Gulfam Muhammad, Matini Teresa, Monteiro Patrícia F, Riva Raphaël, Collins Hilary, Spriggs Keith, Howdle Steven M, Jérôme Christine, Alexander Cameron
School of Pharmacy, University of Nottingham, NG7 2RD, UK.
Center for Education and Research on Macromolecules (CERM), University of Liège, Sart-Tilman, B6, 4000 Liège, Belgium.
Biomater Sci. 2017 Feb 28;5(3):532-550. doi: 10.1039/c6bm00888g.
Polymer micelles have emerged as promising carriers for controlled release applications, however, several limitations of micelle-based drug delivery have also been reported. To address these issues, we have synthesized a functional biodegradable and cytocompatible block copolymer based on methoxypoly(ethyleneglycol)-b-poly(ε-caprolactone-co-α-azido-ε-caprolactone) (mPEG-b-poly(εCL-co-αNεCL)) as a precursor of reduction sensitive core-crosslinked micelles. The synthesized polymer was formulated as micelles using a dialysis method and loaded with the anti-inflammatory and anti-cancer drug methotrexate (MTX). The micellar cores were subsequently crosslinked at their pendent azides by a redox-responsive bis(alkyne). The size distributions and morphology of the polymer micelles were assessed using dynamic light scattering (DLS) and transmission electron microscopy, and drug release assays were performed under simplified (serum free) physiological and reductive conditions. Cellular uptake studies in human breast cancer cells were performed using Oregon-green loaded core-crosslinked micelles. The MTX-loaded core-crosslinked micelles were assessed for their effects on metabolic activity in human breast cancer (MCF-7) cells by evaluating the reduction of the dye MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. The apoptosis inducing potential of MTX-loaded core-crosslinked micelles was analysed using Hoechst/propidium iodide (PI) and annexin-V/PI assays. The data from these experiments indicated that drug release from these cross-linked micelles can be controlled and that the redox-responsive micelles are more effective carriers for MTX than non-crosslinked analogues and the free drug in the cell-lines tested.
聚合物胶束已成为用于控释应用的有前景的载体，然而，基于胶束的药物递送也存在一些局限性。为了解决这些问题，我们合成了一种功能性可生物降解且具有细胞相容性的嵌段共聚物，其基于甲氧基聚（乙二醇）-b-聚（ε-己内酯-co-α-叠氮基-ε-己内酯）（mPEG-b-聚（εCL-co-αNεCL））作为还原敏感型核交联胶束的前体。使用透析法将合成的聚合物制成胶束，并负载抗炎和抗癌药物甲氨蝶呤（MTX）。随后，胶束核心通过氧化还原响应性双炔在其侧链叠氮处进行交联。使用动态光散射（DLS）和透射电子显微镜评估聚合物胶束的尺寸分布和形态，并在简化（无血清）生理和还原条件下进行药物释放测定。使用负载俄勒冈绿的核交联胶束在人乳腺癌细胞中进行细胞摄取研究。通过评估染料MTT 3-（4,5-二甲基噻唑-2-基）-2,5-二苯基四氮唑溴化物的还原，评估负载MTX的核交联胶束对人乳腺癌（MCF-7）细胞代谢活性的影响。使用Hoechst/碘化丙啶（PI）和膜联蛋白-V/PI测定分析负载MTX的核交联胶束的凋亡诱导潜力。这些实验的数据表明，这些交联胶束的药物释放可以得到控制，并且在测试的细胞系中，氧化还原响应性胶束作为MTX的载体比非交联类似物和游离药物更有效。
