Abstract
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.
Highlights
Methotrexate (MTX) is classified as an anti-folate and anti-metabolite drug
We have evaluated the cytotoxicity of niosomal MTX on tumor and normal cells in comparison to free MTX
We calculated the area per lipid (APL) using the XY surface area of the simulation box divided by the number of Span 60, Tween 60, and ergosterol in one leaflet
Summary
Methotrexate (MTX) is classified as an anti-folate and anti-metabolite drug. It is a well-known chemotherapeutic and immunosuppressive agent [1]. MTX inhibits the synthesis of purines and pyrimidines involved in producing DNA and RNA of rapidly dividing cells, impeding cancer cell growth and progression [1,2]. Another study reported that combination treatment with MTX and α-tocopherol suppressed TNBC cell proliferation. Caspase-3 activation and poly(adenosine diphosphateribose) polymerase cleavage were observed in the α-tocopherol succinate/MTX-treated cells [5]. Another study performed on 64 patients showed that continuous low-dose CTX and MTX are minimally toxic and effective in heavily pretreated breast cancer patients [6]
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