Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy.
Eur J Pharm Biopharm. 2013 Apr;83(3):346-57. doi: 10.1016/j.ejpb.2012.11.002. Epub 2012 Nov 29.
A new acid-sensitive drug-delivery nanocarrier has been developed for tumour targeting. The self-assembling co-polymer stearoyl-PEG-poly-sulfadimethoxine methacrylate (stearoyl-PEG-polySDM) was prepared to obtain micelles with responsive behaviour in the physiopathologic pH range. Stearoyl-PEG-polySDM was synthesised using a multi-step procedure that includes pH-sensitive sulfadimethoxine methacrylate polymerisation by AGET-ATRP at the amino terminal side of stearoyl-PEG-NH2. Chemical analysis showed that the stearoyl-PEG-polySDM co-polymer contained a mean of seven methacryloyl sulfadimethoxines per molecule. Potentiometric and turbidimetric analyses showed that stearoyl-PEG-polySDM has an apparent pKa of 7.2 and a cloud point at pH 7.0. In water at pH 7.4, the co-polymer assembled spontaneously into 13.2±3.1 nm micelles with a critical micelle concentration (CMC) of 36 μM. Cell-culture studies showed that the material was more biocompatible with respect to the control Brij-700®. The paclitaxel loading capacity of the micelles was 3.25±0.25% (w/w, %). The colloidal formulations were stable at pH 7.4 for several hours, while at pH 6.5, they rapidly rearranged and aggregated. Fluorescence spectroscopic and cytofluorimetric studies showed that the incubation of MCF-7 tumour cells with fluorescein-labelled stearoyl-PEG-polySDM at pH 6.5 resulted in massive time-dependent cell association, while the incubation at pH 7.4 showed significantly lower cell interaction. Confocal microscopy confirmed that at pH 6.5, the micelles are taken up by cells and that the fluorescein-labelled stearoyl-PEG-polySDM is distributed into the cytosol. At pH 6.5, paclitaxel-loaded stearoyl-PEG-polySDM micelles had a higher cytotoxic effect than the micelles incubated at pH 7.4. The former displayed similar cytotoxic activity to free paclitaxel.
一种新的酸敏药物递送纳米载体已被开发用于肿瘤靶向。自组装共聚物硬脂酰-PEG-聚磺胺二甲氧嘧啶甲基丙烯酸酯（硬脂酰-PEG-聚 SDM）被制备以获得在生理病理 pH 范围内具有响应行为的胶束。硬脂酰-PEG-聚 SDM 是通过 AGET-ATRP 在硬脂酰-PEG-NH2 的氨基末端侧聚合 pH 敏感的磺胺二甲氧嘧啶甲基丙烯酸酯合成的，该反应经过多步反应完成。化学分析表明，硬脂酰-PEG-聚 SDM 共聚物每个分子中含有平均 7 个甲丙烯酰磺胺二甲氧嘧啶。电位和浊度分析表明，硬脂酰-PEG-聚 SDM 的表观 pKa 为 7.2，在 pH 7.0 时有一个浊点。在 pH 7.4 的水中，共聚物自发组装成 13.2±3.1nm 的胶束，临界胶束浓度（CMC）为 36μM。细胞培养研究表明，与对照 Brij-700®相比，该材料具有更好的生物相容性。胶束的紫杉醇负载能力为 3.25±0.25%（w/w，%）。胶态制剂在 pH 7.4 下稳定数小时，而在 pH 6.5 下，它们迅速重排和聚集。荧光光谱和细胞荧光计研究表明，在 pH 6.5 下，MCF-7 肿瘤细胞与荧光素标记的硬脂酰-PEG-聚 SDM 孵育导致大量的时间依赖性细胞结合，而在 pH 7.4 下孵育则显示出明显较低的细胞相互作用。共聚焦显微镜证实，在 pH 6.5 下，胶束被细胞摄取，荧光素标记的硬脂酰-PEG-聚 SDM 分布在细胞质中。在 pH 6.5 下，载紫杉醇的硬脂酰-PEG-聚 SDM 胶束比在 pH 7.4 下孵育的胶束具有更高的细胞毒性作用。前者显示出与游离紫杉醇相似的细胞毒性活性。
