Cationic poly-L-lysine dendrimers: Pharmacokinetics, biodistribution, and evidence for metabolism and bioresorption after intravenous administration to rats
Cationic poly-L-lysine dendrimers: Pharmacokinetics, biodistribution, and evidence for metabolism and bioresorption after intravenous administration to rats
复制标题
DOI：
10.1021/mp060032e
复制
发表时间：
2006-09-01
影响因子：
4.9
通讯作者：
Porter, Christopher J. H.
中科院分区：
文献类型：
--
作者：
Boyd, Ben J.;Kaminskas, Lisa M.;Porter, Christopher J. H.
已合成具有 16 或 32 个表面胺基团的阳离子聚-L-赖氨酸 H-3-树枝状聚合物（BHALys [Lys](4) [H-3-Lys](8) [NH2](16) 和 BHALys [Lys](8) [H-3-Lys](16) [NH2](32)，分别为第 3 代和第 4 代）并研究了它们的药代动力学并研究大鼠静脉注射后的生物分布。血浆中与放射性标记相关的物质也通过尺寸排阻色谱法（SEC）进行了研究。对于两种树枝状聚合物，放射性标记从血浆中的快速初始去除是明显的（t(1/2) < 5 分钟）。然而，给药后约 1 小时，放射性标记以游离赖氨酸和较大（但非树枝状大分子）物质的形式重新出现在血浆中，并通过 SEC 与白蛋白共洗脱。血浆和全血药代动力学相似，排除了与血液成分的相互作用作为血浆中放射性快速去除或重新出现的致病因素。施用单体 H-3 L-赖氨酸还导致血浆中出现放射性标记的大分子物质，通过 SEC 与白蛋白共洗脱，这表明树枝状聚合物生物降解为 L-赖氨酸和随后的生物再吸收可以解释药代动力学特征。用 D-赖氨酸封端 Lys(8) 树枝状聚合物，形成 BHALys [Lys](4) [H-3-Lys](8) [D-Lys](16) [NH2](32) 与 L-赖氨酸封端树枝状聚合物相比，产生类似且非常快速的血浆初始消失动力学。由于这些大的亲水分子似乎不太可能显着外渗，这很可能反映了消除和与血管表面的广泛结合。用“非天然”D-赖氨酸封端似乎也使树枝状聚合物对生物降解过程基本上呈惰性。对于 L-赖氨酸封端的树枝状聚合物，放射性标记广泛分布在主要器官中，对网状内皮系统的器官没有明显的选择性。相比之下，对于D-赖氨酸封端系统，在网状内皮系统的器官中回收了更大比例的所施用的放射性标记，正如对于不可降解的循环外来胶体所预期的那样。据我们所知，这是证明聚-L-赖氨酸树枝状聚合物的生物降解/生物再吸收的第一个数据，并且对于这些系统作为药物或药物递送系统的效用具有重要意义。
Cationic poly-L-lysine H-3-dendrimers with either 16 or 32 surface amine groups (BHALys [Lys](4) [H-3-Lys](8) [NH2](16) and BHALys [Lys](8) [H-3-Lys](16) [NH2](32), generation 3 and 4, respectively) have been synthesized and their pharmacokinetics and biodistribution investigated after intravenous administration to rats. The species in plasma with which radiolabel was associated was also investigated by size exclusion chromatography (SEC). Rapid initial removal of radiolabel from plasma was evident for both dendrimers (t(1/2) < 5 min). Approximately 1 h postdose, however, radiolabel reappeared in plasma in the form of free lysine and larger (but nondendrimer) species that coeluted with albumin by SEC. Plasma and whole blood pharmacokinetics were similar, precluding interaction with blood components as a causative factor in either the rapid removal or reappearance of radioactivity in plasma. Administration of monomeric H-3 L-lysine also resulted in the appearance in plasma of a radiolabeled macromolecular species that coeluted with albumin by SEC, suggesting that biodegradation of the dendrimer to L-lysine and subsequent bioresorption may explain the pharmacokinetic profiles. Capping the Lys(8) dendrimer with D-lysine to form BHALys [Lys](4) [H-3-Lys](8) [D-Lys](16) [NH2](32) resulted in similar, and very rapid, initial disappearance kinetics from plasma when compared to the L-lysine capped dendrimer. Since significant extravasation of these large hydrophilic molecules seems unlikely, this most likely reflects both elimination and extensive binding to vascular surfaces. Capping with "non-natural" D-lysine also appeared to render the dendrimer essentially inert to the biodegradation process. For the L-lysine capped dendrimers, radiolabel was widely distributed throughout the major organs, with no apparent selectivity for organs of the reticuloendothelial system. In contrast, a greater proportion of the administered radiolabel was recovered in the organs of the reticuloendothelial system for the D-lysine capped system, as might be expected for a nondegrading circulating foreign colloid. To our knowledge this is the first data to demonstrate the biodegradation/bioresorption of poly-L-lysine dendrimers and has significant implications for the utility of these systems as drugs or drug delivery systems.