Zhang Xiaolan, Huang Yixian, Ghazwani Mohammed, Zhang Peng, Li Jiang, Thorne Stephen H, Li Song
Center for Pharmacogenetics, ‡Department of Pharmaceutical Sciences, School of Pharmacy, and §University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States.
Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, and §University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States.
ACS Macro Lett. 2015 Jun 16;4(6):620-623. doi: 10.1021/acsmacrolett.5b00165. Epub 2015 May 18.
The development of bioresponsive polymers is important in drug delivery systems. Herein, we reported the construction of a series of pH-sensitive micelles by conjugating the hydrophilic polyethylene glycol (PEG) segment to a hydrophobic farnesylthiosalicylate derivative, FTS-hydrazide (FTS-H), with a hydrazone linker, whose cleavability can be conveniently modulated by choosing various lengths of the carbon chain or appropriate electron-withdrawing groups with different steric environment around the hydrazone linker. We examined the hydrolysis rates of these pH-sensitive micelles in both neutral and acidic conditions. One of the pH-sensitive micelles (PHF-2) was found to be highly sensitive to acidic conditions while being fairly stable in neutral conditions. Furthermore, PHF-2 micelles well retained the antitumor activity of free FTS-H. We further evaluated the use of PHF-2 micelles as a carrier for delivering paclitaxel (PTX) and the triggered release of PTX under the acidic environment. PTX-loaded PHF-2 micelles showed enhanced antitumor activity compared with free PTX, likely because of the combinational effect between PHF-2 micelles and loaded PTX.
生物响应性聚合物的发展在药物递送系统中至关重要。在此，我们报道了通过将亲水性聚乙二醇（PEG）链段与疏水性法尼基硫代水杨酸酯衍生物FTS-酰肼（FTS-H）通过腙连接子共轭来构建一系列pH敏感胶束，通过选择不同长度的碳链或在腙连接子周围具有不同空间环境的合适吸电子基团，可以方便地调节其可裂解性。我们研究了这些pH敏感胶束在中性和酸性条件下的水解速率。发现其中一种pH敏感胶束（PHF-2）对酸性条件高度敏感，而在中性条件下相当稳定。此外，PHF-2胶束很好地保留了游离FTS-H的抗肿瘤活性。我们进一步评估了将PHF-2胶束用作递送紫杉醇（PTX）的载体以及在酸性环境下PTX的触发释放。与游离PTX相比，负载PTX的PHF-2胶束显示出增强的抗肿瘤活性，这可能是由于PHF-2胶束与负载的PTX之间的联合效应。
