Centre for Advanced Macromolecular Design (CAMD), St. George Hospital, University of New South Wales , Sydney, NSW 2052, Australia.
Biomacromolecules. 2012 Mar 12;13(3):814-25. doi: 10.1021/bm201730p. Epub 2012 Feb 27.
Poly(polyethylene glycol methyl ether methacrylate-co-methacrylic acid)-block-poly(methyl methacrylate) P(PEGMEMA-co-MAA)-b-PMMA block copolymer were prepared via RAFT (reversible addition-fragmentation chain transfer) polymerization and subsequently self-assembled into micelles as a drug delivery carrier for albendazole (ABZ). For comparison, the micelles were additionally cross-linked to study the effect of shell-cross-linking on the biological activity. The hydrodynamic diameter of cross-linked and un-cross-linked micelles was approximately 40 nm in both cases. While the cross-linked micelle was stable even in good solvents for both blocks, the un-cross-linked micelle was found to lose its integrity in cell growth media. Crosslinking had a major effect on the rate of drug release reducing it dramatically from 50% (uncrosslinked) to around 20% (crosslinked) over a 30 h incubation period. Both drug delivery systems were tested on human prostate cancer cells (PC-3, DU-145) and human ovarian cancer cells (OVCAR-3, A-2780). No toxic effects were measured with the unloaded micelle while the ABZ loaded un-cross-linked micelle lead to IC(50) values between 0.2 and 0.9 μM depending on the cell line. The IC(50) dropped to values between 0.006 and 0.06 μM, depending on cell line, once the micelles were stabilized by cross-linking. Three treatment cycles with ABZ for one day, followed by two days incubation in media using ABZ-loaded drug carriers led to complete cell death even at low concentrations in the case of the cross-linked micelle only. Cellular uptake has been studied using fluorescently labeled micelles and Nile red as model drug, showing cell uptake above the CMC but no micelle uptake below the CMC. Additional biological studies, such as colony formation assay and tubulin disorganization tests, were also performed to gain more insight into the effect of cross-linking of the shell of the micelle. In conclusion, shell-cross-linking is highly recommended, even for glassy micelles, for an efficient cellular uptake at low concentrations.
聚（聚乙二醇甲基醚甲基丙烯酸酯-共-甲基丙烯酸）-嵌段-聚（甲基丙烯酸甲酯）P（PEGMEMA-co-MAA）-b-PMMA 嵌段共聚物通过 RAFT（可逆加成-断裂链转移）聚合制备，随后自组装成胶束作为阿苯达唑（ABZ）的药物递送载体。为了进行比较，还将胶束交联以研究壳交联对生物活性的影响。两种情况下，交联和未交联胶束的水动力直径均约为 40nm。虽然交联胶束即使在两种嵌段的良溶剂中也很稳定，但未交联的胶束在细胞生长培养基中发现其完整性丧失。交联对药物释放速率有重大影响，使药物释放从 30h 孵育期内的 50%（未交联）降低至约 20%（交联）。两种药物递送系统均在人前列腺癌细胞（PC-3、DU-145）和人卵巢癌细胞（OVCAR-3、A-2780）上进行了测试。未负载胶束没有测量到毒性作用，而载有 ABZ 的未交联胶束导致 IC50 值在 0.2 和 0.9μM 之间，具体取决于细胞系。一旦通过交联稳定胶束，IC50 值降低至 0.006 和 0.06μM 之间，具体取决于细胞系。只有交联胶束进行了为期三天的 ABZ 治疗，然后在含有载有 ABZ 的药物载体的培养基中孵育两天，导致即使在低浓度下也完全细胞死亡。使用荧光标记的胶束和尼罗红作为模型药物研究细胞摄取，结果表明在 CMC 以上存在细胞摄取，但在 CMC 以下不存在胶束摄取。还进行了其他生物学研究，如集落形成测定和微管蛋白解聚试验，以更深入地了解胶束壳交联的影响。总之，即使对于玻璃态胶束，壳交联也强烈推荐用于在低浓度下实现有效的细胞摄取。
