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

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.

Self-Healing of Pluronic® F127 Hydrogels in the Presence of Various Polysaccharides

“…This thermoreversible micellar mode of chains association ( Scheme 2 ) makes PL attractive for various applications [ 34 , 35 , 36 ]. Several studies have proposed XG-PL-based hydrogels formulations with potential applications as ophthalmic drug-delivery systems [ 37 , 38 ], buccal drug-delivery systems [ 39 ], and for topical application and administration of different active principles [ 40 , 41 , 42 ]. Injectable Pluronic hydrogels were considered suitable systems to assist local cancer treatment (for chemotherapy, phototherapy, immunotherapy, or gene therapy).…”

Heme Oxygenase-1 Expression in Dendritic Cells Contributes to Protective Immunity against Herpes Simplex Virus Skin Infection

“…Importantly, a previous study found that DMF improved herpetic keratitis by increasing IL-4 and IL-5 secretion, both Th2-related cytokines, by activated lymphocytes [ 81 ]. Moreover, another research group recently reported antiviral effects for DMF against HSV infections in vitro, reducing viral yields both at 1 h and 4 h post-infection [ 82 ]. Notably, this study suggests the possibility of using a DMF-loaded gel composed of ethosomes for the topical treatment of HSV-1 infections, which remains to be assessed [ 82 ].…”

“…Moreover, another research group recently reported antiviral effects for DMF against HSV infections in vitro, reducing viral yields both at 1 h and 4 h post-infection [ 82 ]. Notably, this study suggests the possibility of using a DMF-loaded gel composed of ethosomes for the topical treatment of HSV-1 infections, which remains to be assessed [ 82 ]. Importantly, an in vivo irritation test demonstrated that this gel is safe to apply over intact human skin.…”

Novel potential pharmacological applications of dimethyl fumarate—an overview and update

“…Moreover, treatment with DMF (15 mg/kg) for 28 days pre-infection and 14 days post-infection with Herpes simplex Virus 1 (HSV1) improved severe keratitis by reducing corneal inflammation in mice ( Heiligenhaus et al, 2004 ). The antiviral effect of DMF against HSV1 has been recently confirmed in vitro by a study also investigating the topical use of DMF loaded in ethosome gel, which displays favourable skin tolerability and safety in human volunteers ( Sicurella et al, 2023 ). Of interest, recent in vitro evidence in human primary retinal endothelial cells showed cytoprotective and antioxidant effects of DMF under high glucose conditions, opening an interesting perspective and rationale for further evaluation of this molecule in retinal pathologies featured by vascular complications, such as diabetic retinopathy ( Manai et al, 2022 ).…”