Biopharmaceutical properties of uricase conjugated to neutral and amphiphilic polymers
Biopharmaceutical properties of uricase conjugated to neutral and amphiphilic polymers
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DOI：
10.1021/bc980155k
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发表时间：
1999-07-01
影响因子：
4.7
通讯作者：
Veronese, FM
中科院分区：
文献类型：
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作者：
Caliceti, P;Schiavon, O;Veronese, FM
以尿酸酶为模型，比较了不同两亲性聚合物制备的聚合物-蛋白质偶联物的药代动力学和生物分布。通过共价结合类似数目的线性聚尿酸酶的聚合物链，（乙二醇）（M-w 5000 Da）;（B）支化聚（乙二醇）（分子量10 000 Da）;（c）聚（N-乙烯基吡咯烷酮）（分子量6000 Da）;（d）聚乙烯（N-丙烯酰吗啉）（M-w，6000 Dal，通过静脉内给药于Balb/c小鼠，偶联物显示出不同的药代动力学和器官分布行为。(1)未修饰的酶和聚（N-乙烯基吡咯烷酮）共轭物分别是在血液中具有最短和最长持久性的酶形式（平均停留时间45和4378分钟）。(2)发现天然尿酸酶在给药后不久显著定位于心脏、肺和肝脏中，在那里它也被迅速清除。(3)聚（N-丙烯酰吗啉）衍生物在肝脏中的浓度水平最高（高达剂量的25.5%），在其他考虑的器官中也发生了相当大的蓄积。(4)聚（N-乙烯吡咯烷酮）尿酸酶对肝脏有一定的趋化性，但对其他器官的摄取指数较低。（5）支链聚乙二醇衍生物在肝脏和脾脏中的蓄积较优先。(6)在各种尿酸酶形式中，线性聚（乙二醇）结合物是所有检查器官中分布水平最低的物质。(7)最后，所有的酶形式在肾脏中缓慢地处置，其中聚（N-丙烯酰吗啉）衍生物（2880分钟后为15%）和未修饰的尿酸酶（1440分钟后为14%）的水平较高。
A comparative pharmacokinetic and biodistribution investigation of polymer-protein conjugates prepared with various amphiphilic polymers was carried out using uricase as a model. Four polymeruricase derivatives have been obtained by covalent binding of a similar number of polymer chains of (a) linear poly(ethylene glycol) (M-w 5000 Da); (b) branched poly(ethylene glycol) (M-w 10 000 Da); (c) poly(N-vinylpyrrolidone) (M-w 6000 Da); (d) poly(N-acryloilmorpholine) (M-w, 6000 Dal, By intravenous administration to Balb/c mice, the conjugates displayed different pharmacokinetic and organ distribution behaviors. (1) The unmodified enzyme and the poly(N-vinylpyrrolidone) conjugate were the enzyme forms with the shortest and the longest permanence in blood respectively (mean residence time 45 and 4378 min). (2) Native uricase was found to localize soon after administration significantly in heart, lungs, and liver from where it was also rapidly cleared. (3) The poly(N-acryloilmorpholine) derivative showed the highest concentration levels in liver (up to 25.5% of the dose) and considerable accumulation took also place in the other considered organs. (4) Poly(N-vinylpyrrolidone)-uricase displayed a relevant tropism for liver but low uptake indexes were found for the other organs, (5) The branched poly(ethylene glycol) derivative accumulated preferentially in liver and spleen. (6) The linear poly(ethylene glycol) conjugate was, among the various uricase forms, the species with the lowest distribution levels in all the examined organs. (7) Finally, all the enzyme forms slowly disposed in kidneys with higher levels for the poly(N-acryloilmorpholine) derivative (15% after 2880 min) and unmodified uricase (14% after 1440 min).