Abstract
The study aimed to develop a new glutathione (GSH) oral formulation to enhance the delivery of GSH and counter the nephrotoxicity of the anticancer drug, cyclophosphamide (CP). A nanostructured lipid carrier glutathione formulation (GSH-NLCs) composed of glutathione (500 mg), stearic and oleic acid (300 mg, each), and Tween® 80 (2%, w/v) was prepared through the emulsification-solvent-evaporation technique, which exhibited a 452.4 ± 33.19 nm spheroidal-sized particulate material with narrow particle size distributions, −38.5 ± 1.4 mV zeta potential, and an entrapment efficiency of 79.8 ± 1.9%. The GSH formulation was orally delivered, and biologically tested to ameliorate the CP-induced renal toxicity in a rat model. Detailed renal morphology, before and after the GSH-NLCs administration, including the histopathological examinations, confirmed the ameliorating effects of the prepared glutathione formulation together with its safe oral delivery. CP-induced oxidative stress, superoxide dismutase depletion, elevation of malondialdehyde levels, depletion of Bcl-2 concentration levels, and upregulated NF-KB levels were observed and were controlled within the recommended and near normal/control levels. Additionally, the inflammatory mediator marker, IL-1β, serum levels were marginally normalized by delivery of the GHS-NLCs formulation. Oral administration of the pure glutathione did not exhibit any ameliorating effects on the renal tissues, which suggested that the pure glutathione is reactive and is chemically transformed during the oral delivery, which affected its pharmacological action at the renal site. The protective effects of the GSH-NLCs formulation through its antioxidant and anti-inflammatory effects suggested its prominent role in containing CP-induced renal toxicity and renal tissue damage, together with the possibility of administrating higher doses of the anticancer drug, cyclophosphamide, to achieve higher and effective anticancer action in combination with the GSH-NLCs formulation.
Highlights
The spontaneous uncontrolled proliferation of cells, named cancers, represents complicated disorders, and one of the most common diseases that affects a large population in the world
Nanostructured lipid carriers with GSH concentrations of 50 mg/mL were successfully prepared using emulsification-solvent evaporation technique followed by ultrasonication
It was noticed that the higher solid lipid to liquid lipid ratios (F7 contains 300 mg of oleic acid and 300 mg of stearic acid) formed highly stable nanostructures with improved encapsulation efficiency (EE value of 79.8 ± 1.9%)
Summary
The spontaneous uncontrolled proliferation of cells, named cancers, represents complicated disorders, and one of the most common diseases that affects a large population in the world. Studies on drug discovery and delivery for cancer treatment are of global interest and their progression has increased dramatically in recent years in order to find new anticancer candidates, improve drug selectivity, and reduce the side effects of current anticancer drugs, which are the major challenges in cancer drug therapy [4,5,6]. Common side effects have been recorded for chemotherapeutic agents. Some of these side effects were described as critical, e.g., severe vomiting, diarrhea, myelosuppression, and liver and renal impairments [7]. Continuous trials have attempted to provide alternative dosage forms for chemotherapeutic agents and co-administration with other curative drugs to solve this problem [8,9,10,11]
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