation of liver into hepatocytes and non-parenchymal cells indicated that polymer was largely associated with the hepatocytes, and density-gradient subcellular fractionation of liver at various times after administration confirmed that polymer was internalized by liver cells and transported, with time, into the secondary lysosomes. Experiments using isolated rat hepatocytes indicated that HPMA copolymers with high galactosamine and in addition glycylglycyltyrosinamide side-chains were used to demonstrate release of a drug analogue across the lysosomal membrane. These polymers were radioiodinated and, following intravenous administration to rats, the liver lysomes were isolated and incubated at 37.degree. C in 0.25 M sucrose. Radioactivity was released from the lysomes faster than the lysosomal enzyme arylsulphatase, an observation that indicates intralysosomal hydrolysis of the copolymer side-chain with subsequent passage of low molecular weight degradation product across the lysosomal membrane.