Center for Chemistry and Biomedicine, Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria; Department of Industrial Pharmacy, Faculty of Pharmacy, University of Medicine and Pharmacy at Ho Chi Minh City, 700000 Ho Chi Minh city, Viet Nam.
Center for Chemistry and Biomedicine, Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria; Department of Pharmacy, COMSATS University Islamabad, Abbottabad Campus, 22060 Abbottabad, Pakistan.
Int J Biol Macromol. 2019 Jul 15;133:647-655. doi: 10.1016/j.ijbiomac.2019.04.081. Epub 2019 Apr 12.
Mucus permeation, mucoadhesion and cell membrane interaction are properties that a drug carrier needs to deliver macromolecule compounds through the mucus barrier and inside epithelial cells effectively. Herein, we prepared micelles from phosphorylated chitosan-stearic acid conjugates (CSSAP) possessing those properties. Their zeta potential can be shifted from negative to neutral once contacting with alkaline phosphatase (ALP). CSSAP micelles showed effective mucus permeation and cell association, thus could be used as a promising platform for mucosal drug delivery. CSSAP was obtained via two modifications: alkylation of CS with stearic acid (termed CSSA) followed by phosphorylation utilizing phosphorus pentoxide. CSSAP had critical micelle concentration value of 76 μg/mL and phosphate content of 1066 μmol/g polymer. Micelle hydrodynamic size was 50-60 nm. Upon contacting with ALP, the polymeric micelles showed a phosphate release of 626 μmol/g polymer (~60%) and a zeta potential shift from -20 to -9 mV within 30 min. They exhibited 6-times higher mucus permeation capacity than positively charged CSSA micelles. CSSAP micelles association to Caco-2 and HEK 293 cells depended on the ALP activity. On Caco-2 cells, cell association rate after 3 h was 2-times higher compared to association rate in the presence of 0.5% phosphatase inhibitors.
黏液渗透、黏膜黏附以及细胞膜相互作用是药物载体有效递送至黏液屏障和上皮细胞内的大分子化合物所必需的性质。在此，我们制备了具有这些性质的磷酸化壳聚糖-硬脂酸缀合物（CSSAP）胶束。一旦与碱性磷酸酶（ALP）接触，它们的 ζ 电位可以从负变为中性。CSSAP 胶束表现出有效的黏液渗透和细胞结合能力，因此可用作黏膜药物递送的有前途的平台。CSSAP 通过两种修饰获得：CS 与硬脂酸（称为 CSSA）的烷基化，然后利用五氧化二磷进行磷酸化。CSSAP 的临界胶束浓度值为 76μg/mL，磷酸盐含量为 1066μmol/g 聚合物。胶束水动力直径为 50-60nm。与 ALP 接触后，聚合物胶束在 30min 内释放出 626μmol/g 聚合物（约 60%）的磷酸盐和从-20 到-9mV 的 ζ 电位变化。它们的黏液渗透能力比带正电荷的 CSSA 胶束高 6 倍。CSSAP 胶束与 Caco-2 和 HEK 293 细胞的结合取决于 ALP 活性。在 Caco-2 细胞上，与存在 0.5%磷酸酶抑制剂时的结合率相比，3h 后的细胞结合率高 2 倍。
