Chemical Engineering and Pharmaceutics School, Henan University of Science and Technology, Luoyang, China.
Chemical Engineering and Pharmaceutics School, Henan University of Science and Technology, Luoyang, China.
Int J Pharm. 2017 Feb 25;518(1-2):213-219. doi: 10.1016/j.ijpharm.2016.11.044. Epub 2016 Nov 24.
As a new kind of drug carries, pH-sensitive liposomes have been widely studied in tumor therapy for their advantages of target ability and sustained-release. Here, we synthesized a pH-sensitive material, N-(3-Aminopropyl)imidazole-cholesterol (IM-Chol) and prepared a novel pH-sensitive liposomes using IM-Chol and phosphatidylcholine. IM-Chol was synthesized through amidation reaction between the amino group of N-(3-Aminopropyl)imidazole and acyl chloride group of cholesteryl chloroformate in a weak base solution. Optimal conditions to prepare liposomes were obtained by the orthogonal experiment with the higher encapsulation efficiency as the evaluation indicator. The properties of liposomes, such as particle size, zeta potential, morphology, encapsulation efficiency, drug release behavior and in vitro cell toxicity were evaluated by transmission electron microscopy (TEM), dynamic light scattering (DLS) and MTT assay respectively. The results showed that the average particle size of IM-Chol liposomes was 141nm (PDI 0.323). Liposomes can assemble into uniform spheres at pH 7.4, but under the condition of pH 5.0, the spherical structure of IM-Chol liposomes was broken, exhibiting pH-sensitive property. In vitro drug releasing studies demonstrated the controlled-release behavior of the curcumin (CUR) in the IM-Chol liposomes. The cumulative release of CUR reached to 72.5% in the first 24h at pH 5.0, faster than that at pH 7.4, which confirmed that the drug carrier displayed pH-sensitive release behaviors. In addition, the MTT assay was employed to test the cytotoxicity of IM-Chol liposomes and CUR IM-Chol liposomes. All cell viabilities were greater than 80% after incubating for 24h, even up to the highest dose of 500mg/L, indicating that IM-Chol liposomes had good biocompatibility. The tumor inhibitory results towards EC109 cells of free CUR and CUR-loaded IM-Chol liposomes indicated that IM-Chol liposomes indeed enhanced the cell killing effect of CUR. These results showed that the novel IM-Chol liposomes prepared in this paper had pH-sensitive property and were expected to play a huge potential in tumor treatment.
作为一种新型药物载体，pH 敏感脂质体因其靶向能力和缓释作用而在肿瘤治疗中得到了广泛的研究。在这里，我们合成了一种 pH 敏感材料 N-(3-氨丙基)咪唑-胆固醇（IM-Chol），并使用 IM-Chol 和磷脂酰胆碱制备了一种新型 pH 敏感脂质体。IM-Chol 是通过 N-(3-氨丙基)咪唑的氨基与胆固醇氯甲酸酯的酰氯基团在弱碱溶液中的酰胺反应合成的。以包封率为评价指标，通过正交实验得到了制备脂质体的最佳条件。通过透射电子显微镜（TEM）、动态光散射（DLS）和 MTT 测定分别评估脂质体的性质，如粒径、Zeta 电位、形态、包封率、药物释放行为和体外细胞毒性。结果表明，IM-Chol 脂质体的平均粒径为 141nm（PDI 0.323）。脂质体在 pH 7.4 下可以组装成均匀的球体，但在 pH 5.0 条件下，IM-Chol 脂质体的球形结构被破坏，表现出 pH 敏感性。体外药物释放研究表明，姜黄素（CUR）在 IM-Chol 脂质体中的释放具有控制释放行为。在 pH 5.0 下，CUR 的累积释放在 24h 内达到 72.5%，快于 pH 7.4 下的释放，这证实了药物载体表现出 pH 敏感的释放行为。此外，还采用 MTT 法测定了 IM-Chol 脂质体和 CUR-IM-Chol 脂质体的细胞毒性。孵育 24h 后，所有细胞活力均大于 80%，即使达到最高剂量 500mg/L，表明 IM-Chol 脂质体具有良好的生物相容性。游离 CUR 和载 CUR 的 IM-Chol 脂质体对 EC109 细胞的肿瘤抑制结果表明，IM-Chol 脂质体确实增强了 CUR 的细胞杀伤作用。这些结果表明，本文制备的新型 IM-Chol 脂质体具有 pH 敏感性，有望在肿瘤治疗中发挥巨大潜力。
