Bioreducible cross-linked core polymer micelles enhance in vitro activity of methotrexate in breast cancer cells
Bioreducible cross-linked core polymer micelles enhance in vitro activity of methotrexate in breast cancer cells
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DOI：
10.1039/c6bm00888g
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发表时间：
2017-03-01
影响因子：
6.6
通讯作者：
Alexander, Cameron
中科院分区：
文献类型：
--
作者：
Gulfam, Muhammad;Matini, Teresa;Alexander, Cameron
聚合物胶束已成为控制释放应用的有前途的载体，然而，也报道了基于胶束的药物递送的一些限制。为了解决这些问题，我们合成了一种功能性的可生物降解的和细胞相容的嵌段共聚物，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（ε-CL-co-α N-3 ε-CL））作为还原敏感性核交联胶束的前体。使用透析方法将合成的聚合物配制为胶束，并装载有抗炎和抗癌药物甲氨蝶呤（MTX）。胶束核心随后交联在其悬挂叠氮化物的氧化还原响应双（炔）。使用动态光散射（DLS）和透射电子显微镜的聚合物胶束的尺寸分布和形态进行了评估，并在简化（无血清）的生理和还原条件下进行药物释放测定。在人乳腺癌细胞中的细胞摄取研究使用俄勒冈绿负载的核交联胶束进行。通过评估染料MTT 3-（4，5-二甲基噻唑-2-基）-2，5-二苯基四唑溴化盐的还原，评估了载MTX的核交联胶束对人乳腺癌（MCF-7）细胞中代谢活性的影响。使用Hoechst/碘化丙啶（PI）和膜联蛋白-V/PI测定法分析MTX负载的核交联胶束的凋亡诱导潜力。来自这些实验的数据表明，可以控制从这些交联胶束的药物释放，并且氧化还原响应性胶束是比非交联类似物和测试的细胞系中的游离药物更有效的MTX载体。
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(epsilon-caprolactone-co-alpha-azido-epsilon-caprolactone) (mPEG-b-poly(epsilon CL-co-alpha N-3 epsilon CL)) 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)-2,5diphenyltetrazolium 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.