Abstract
Skin cancer is one of the most dangerous diseases, leading to massive losses and high death rates worldwide. Topical delivery of nutraceuticals is considered a suitable approach for efficient and safe treatment of skin cancer. Nobiletin; a flavone occurring in citrus fruits has been reported to inhibit proliferation of carcinogenesis since 1990s, is a promising candidate in this regard. Nobiletin was loaded in various vesicular systems to improve its cytotoxicity against skin cancer. Vesicles were prepared using the thin film hydration method, and characterized for particle size, zeta potential, entrapment efficiency, TEM, ex-vivo skin deposition and physical stability. Nobiletin-loaded composite penetration enhancer vesicles (PEVs) and composite transfersomes exhibited particle size 126.70 ± 11.80 nm, 110.10 ± 0.90 nm, zeta potential + 6.10 ± 0.40 mV, + 9.80 ± 2.60 mV, entrapment efficiency 93.50% ± 3.60, 95.60% ± 1.50 and total skin deposition 95.30% ± 3.40, 100.00% ± 2.80, respectively. These formulations were selected for cytotoxicity study on epidermoid carcinoma cell line (A431). Nobiletin-loaded composite PEVs displayed the lowest IC50 value, thus was selected for the in vivo study, where it restored skin condition in DMBA induced skin carcinogenesis mice, as delineated by histological and immuno-histochemical analysis, biochemical assessment of skin oxidative stress biomarkers, in addition to miRNA21 and miRNA29A. The outcomes confirmed that nobiletin- loaded composite PEVs is an efficient delivery system combating skin cancer.
Highlights
Skin cancer has one of the highest incidence rates compared to other types of cancer, and this rate is currently increasing worldwide[1], owing to ozone depletion and the accompanying increase in the ultraviolet (UV) radiation reaching the Earth
PC, penetration enhancer (PE) and nobiletin were dissolved in an organic solvent mixture of chloroform and methanol (2:1 v/v) based on preliminary solubility studies conducted on nobiletin, ensuring its solubility in both solvents
The thin film hydration was the method of choice for preparation of vesicles since nobiletin is a hydrophobic drug; this method ensures the production of multilamellar vesicles which increase the entrapment of hydrophobic d rugs[38,66]
Summary
Skin cancer has one of the highest incidence rates compared to other types of cancer, and this rate is currently increasing worldwide[1], owing to ozone depletion and the accompanying increase in the ultraviolet (UV) radiation reaching the Earth. Liposomes are considered the older generation of vesicles, after which other modified vesicular systems, containing edge activators in the case of transfersomes, ethanol in case of ethosomes, penetration enhancers in case of penetration enhancer vesicles (PEVs), or the lipid ceramide in case of cerosomes have been introduced These modifications were primarily introduced to augment the skin deposition/permeation of the drugs encapsulated within the vesicles, since liposomes lack the deep-skin penetration ability, but rather accumulate in the stratum corneum (SC), leading to inefficient drug delivery[31,32,33]. This study is the first attempt to evaluate the effect of nobiletin on antioxidant enzymes and mi-RNAs in the treatment of skin cancer
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