Essam Eldin Noha, Elnahas Hanan Mohamed, Mahdy Mahmoud Abd-Elghany, Ishida Tatsuhiro
Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Zagazig University 44 519, Egypt; Department of Pharmacokinetics and Biopharmaceutics, Institute of Health Biosciences, University of Tokushima.
Biol Pharm Bull. 2015;38(3):461-9. doi: 10.1248/bpb.b14-00769.
Pemetrexed (PMX) is a newly developed multi-targeted anti-folate with promising clinical activity in many solid tumors including malignant pleural mesothelioma (MPM). However, PMX does not show sufficient anti-tumor activity in vivo when used alone either due to inefficient delivery of adequate concentrations to tumor tissue or dose-limiting side effects. In order to overcome these problems and to achieve potent anti-tumor activity, PMX was encapsulated into a liposomal delivery system. In the present study, various formulations of liposomal PMX were prepared. The effect of formulation parameters on the encapsulation efficiency of PMX within liposomes was evaluated. In addition, the influence of drug release rate on the in vitro cytotoxicity was investigated. Encapsulation of PMX within liposomes was remarkably increased by the incorporation of cholesterol within liposomal membranes and by increasing the total lipid concentration. Encapsulation efficiency was found to be unaffected by the type of phospholipid used or the inclusion of a cation lipid, DC-6-14. Interestingly, encapsulation of PMX within "fluid" liposomes was found to allow efficient release of PMX from liposomes resulting in a potent in vitro cytotoxicity against MPM MSTO-211H cell line. On the other hand, entrapment of PMX within "solid" liposomes substantially hindered PMX release from liposomes, and thus PMX failed to exert any in vitro cytotoxicity. These results suggest that encapsulation of PMX within "fluid" liposomes might represent a novel strategy to enhance the therapeutic efficacy of PMX while minimizing the side effect encountered by the non selective delivery of free PMX to various body tissues.
培美曲塞（PMX）是一种新开发的多靶点抗叶酸药物，在包括恶性胸膜间皮瘤（MPM）在内的多种实体瘤中具有良好的临床活性。然而，单独使用时，PMX在体内并未表现出足够的抗肿瘤活性，这要么是由于向肿瘤组织输送足够浓度的药物效率低下，要么是由于剂量限制性副作用。为了克服这些问题并实现强效抗肿瘤活性，PMX被封装到脂质体递送系统中。在本研究中，制备了脂质体PMX的各种制剂。评估了制剂参数对PMX在脂质体内包封效率的影响。此外，还研究了药物释放速率对体外细胞毒性的影响。通过在脂质体膜中加入胆固醇和增加总脂质浓度，PMX在脂质体内的包封率显著提高。发现包封效率不受所用磷脂类型或阳离子脂质DC-6-14的加入的影响。有趣的是，发现PMX在“流体”脂质体内的包封允许PMX从脂质体中有效释放，从而对MPM MSTO-211H细胞系产生强效体外细胞毒性。另一方面，PMX在“固体”脂质体内的包封大大阻碍了PMX从脂质体中的释放，因此PMX未能发挥任何体外细胞毒性。这些结果表明，将PMX封装在“流体”脂质体内可能是一种提高PMX治疗效果的新策略，同时将游离PMX非选择性递送至身体各个组织所遇到的副作用降至最低。
