Laboratory of Pharmaceutical Technology, Department of Pharmacy, University of Patras, 26504 Patras, Greece.
Department of Chemical Engineering, University of Patras, 26504 Patras, Greece.
Eur J Pharm Sci. 2018 May 30;117:177-186. doi: 10.1016/j.ejps.2018.02.021. Epub 2018 Mar 21.
Paclitaxel (PTX)-loaded gold nanoparticles functionalized with mercaptooctanoic acid (MOA) and folic acid (FA) (AuMOA-FA) were encapsulated within pH-sensitive poly(2-vinylpyridine)-b-poly(ethylene oxide) (P2VP-PEO) vesicles with the aim to develop a more selective injectable nano-formulation for PTX, lacking the side effects of the conventional PTX delivery system. The size of the resulting composite vesicles was lower than 200 nm, i.e. it is suitable for tumor targeting applications taking advantage of the enhanced permeability and retention (EPR) effect. The vesicles did not aggregate in the presence of high electrolyte concentrations, indicating the colloidal stability of the vesicles. The vesicles did not leak their AuMOA-FA or PTX content at physiological pH of 7.4. However, AuMOA-FA and PTX release were significantly accelerated at acidic pHs resembling tumor environment and acidic intracellular compartments. PTX release from the vesicles at acidic pH apparently follows AuMOA-FA release from the vesicles. Flow cytometry measurements and confocal laser scanning microscopy images showed that the vesicles could enter A549 cancer cells in culture and that cellular uptake increased with time. Blank vesicles did not exhibit cytotoxicity and did not induce apoptosis in A549 cancer cells. The PTX currying vesicles exhibited comparable or a little higher cytotoxicity than free PTX. Both the PTX currying vesicles and free PTX induced A549 cells apoptosis, however the vesicle-encapsulated PTX induced a higher percentage of late apoptotic cells than free PTX.
载紫杉醇（PTX）的金纳米颗粒经巯基辛酸（MOA）和叶酸（FA）功能化（AuMOA-FA）后被包裹在 pH 敏感的聚（2-乙烯基吡啶）-b-聚（环氧乙烷）（P2VP-PEO）囊泡内，目的是开发一种更具选择性的可注射纳米制剂用于 PTX，避免常规 PTX 给药系统的副作用。所得复合囊泡的粒径小于 200nm，即适合利用增强型通透性和保留（EPR）效应进行肿瘤靶向应用。在存在高电解质浓度的情况下，囊泡不会聚集，表明囊泡具有胶体稳定性。在生理 pH 值 7.4 下，囊泡不会泄漏其 AuMOA-FA 或 PTX 内容物。然而，在类似于肿瘤环境和酸性细胞内隔室的酸性 pH 下，AuMOA-FA 和 PTX 的释放明显加速。囊泡在酸性 pH 下释放 PTX 显然遵循囊泡中 AuMOA-FA 的释放。流式细胞术测量和共聚焦激光扫描显微镜图像显示，囊泡可以进入培养中的 A549 癌细胞，并且细胞摄取随时间增加。空白囊泡没有表现出细胞毒性，也没有诱导 A549 癌细胞凋亡。载紫杉醇的囊泡表现出与游离 PTX 相当或稍高的细胞毒性。游离 PTX 和载紫杉醇的囊泡均诱导 A549 细胞凋亡，然而囊泡包封的 PTX 诱导的晚期凋亡细胞百分比高于游离 PTX。
