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Pivotal role of Acitretin nanovesicular gel for effective treatment of psoriasis: ex vivo-in vivo evaluation study.

ABSTRACT: The goal of the current study was to explore the potential benefits of Acitretin (Act) nanovesicular gel as a prospective antipsoriatic topical delivery system counteracting the drug challenges in terms of its extremely low aqueous solubility, instability, skin irritation, and serious systemic adverse effects. Act-loaded niosomes were successfully developed, entirely characterized, and optimized. Further evaluation of the optimized formula was conducted regarding its stability and ex vivo cytotoxicity on different cell lines. The optimized niosomal vesicles were then incorporated in gel base matrix and investigated by sequential ex vivo (skin permeation and deposition) and in vivo (skin irritation and antipsoriatic activity using mouse tail model) experiments. The optimized Act-loaded niosomes (span 60:cholesterol molar ratio 1:1) were spherical in shape and exhibited the highest entrapment efficiency (90.32±3.80%) with appropriate nanosize and zeta potential of 369.73±45.45 nm and -36.33±1.80 mV, respectively. Encapsulation of the drug in the nanovesicles was further emphasized by differential scanning calorimetric and powder X-ray diffraction studies. After 3 months storage at 4±1°C, the optimized formula preserved its stability. Act nano niosomal gel produced a remarkable enhanced ex vivo permeation profile up to 30 h and significant drug deposition in the viable epidermal-dermal layers compared with those of Act gel. The pronounced antipsoriatic activity of the medicated nano niosomes was proved ex vivo in HaCaT cells (a keratinocyte cell line). Topical application of Act nano niosomal gel to mouse tail model further established its distinct in vivo antipsoriatic superiority in terms of significantly higher orthokeratosis, drug activity, and reduction in epidermal thickness compared with the control and other gel formulations. Also, negligible skin irritation and better skin tolerability of Act nanovesicular gel were revealed by primary irritation index and histopathologic examination.

SUBMITTER: Abu Hashim II

PROVIDER: S-EPMC5824759 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Pivotal role of Acitretin nanovesicular gel for effective treatment of psoriasis: ex vivo-in vivo evaluation study.

Abu Hashim Irhan Ibrahim II Abo El-Magd Noha Fawzy NF El-Sheakh Ahmed Ramadan AR Hamed Mohammed Fawzy MF Abd El-Gawad Abd El-Gawad Helmy AEH

International journal of nanomedicine 20180220

The goal of the current study was to explore the potential benefits of Acitretin (Act) nanovesicular gel as a prospective antipsoriatic topical delivery system counteracting the drug challenges in terms of its extremely low aqueous solubility, instability, skin irritation, and serious systemic adverse effects. Act-loaded niosomes were successfully developed, entirely characterized, and optimized. Further evaluation of the optimized formula was conducted regarding its stability and ex vivo cytoto ...[more]

PMID: 29503541

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Project description:BackgroundAcitretin and matrine have been used in the treatment of psoriasis in China. This study was designed to investigate the role and related mechanisms of matrine alone and in combination with acitretin in the treatment of psoriasis in vitro and in vivo.MethodsHaCaT cells were treated with matrine at different concentrations of 0 (blank control), 0.2, 0.4, 0.8, and 1.6 mg/mL for 24, 48, 72 h, respectively. 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium cell viability assay was used to assess the growth and proliferation of HaCaT cells. Cell cycle and apoptosis were detected by flow cytometry. Expression of protein was detected by Western blotting. Autophagy was observed by transmission electron microscopy. Then HaCaT cells were assigned to normal saline (NS) control group, matrine (0.4 mg/mL) group, acitretin (10 μmol/L) group, and matrine plus acitretin group, and the above methods were repeated. In animal experiments, the cumulative score (erythema, scaling, thickening) as a measure of the severity of inflammation was used to measure the skin performance of mice after treated with matrine 50 mg/kg, acitretin 4.5 mg/kg or combination of the two drugs on the psoriasis-like mouse models, respectively. Pathological findings of the lesions were observed, and the protein expressions in the lesions were detected by immunohistochemistry.ResultsCell proliferation inhibition was seen in HaCaT cells with treatment of matrine in a dose- and time-dependent manner (P < 0.01, respectively). Cell cycle G0/G1 phase arrest was observed in a dose-dependent way (P < 0.01). The expression of p21 (P < 0.05), LC3II/I (P < 0.01), and Beclin 1 (P < 0.01) increased and the expression of cyclin D1 (P < 0.05) decreased with increasing doses of matrine. Compared with the blank control, more autophagosomes were seen in HaCaT cells treated with matrine at 0.4 mg/mL by transmission electron microscopy (2.667 ± 1.202 vs. 21.33 ± 1.453, t = 9.899, P < 0.01). Cell proliferation inhibition and degree of the G0/G1 phase arrest was significantly higher in matrine plus acitretin group than those in matrine, acitretin, or the NS control group (P < 0.01, respectively). Compared with matrine or acitretin group, the expression of p21 (P < 0.05, P < 0.05) and LC3II/I (P < 0.01, P < 0.05) in matrine plus acitretin group increased significantly and the expression of cyclin D1 (P < 0.01, P < 0.05) and p62 (P < 0.05, P < 0.05) was reduced significantly. Compared with matrine or acitretin, matrine plus acitretin significantly down-regulated the phosphorylation of phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway (P < 0.05) and its downstream p-p70S6K (P < 0.05). In addition, the cumulative score of mice in the matrine plus acitretin group was significantly better than that in the matrine or acitretin group (1.480 ± 0.230 vs. 2.370 ± 0.241, P < 0.01; 1.480 ± 0.230 vs. 2.888 ± 0.341, P < 0.01). The expression of LC3 protein in the matrine plus acitretin group was also higher than that in the matrine, acitretin, or the NS control group (P < 0.05, respectively).ConclusionsMatrine has therapeutic potentials for psoriasis. Matrine and acitretin show synergistic effect via cell cycle arrest and autophagy induction by PI3K/Akt/mTOR pathway.

Dataset Information

Pivotal role of Acitretin nanovesicular gel for effective treatment of psoriasis: ex vivo-in vivo evaluation study.

Publications

Pivotal role of Acitretin nanovesicular gel for effective treatment of psoriasis: ex vivo-in vivo evaluation study.

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