SOLUBLE CROSSLINKED N-2 HYDROXYPROPYLMETHACRYLAMIDE COPOLYMERS AS POTENTIAL DRUG CARRIERS 3. TARGETING BY INCORPORATION OF GALACTOSAMINE RESIDUES EFFECT OF ROUTE OF ADMINISTRATION
SOLUBLE CROSSLINKED N-2 HYDROXYPROPYLMETHACRYLAMIDE COPOLYMERS AS POTENTIAL DRUG CARRIERS 3. TARGETING BY INCORPORATION OF GALACTOSAMINE RESIDUES EFFECT OF ROUTE OF ADMINISTRATION
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DOI：
10.1016/0168-3659(87)90018-6
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发表时间：
1987-01-01
影响因子：
10.8
通讯作者：
KOPECEK J
中科院分区：
文献类型：
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作者：
CARTLIDGE S A;DUCAN R;KOPECEK J
N-（2-羟丙基）甲基丙烯酰胺（HPMA）共聚物的寡肽侧链（GlyGly）终止于酯连接的对硝基苯酚，与二（苯丙酰）-六亚甲二胺交联至低于凝胶点的水平。制备了半乳糖残基通过甘酰基侧链与交联聚合物结合的样品。该聚合物还含有酪氨酸酰胺残基，可以用[125I]碘化物进行放射性标记，从而监测聚合物在体内的命运。静脉给药后，含半乳糖胺的HPMA共聚物比未取代的共聚物更快地从循环中清除，这伴随着肝脏的有效沉积（1小时后60%）。在腹腔和皮下给药后，也观察到肝脏的靶向性。腹腔注射24 h后回收的含半乳糖胺的共聚物中有52%在肝脏中被发现，而未修饰的对照共聚物中只有4%在肝脏中被发现，此时在尿液中发现67%。皮下给药后，HPMA共聚物远离注射部位的迁移速度相对较慢，使用含半乳糖胺的聚合物，肝脏中检测到的放射性水平从未超过总放射性恢复的25%。口服给药后，交联HPMA共聚物没有明显转移到组织中。然而，半乳糖胺的掺入确实加速了聚合物从胃向小肠的转移。
N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymers with oligopeptide side-chains (GlyGly) terminating in ester-linked p-nitrophenol were crosslinked with di(phenylalanyl)-hexamethylenediamine to a level below the gel point. A sample was also prepared with galactosame residues bound to the crosslinked polymer via the glycylglycyl side chains. The polymer also contained tyrosinamide residues enabling radiolabelling with [125I]iodide and thus monitoring of polyumer fate in vivo. Following intravenous administration, the galactosamine-containing HPMA copolymer was cleared from the circulation more rapidly than the unsubstituted copolymer and this was accompanied by efficient deposition in the liver (60% after 1 h). Targeting to the liver was also observed after intraperitoneal and subcutaneous administration. After intraperitoneal injection 52% of the galactosamine-containing copolymer recovered after 24 h was found in the liver, whereas only 4% of the unmodified control copolymer was recovered there, 67% being found in the urine at this time. After subcutaneous administration the rate of migration of HPMA copolymer away from the injection site was comparatively slow and with the galactosamine-containing polymer, the level of radioactivity detected in the liver never exceeeded 25% of the total radioactivity recovered. There was no significant transfer of crosslinked HPMA copolymer into the tissues following oral administration. Incorporation of galactosamine, did, however, accelerate polymer transfer from the stomach into the small intestine.