Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada.
J Control Release. 2012 Feb 10;157(3):366-74. doi: 10.1016/j.jconrel.2011.09.088. Epub 2011 Oct 1.
The physico-chemical characteristics and composition of block copolymer micelles (BCMs) may influence the pharmacokinetics and consequently, the desired delivery characteristics. In this study the influence of formulation variables such as size, density of targeting ligand [i.e. epidermal growth factor (hEGF)] and the bifunctional chelator (BFC) used for labelling the BCMs with (111)In, on the pharmacokinetics and biodistribution in mice were evaluated. BCMs were prepared from Me-PEG(x)-b-PCL(y) (x=2.5 k, y=1.2 k for 15 nm BCMs and x=5 k, y=5 k for 60 nm BCMs) with (targeted, 1 or 5 mol% hEGF) or without (non-targeted) hEGF-PEG(x)-b-PCL(y). To investigate the effect of the BFC on the pharmacokinetics, the BCMs were labelled with (111)In using p-SCN-Bn-DOTA (Bn-DOTA-PEG(x)-b-PCL(y)), H(2)N-DOTA (DOTA-PEG(x)-b-PCL(y)), DTPA anhydride (DTPA-PEG(x)-b-PCL(y)) or p-SCN-Bn-DTPA (Bn-DTPA-PEG(x)-b-PCL(y)). The resulting 15 nm or 60 nm non-targeted or targeted (1 or 5 mol% hEGF) were injected via a tail vein to mice bearing MDA-MB-468 human breast cancer xenograft that overexpress EGFR, followed by pharmacokinetics and biodistribution studies. Pharmacokinetic parameters were determined by fitting the blood concentration vs time data using a two compartment model with i.v. bolus input. Pharmacokinetic parameters were found to depend on BCM size, the BFC used as well as the density of hEGF on the surface of the BCMs. BCMs labelled with p-SCN-Bn-DTPA ((111)In-Bn-BCMs) showed improved pharmacokinetics (i.e. extended circulation lifetime) and tumor uptake compared to those labelled with DOTA-PEG(x)-b-PCL(y), p-SCN-Bn-DOTA or DTPA dianhydride. Formulations with a high density of hEGF (5 mol% hEGF) had short circulation half-lives. BCMs labelled with (111)In via p-SCN-Bn-DTPA showed highest accumulation in the liver and spleen and slower whole body elimination. Smaller sized BCMs were rapidly cleared from the circulation. Increasing the density of hEGF on the surface did not improve tumor uptake due to faster clearance from the circulation. To achieve improved pharmacokinetics and in turn effective exploitation of the EPR effect, p-SCN-Bn-DTPA emerged as the optimal BFC for radiolabelling BCMs while a lower density of hEGF gave more favourable organ distribution.
两亲性嵌段共聚物胶束（BCMs）的物理化学特性和组成可能会影响其药代动力学，进而影响预期的递药特性。本研究评估了制剂变量（如大小、靶向配体[即表皮生长因子（hEGF）]的密度和用于用（111）In 标记 BCM 的双功能螯合剂（BFC））对小鼠体内药代动力学和生物分布的影响。BCMs 由 Me-PEG(x)-b-PCL(y)（15nm BCM 的 x=2.5k，y=1.2k 和 60nm BCM 的 x=5k，y=5k）制备而成，具有（靶向，1 或 5mol% hEGF）或无（非靶向）hEGF-PEG(x)-b-PCL(y)。为了研究 BFC 对药代动力学的影响，使用 p-SCN-Bn-DOTA（Bn-DOTA-PEG(x)-b-PCL(y)）、H 2 N-DOTA（DOTA-PEG(x)-b-PCL(y)）、DTPA 酐（DTPA-PEG(x)-b-PCL(y)）或 p-SCN-Bn-DTPA（Bn-DTPA-PEG(x)-b-PCL(y)）将 BCMs 标记为（111）In。将所得的 15nm 或 60nm 非靶向或靶向（1 或 5mol% hEGF）通过尾静脉注射到表达 EGFR 的 MDA-MB-468 人乳腺癌异种移植瘤小鼠体内，随后进行药代动力学和生物分布研究。通过使用静脉内推注的两室模型拟合血液浓度随时间变化的数据来确定药代动力学参数。发现药代动力学参数取决于 BCM 大小、用作 BFC 的物质以及 BCM 表面上 hEGF 的密度。与使用 DOTA-PEG(x)-b-PCL(y)、p-SCN-Bn-DOTA 或 DTPA 二酰亚胺标记的 BCM 相比，用 p-SCN-Bn-DTPA 标记的 BCMs（（111）In-Bn-BCMs）表现出改善的药代动力学（即延长循环寿命）和肿瘤摄取。具有高 hEGF 密度（5mol% hEGF）的制剂具有较短的循环半衰期。用 p-SCN-Bn-DTPA 标记的 BCMs 在肝脏和脾脏中积累最高，全身清除速度较慢。较小的 BCMs 从循环中迅速清除。增加表面上 hEGF 的密度不会因从循环中更快清除而提高肿瘤摄取率。为了改善药代动力学并进而有效利用 EPR 效应，p-SCN-Bn-DTPA 成为用于标记 BCM 的最佳 BFC，而 hEGF 的较低密度则提供了更有利的器官分布。
