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首页> 外文期刊>Journal of Controlled Release: Official Journal of the Controlled Release Society >Dendrimers: Relationship between structure and biocompatibility in vitro, and preliminary studies on the biodistribution of I-125-labelled polyamidoamine dendrimers in vivo
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Dendrimers: Relationship between structure and biocompatibility in vitro, and preliminary studies on the biodistribution of I-125-labelled polyamidoamine dendrimers in vivo

机译：树状聚合物：体外结构与生物相容性之间的关系，以及I-125标记的聚酰胺酰胺树状聚合物在体内的生物分布的初步研究

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摘要

Dendrimers are highly branched macromolecules of low polydispersity that provide many exciting opportunities for design of novel drug-carriers, gene delivery systems and imaging agents. They hold promise in tissue targeting applications, controlled drug release and moreover, their interesting nanoscopic architecture might allow easier passage across biological barriers by transcytosis. However, from the vast array of structures currently emerging from synthetic chemistry it is essential to design molecules that have real potential for in vivo biological use. Here, polyamidoamine (PAMAM, Starburst(TM)), poly(propyleneimine) with tither diaminobutane or diaminoethane as core, and poly(ethylene oxide) (PEO) grafted carbosilane (CSi-PEO) dendrimers were used to study systematically the effect of dendrimer generation and surface functionality on biological propel-ties in vitro. Generally, dendrimers bearing -NH2 termini displayed concentration- and in the case of PAMAM dendrimers generation-dependent haemolysis, and changes in red cell morphology were observed after 1 h even at low concentrations (10 mu g/ml). At concentrations below 1 mg/ml CSi-PEO dendrimers and those dendrimers with carboxylate (COONa) terminal groups were neither haemolytic nor cytotoxic towards a panel of cell lines in vitro. In general, cationic dendrimers were cytotoxic (72 h incubation), displaying IC50 values=50-300 mu g/ml dependent on dendrimer-type, cell-type and generation. Preliminary studies: with polyether dendrimers prepared by the convergent route showed that dendrimers with carboxylate and malonate surfaces were not haemolytic at 1 h, but after 23 h, unlike anionic PAMAM dendrimers they were lyric. Cationic I-125-labelled PAMAM dendrimers (gen 3 and 4) administered intravenously (i.v.) to Wistar rats. (similar to 10 mu g/ml) were cleared rapidly from the circulation (<2% recovered dose in blood at I h). Anionic PAMAM dendrimers (gen 2.5, 3.5 and 5.5) showed longer circulation times (similar to 20-40% recovered dose in blood at 1 h) with generation-dependent clearance rates: lower generations circulated longer. For both anionic and cationic species blood levels at 1 h correlated with the extent of liver capture observed (30-90% recovered dose at 1 h). (125)-Labelled PAMAM dendrimers injected intraperitoneally were transferred to the bloodstream within an hour and their subsequent biodistribution minored that seen following i.v. injection. Inherent toxicity would suggest it unlikely that higher generation cationic dendrimers will be suitable for parenteral administration, especially if they are to be used at a high dose. In addition it is clear that dendrimer structure must also be carefully tailored to avoid rapid hepatic uptake if targeting elsewhere (e.g. tumour targeting) is a primary objective. (C) 2000 Elsevier Science B.V. All rights reserved. [References: 41]
机译：树状聚合物是低多分散性的高度分支的大分子，为新型药物载体，基因传递系统和显像剂的设计提供了许多令人兴奋的机会。它们在组织靶向应用，控制药物释放等方面具有广阔的前景，此外，它们有趣的纳米结构可能使通过胞吞作用更容易穿过生物屏障。然而，从合成化学中当前出现的大量结构中，设计具有体内生物应用真正潜力的分子至关重要。在这里，使用聚酰胺胺（PAMAM，StarburstTM），以二氨基丁烷或二氨基乙烷为十分之一的聚（丙烯亚胺）和聚环氧乙烷（PEO）接枝的碳硅烷（CSi-PEO）树状聚合物来系统地研究树状聚合物的作用体外生物推动力的产生和表面功能。通常，带有-NH2末端的树状聚合物表现出浓度-，而在PAMAM树状聚合物生成依赖性溶血的情况下，即使在低浓度（10μg / ml）下1 h后也观察到红细胞形态的变化。在低于1 mg / ml的浓度下，CSi-PEO树枝状聚合物和那些带有羧酸根（COONa）末端基团的树枝状聚合物在体外对一组细胞系均无溶血性或细胞毒性。通常，阳离子树状聚合物具有细胞毒性（孵育72小时），显示IC50值= 50-300μg / ml，这取决于树状聚合物的类型，细胞类型和生成。初步研究：采用收敛路线制备的聚醚树枝状大分子显示，具有羧酸盐和丙二酸表面的树枝状大分子在1小时内没有溶血，但在23小时后，与阴离子PAMAM树状大分子不同，它们是抒情的。对Wistar大鼠静脉内（i.v.）施用阳离子I-125标记的PAMAM树状大分子（第3和第4代）。 （类似于10μg / ml）从循环中迅速清除（在1 h时血液中的回收剂量<2％）。阴离子PAMAM树状大分子（2.5、3.5和5.5代）显示出更长的循环时间（类似于1 h时血液中20-40％的回收剂量），具有取决于世代的清除率：更低的世代循环时间更长。对于阴离子和阳离子物种，在1 h时的血液水平与观察到的肝捕获程度相关（在1 h时恢复剂量为30-90％）。腹膜内注射的（125）Labelled PAMAM树状聚合物在一个小时内转移到血液中，其随后的生物分布较小。注射。固有的毒性表明，更高世代的阳离子树状聚合物不太可能适合肠胃外给药，尤其是如果它们要以高剂量使用时。另外，很明显，如果靶向于其他地方（例如靶向肿瘤）是主要目的，则也必须仔细地调整树状聚合物的结构，以避免肝的快速摄取。 （C）2000 Elsevier Science B.V.保留所有权利。 [参考：41]

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