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. 2023 Feb 18;24(4):4133.
doi: 10.3390/ijms24044133.

Ethosomal Gel for Topical Administration of Dimethyl Fumarate in the Treatment of HSV-1 Infections

Mariaconcetta Sicurella  1 , Walter Pula  2 , Karolina Musiał  3 , Katarzyna Cieślik-Boczula  3 , Maddalena Sguizzato  2 , Agnese Bondi  2 , Markus Drechsler  4 , Leda Montesi  5 , Elisabetta Esposito  2 , Peggy Marconi  2
Affiliations

Ethosomal Gel for Topical Administration of Dimethyl Fumarate in the Treatment of HSV-1 Infections

Mariaconcetta Sicurella et al. Int J Mol Sci. .

Abstract

The infections caused by the HSV-1 virus induce lesions on the lips, mouth, face, and eye. In this study, an ethosome gel loaded with dimethyl fumarate was investigated as a possible approach to treat HSV-1 infections. A formulative study was conducted, evaluating the effect of drug concentration on size distribution and dimensional stability of ethosomes by photon correlation spectroscopy. Ethosome morphology was investigated by cryogenic transmission electron microscopy, while the interaction between dimethyl fumarate and vesicles, and the drug entrapment capacity were respectively evaluated by FTIR and HPLC. To favor the topical application of ethosomes on mucosa and skin, different semisolid forms, based on xanthan gum or poloxamer 407, were designed and compared for spreadability and leakage. Dimethyl fumarate release and diffusion kinetics were evaluated in vitro by Franz cells. The antiviral activity against HSV-1 was tested by plaque reduction assay in Vero and HRPE monolayer cells, while skin irritation effect was evaluated by patch test on 20 healthy volunteers. The lower drug concentration was selected, resulting in smaller and longer stable vesicles, mainly characterized by a multilamellar organization. Dimethyl fumarate entrapment in ethosome was 91% w/w, suggesting an almost total recovery of the drug in the lipid phase. Xanthan gum 0.5%, selected to thicken the ethosome dispersion, allowed to control drug release and diffusion. The antiviral effect of dimethyl fumarate loaded in ethosome gel was demonstrated by a reduction in viral growth both 1 h and 4 h post-infection. Moreover, the patch test demonstrated the safety of the ethosomal gel applied on the skin.

Keywords: HSV-1; cryogenic transmission electron microscopy; dimethylfumarate; in vitro diffusion; infection control.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 8
Figure 8
Evaluation of antiviral activity of the treatment during HSV-1 KOS infection on Vero (a) or HRPE cells (b). Data are expressed as mean ± s.d. of three different experiments: *** p values < 0.001, **** p values < 0.0001.To test the antiviral activity of the substance after viral entry and during the replication, SOL-DMF0.5, ETHO-DMF0.5, G-DMF0.5, and EG-DMF0.5 (DMF 35 μg/mL) were added 1 h or 4 h post-infection (Figure 9). A strong and significant reduction in viral growth was observed in the case of Vero cells treated with ETHO-DMF0.5 and EG-DMF0.5, with respect to untreated control (Figure 9).
Figure 9
Figure 9
Evaluation of antiviral activity of the treatment post HSV-1 KOS infection on Vero (a) or HRPE cells (b). Data are expressed as mean ± s.d. of three different experiments: *** p values < 0.001, **** p values < 0.0001.
Figure 1
Figure 1
Variation of Z Average of ETHO (criss-cross), ETHO-DMF0.5 (light blue) and ETHO-DMF1.0 (blue), as measured by PCS for 3 months on samples stored at 22 °C.
Figure 2
Figure 2
Cryo-TEM image of ETHO-DMF0.5. The bar corresponds to 100 nm.
Figure 3
Figure 3
The relationship between the maximum position of νC=O (A) and νasPO2-band (B) and the integrated peak area of νOH band for ETHO (gray line) and ETHO-DMF0.5 (blue line) samples.
Figure 4
Figure 4
Spreadability (a) and leakage (b) parameters of ETHO and ETHO gels. Data are the mean of three independent experiments ± s.d.
Figure 5
Figure 5
DMF release kinetics from ETHO-DMF0.5 (open blue circles), EG-DMF0.5 (closed blue circles), G-DMF0.5 (red squares), and SOL-DMF0.5 (black crosses), as determined by Franz cell associated to PTFE membranes. Data are the mean of six independent experiments ± s.d.
Figure 6
Figure 6
DMF permeability kinetics from ETHO-DMF0.5 (blue open circles), EG-DMF0.5 (blue closed circles), SOL-DMF0.5 (black crosses), and G-DMF0.5 (red open squares), as determined by Franz cell associated to STRAT-M® membrane. Data are the mean of six independent experiments ± s.d.
Figure 7
Figure 7
Percentage of cell viability after treatment with SOL-DMF0.5 (black), EG-DMF0.5 (gray), and ETHO-DMF0.5 (white). The neutral red uptake assay provides a quantitative measurement of the number of viable cells measured at OD 540 nm. Panel (a) cell viability of the Vero cell line, panel (b) cell viability of the HRPE cell line. Data are expressed as mean ± SEM of three different experiments.
Figure 10
Figure 10
Evaluation of antiviral activity on HRPE cells treated by the indicated formulations 1 h (a), or 4 h (b) post-infection. Data are expressed as mean ± s.d. of three different experiments: * p-values < 0.05.
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