Dendrimers:: Relationship between structure and biocompatibility in vitro, and preliminary studies on the biodistribution of 125I-labelled polyamidoamine dendrimers in vivo
Dendrimers:: Relationship between structure and biocompatibility in vitro, and preliminary studies on the biodistribution of 125I-labelled polyamidoamine dendrimers in vivo
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DOI：
10.1016/s0168-3659(99)00246-1
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发表时间：
2000-03-01
影响因子：
10.8
通讯作者：
Duncan, R
中科院分区：
文献类型：
--
作者：
Malik, N;Wiwattanapatapee, R;Duncan, R
树状大分子是高度分枝的低多分散性大分子，为设计新型药物载体、基因传递系统和显像剂提供了许多令人兴奋的机会。它们在组织靶向应用、控制药物释放方面前景光明，此外，它们有趣的纳米结构可能使胞吞作用更容易通过生物屏障。然而，从目前合成化学中出现的大量结构中，设计具有体内生物学应用潜力的分子是至关重要的。本文采用聚氨基胺（PAMAM）、Starburst（TM）、以二氨基丁烷或二氨基乙烷为核心的聚丙胺（propylene亚胺）和聚环氧乙烷（PEO）接枝的碳硅烷（CSi-PEO）枝状大分子，系统地研究了枝状大分子生成和表面功能对体外生物推进剂的影响。一般来说，携带- nh2末端的树突状大分子表现出浓度依赖性的溶血，在PAMAM树突状大分子的情况下，即使在低浓度（10 μ g/ml）下，1小时后也能观察到红细胞形态的变化。在浓度低于1 mg/ml的CSi-PEO树状大分子和羧酸（COONa）末端组的树状大分子对体外细胞系既没有溶血作用，也没有细胞毒性。总的来说，阳离子树状大分子具有细胞毒性（孵卵72 h），其IC50值为50-300 μ g/ml，取决于树状大分子类型、细胞类型和代。对聚合途径制备的聚醚树状大分子的初步研究表明，具有羧酸盐和丙二酸盐表面的树状大分子在1 h时不具有溶血性，但在23 h后，与阴离子PAMAM树状大分子不同，它们具有溶血性。给Wistar大鼠静脉注射阳离子i -125标记的PAMAM树突状大分子（第3代和第4代）。（类似于10 μ g/ml）迅速从循环中清除(
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 (