Barani Mahmood, Reza Hajinezhad Mohammad, Sargazi Saman, Zeeshan Mahira, Rahdar Abbas, Pandey Sadanand, Khatami Mehrdad, Zargari Farshid
Medical Mycology and Bacteriology Research Center, Kerman University of Medical Sciences, Kerman 7616913555, Iran.
Basic Veterinary Science Department, Veterinary Faculty, University of Zabol, Zabol 9861335856, Iran.
Polymers (Basel). 2021 Sep 17;13(18):3153. doi: 10.3390/polym13183153.
In this study, pH-responsive niosomal methotrexate (MTX) modified with ergosterol was prepared for potential anticancer application. The prepared formulation had a size of 176.7 ± 3.4 nm, zeta potential of -31.5 ± 2.6 mV, EE% of 76.9 ± 2.5%, and a pH-responsive behavior in two different pHs (5.4 and 7.4). In-silico evaluations showed that MTX intended to make a strong hydrogen bond with Span 60 compartments involving N2 and O4 atoms in glutamic acid and N7 atom in pteridine ring moieties, respectively. The cytotoxic effects of free and pH-MTX/Nio were assessed against MCF7 and HUVECs. Compared with free MTX, we found significantly lower IC50s when MCF7 cells were treated with niosomal MTX (84.03 vs. 9.464 µg/mL after 48 h, respectively). Moreover, lower cell killing activity was observed for this formulation in normal cells. The pH-MTX/Nio exhibited a set of morphological changes in MCF7 cells observed during cell death. In-vivo results demonstrated that intraperitoneal administration of free MTX (2 mg/kg) after six weeks caused a significant increase in serum blood urea nitrogen (BUN), serum creatinine, and serum malondialdehyde (MDA) levels of rats compared to the normal control rats. Treatment with 2 and 4 mg/kg doses of pH-MTX/Nio significantly increased serum BUN, serum creatinine, and serum lipid peroxidation. Still, the safety profile of such formulations in healthy cells/tissues should be further investigated.
在本研究中，制备了用麦角固醇修饰的pH响应性脂质体甲氨蝶呤（MTX）用于潜在的抗癌应用。所制备的制剂粒径为176.7±3.4nm，ζ电位为-31.5±2.6mV，包封率为76.9±2.5%，并且在两种不同pH值（5.4和7.4）下具有pH响应行为。计算机模拟评估表明，MTX分别与司盘60隔室形成强氢键，涉及谷氨酸中的N2和O4原子以及蝶啶环部分中的N7原子。评估了游离MTX和pH-MTX/Nio对MCF7和人脐静脉内皮细胞（HUVECs）的细胞毒性作用。与游离MTX相比，我们发现用脂质体MTX处理MCF7细胞时IC50显著降低（48小时后分别为84.03对9.464μg/mL）。此外，在正常细胞中观察到该制剂的细胞杀伤活性较低。pH-MTX/Nio在MCF7细胞死亡过程中表现出一系列形态变化。体内结果表明，与正常对照大鼠相比，六周后腹腔注射游离MTX（2mg/kg）导致大鼠血清血尿素氮（BUN）、血清肌酐和血清丙二醛（MDA）水平显著升高。用2和4mg/kg剂量的pH-MTX/Nio处理显著增加了血清BUN、血清肌酐和血清脂质过氧化。然而，此类制剂在健康细胞/组织中的安全性仍需进一步研究。
