Department of Nanomedicine and Theranostics, Institute for Experimental Molecular Imaging, Uniklinik RWTH Aachen and Helmholtz Institute for Biomedical Engineering, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany.
Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Faculty of Science, Utrecht University, 3508 TB Utrecht, the Netherlands.
Int J Pharm. 2020 Jun 30;584:119409. doi: 10.1016/j.ijpharm.2020.119409. Epub 2020 May 7.
Polymeric micelles (PM) based on poly(ethylene glycol)-b-poly(N-2-benzoyloxypropyl methacrylamide) (mPEG-b-p(HPMA-Bz)) loaded with paclitaxel (PTX-PM) have shown promising results in overcoming the suboptimal efficacy/toxicity profile of paclitaxel. To get insight into the stability of PTX-PM formulations upon storage and to optimize their in vivo tumor-targeted drug delivery properties, we set out to identify a lead PTX-PM formulation with the optimal polymer composition. To this end, PM based on four different mPEG-b-p(HPMA-Bz) block copolymers with varying molecular weight of the hydrophobic block (17-3 kDa) were loaded with different amounts of PTX. The hydrodynamic diameter was 52 ± 1 nm for PM prepared using polymers with longer hydrophobic blocks (mPEG-b-p(HPMA-Bz) and mPEG-b-p(HPMA-Bz)) and 39 ± 1 nm for PM composed of polymers with shorter hydrophobic blocks (mPEG-b-p(HPMA-Bz) and mPEG-b-p(HPMA-Bz)). The best storage stability and the slowest PTX release was observed for PM with larger hydrophobic blocks. On the other hand, smaller sized PM of shorter mPEG-b-p(HPMA-Bz) showed a better tumor penetration in 3D spheroids. Considering better drug retention capacity of the mPEG-b-p(HPMA-Bz) and smaller size of the mPEG-b-p(HPMA-Bz) as two desirable design features, we argue that PM based on these two polymers are the lead candidates for further in vivo studies.
基于聚乙二醇-b-聚（N-2-苯甲酰氧丙基甲基丙烯酰胺）（mPEG-b-p（HPMA-Bz））的聚合物胶束（PM）负载紫杉醇（PTX-PM）已显示出克服紫杉醇疗效/毒性不理想的有希望的结果。为了深入了解 PTX-PM 制剂在储存过程中的稳定性并优化其体内肿瘤靶向药物输送特性，我们着手确定具有最佳聚合物组成的先导 PTX-PM 制剂。为此，使用四种不同的具有不同疏水性嵌段分子量（17-3 kDa）的 mPEG-b-p（HPMA-Bz）嵌段共聚物制备负载不同剂量 PTX 的 PM。采用具有较长疏水性嵌段的聚合物（mPEG-b-p（HPMA-Bz）和 mPEG-b-p（HPMA-Bz））制备的 PM 的水动力直径为 52±1nm，而采用具有较短疏水性嵌段的聚合物（mPEG-b-p（HPMA-Bz）和 mPEG-b-p（HPMA-Bz））制备的 PM 的水动力直径为 39±1nm。具有较大疏水性嵌段的 PM 表现出最佳的储存稳定性和最慢的 PTX 释放。另一方面，较短 mPEG-b-p（HPMA-Bz）的较小 PM 在 3D 球体中显示出更好的肿瘤穿透性。考虑到 mPEG-b-p（HPMA-Bz）的更好药物保留能力和 mPEG-b-p（HPMA-Bz）的较小尺寸是两个理想的设计特征，我们认为基于这两种聚合物的 PM 是进一步体内研究的候选者。
