CDL Research, University Medical Center Utrecht, Utrecht, the Netherlands; Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Faculty of Science, Utrecht University, Utrecht, the Netherlands.
Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Faculty of Science, Utrecht University, Utrecht, the Netherlands.
Int J Pharm. 2022 Apr 25;618:121638. doi: 10.1016/j.ijpharm.2022.121638. Epub 2022 Mar 5.
In the present work, we aim at developing an in vitro release assay to predict circulation times of hydrophobic drugs loaded into polymeric micelles (PM), upon intravenous (i.v.) administration. PM based on poly (ethylene glycol)-b-poly (N-2-benzoyloxypropyl methacrylamide) (mPEG-b-p(HPMA-Bz)) block copolymer were loaded with a panel of hydrophobic anti-cancer drugs and characterized for size, loading efficiency and release profile in different release media. Circulation times in mice of two selected drugs loaded in PM were evaluated and compared to the in vitro release profile. Release of drugs from PM was evaluated over 7 days in PBS containing Triton X-100 and in PBS containing albumin at physiological concentration (40 g/L). The results were utilized to identify crucial molecular features of the studied hydrophobic drugs leading to better micellar retention. For the best and the worst retained drugs in the in vitro assays (ABT-737 and BCI, respectively), the circulation of free and entrapped drugs into PM was examined after i.v. administration in mice. We found in vivo drug retention at 24 h post-injection similar to the retention found in the in vitro assays. This demonstrates that in vitro release assay in buffers supplemented with albumin, and to a lesser degree Triton X-100, can be employed to predict the in vivo circulation kinetics of drugs loaded in PM. Utilizing media containing acceptor molecules for hydrophobic compounds, provide a first screen to understand the stability of drug-loaded PM in the circulation and, therefore, can contribute to the reduction of animals used for circulation kinetics studies.
在本工作中，我们旨在开发一种体外释放测定法，以预测疏水性药物在静脉（i.v.）给药后被载入微胶（PM）中的循环时间。基于聚乙二醇-b-聚（N-2-苯甲酰氧基丙基甲基丙烯酰胺）（mPEG-b-p（HPMA-Bz））嵌段共聚物的 PM 载有一组疏水性抗癌药物，并对其在不同释放介质中的大小、载药效率和释放曲线进行了表征。评估了两种选定药物在 PM 中载药的循环时间，并与体外释放曲线进行了比较。在含有 Triton X-100 的 PBS 和含有生理浓度（40 g/L）白蛋白的 PBS 中分别评估了 PM 中药物的释放情况，为期 7 天。利用这些结果来确定研究疏水性药物的关键分子特征，以更好地保留胶束。对于在体外测定中最好和最差保留的药物（ABT-737 和 BCI），在小鼠静脉注射后，检查了游离药物和包埋药物进入 PM 的循环情况。我们发现，在注射后 24 小时的体内药物保留与体外测定中发现的保留相似。这表明，在含有白蛋白的缓冲液中的体外释放测定法，以及在较小程度上含有 Triton X-100 的缓冲液，可以用于预测载药 PM 的体内循环动力学。利用含有疏水化合物受体分子的介质，可以进行初步筛选，以了解药物载 PM 在循环中的稳定性，从而有助于减少用于循环动力学研究的动物数量。
