EFFECT OF MOLECULAR-WEIGHT (MBARW) OF N-(2-HYDROXYPROPYL)METHACRYLAMIDE COPOLYMERS ON BODY DISTRIBUTION AND RATE OF EXCRETION AFTER SUBCUTANEOUS, INTRAPERITONEAL, AND INTRAVENOUS ADMINISTRATION TO RATS
EFFECT OF MOLECULAR-WEIGHT (MBARW) OF N-(2-HYDROXYPROPYL)METHACRYLAMIDE COPOLYMERS ON BODY DISTRIBUTION AND RATE OF EXCRETION AFTER SUBCUTANEOUS, INTRAPERITONEAL, AND INTRAVENOUS ADMINISTRATION TO RATS
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DOI：
10.1002/jbm.820211106
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发表时间：
1987-11-01
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：
SEYMOUR, LW;DUNCAN, R;KOPECEK, J
制备了N-（2-羟丙基）甲基丙烯酰胺（HPMA）和N-甲基丙烯酰酪氨酸酰胺（N-methacryloyltyrosinamide）的共聚物，并用Sepharose 4 B/6 B（1：1）色谱分离，得到8个多分散性窄、平均分子量（.hivin.MW）在12 ~ 778 kd范围内的HPMA共聚物级分。这些馏分进行放射性碘标记，静脉注射，皮下注射，腹腔注射到大鼠。他们的血流浓度曲线进行了监测和排泄率进行了评估。 静脉给药后，共聚物的循环血容量不依赖于分子量。一个分子量阈值限制肾小球滤过被确定在约45 kD，和制剂大于此阈值从血流中丢失，只有缓慢外渗。腹膜内注射后，分子量不影响共聚物从腹膜腔室到血流的运动。所观察到的转移速率可以通过单独的本体相淋巴引流来解释，没有经毛细血管皮下给药，最大的HPMA共聚物级分（hivin.Mw = 778 kD，直径约30 nm）显示在注射部位的保留增加，21天后约20%的剂量保留在那里。这可能是由于运动的物理限制或内化到局部吞噬细胞中。较小的共聚物组分很容易进入血液，在那里它们或者在尿液中丢失，或者逐渐渗透到其他组织和器官中。腹膜内和皮下给药后共聚物的长期（211天）体内分布显示网状内皮系统器官中存在尺寸依赖性蓄积。
A copolymer of N-(2-hydroxypropyl)methacrylamide (HPMA) and N-methacryloyltyrosinamide was prepared and fractionated using Sepharose 4B/6B (1:1) chromatography to produce eight HPMA copolymer fractions of narrow polydispersity and mean molecular weight (.hivin.MW) ranging from 12 to 778 kd. These fractions were radioiodinated and injected intravenously, subcutaneously, and intraperitoneally into rats. Their bloodstream-concentration profiles were monitored and rates of excretion assessed. Following intravenous administration the circulating blood volume available to the copolymers was not molecular-weight-dependent. A molecular-weight threshold limiting glomerular filtration was identified at approximately 45 kD, and preparations greater than this threshold were lost from the bloodstream only slowly by extravasation. Molecular weight did not influence the movement of copolymers from the peritoneal compartment to the bloodstream after intraperitoneal injection. The transfer rates observed could be accounted for by bulk phase lymphatic drainage alone, no transcapillary subcutaneous administration the largest HPMA copolymer fraction (.hivin.Mw = 778 kD, diameter approximately 30 nm) showed increased retention at the site of injection, approximately 20% of the dose remaining there after 21 days. This could result from physical restriction of movement or from internalization into local phagocytic cells. The smaller copolymer fractions moved readily into the bloodstream whence they were either lost in the urine or they gradually penetrated into other tissues and organs. Long-term (211 days) body distribution of copolymers following both intraperitoneal and subcutaneous administration showed size-dependent accumulation in organs of the reticuloendothelial system.