School of Pharmacy, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand.
Int J Pharm. 2013 Jun 25;450(1-2):278-89. doi: 10.1016/j.ijpharm.2013.04.057. Epub 2013 Apr 28.
PIK-75 is a phosphatidylinositol 3-kinase (PI3K) inhibitor that shows selectivity toward p110-α over the other PI3K class Ia isoforms p110-β and p110-δ, but it lacks solubility, stability and other kinase selectivity. The purpose of this study was to develop folate-targeted PIK-75 nanosuspension for tumor targeted delivery and to improve therapeutic efficacy in human ovarian cancer model. High pressure homogenization was used to prepare the non-targeted and targeted PIK-75 nanosuspensions which were characterized for size, zeta potential, entrapment efficiency, morphology, saturation solubility and dissolution velocity. In vitro analysis of drug uptake, cell viability and cell survival was conducted in SKOV-3 cells. Drug pharmacokinetics and pAkt expression were determined in SKOV-3 tumor bearing mice. PIK-75 nanosuspensions showed an improvement in dissolution velocity and an 11-fold increase in saturation solubility over pre-milled PIK-75. In vitro studies in SKOV-3 cells indicated a 2-fold improvement in drug uptake and 0.4-fold decrease in IC50 value of PIK-75 following treatment with targeted nanosuspension compared to non-targeted nanosuspension. The improvement in cytotoxicity was attributed to an increase in caspase 3/7 and hROS activity. In vivo studies indicated a 5-10-fold increased PIK-75 accumulation in the tumor with both the nanosuspension formulations compared to PIK-75 suspension. The targeted nanosuspension showed an enhanced downregulation of pAkt compared to non-targeted formulation system. These results illustrate the opportunity to formulate PIK-75 as a targeted nanosuspension to enhance uptake and cytotoxicity of the drug in tumor.
PIK-75 是一种磷酸肌醇 3-激酶 (PI3K) 抑制剂，对 p110-α 具有选择性，优于其他 PI3K Ia 同工型 p110-β 和 p110-δ，但它缺乏溶解度、稳定性和其他激酶选择性。本研究旨在开发叶酸靶向 PIK-75 纳米混悬剂用于肿瘤靶向递药，并提高人卵巢癌模型的治疗效果。高压均质法用于制备非靶向和靶向 PIK-75 纳米混悬剂，对其粒径、Zeta 电位、包封效率、形态、饱和溶解度和溶出速度进行了表征。在 SKOV-3 细胞中进行了药物摄取、细胞活力和细胞存活的体外分析。在 SKOV-3 荷瘤小鼠中进行了药物药代动力学和 pAkt 表达的测定。PIK-75 纳米混悬剂的溶出速度提高了 11 倍，饱和溶解度提高了 11 倍，优于预研磨的 PIK-75。在 SKOV-3 细胞的体外研究中，与非靶向纳米混悬剂相比，靶向纳米混悬剂处理后药物摄取增加了 2 倍，IC50 值降低了 0.4 倍。细胞毒性的提高归因于 caspase 3/7 和 hROS 活性的增加。体内研究表明，与 PIK-75 混悬剂相比，两种纳米混悬剂配方在肿瘤中的 PIK-75 积累增加了 5-10 倍。靶向纳米混悬剂显示出比非靶向制剂系统更强的 pAkt 下调。这些结果表明，有机会将 PIK-75 制成靶向纳米混悬剂，以增强药物在肿瘤中的摄取和细胞毒性。
