Enhanced Anti-Herpetic Activity of Valacyclovir Loaded in Sulfobutyl-ether-β-cyclodextrin-decorated Chitosan Nanodroplets

Valacyclovir (VACV) was developed as a prodrug of the most common anti-herpetic drug Acyclovir (ACV), aiming to enhance its bioavailability. Nevertheless, prolonged VACV oral treatment may lead to the development of important side effects. Nanotechnology-based formulations for vaginal administration represent a promising approach to increase the concentration of the drug at the site of infection, limiting systemic drug exposure and reducing systemic toxicity. In this study, VACV-loaded nanodroplet (ND) formulations, optimized for vaginal delivery, were designed. Cell-based assays were then carried out to evaluate the antiviral activity of VACV loaded in the ND system. The chitosan-shelled ND exhibited an average diameter of about 400 nm and a VACV encapsulation efficiency of approximately 91% and was characterized by a prolonged and sustained release of VACV. Moreover, a modification of chitosan shell with an anionic cyclodextrin, sulfobutyl ether β-cyclodextrin (SBEβCD), as a physical cross-linker, increased the stability and mucoadhesion capability of the nanosystem. Biological experiments showed that SBEβCD-chitosan NDs enhanced VACV antiviral activity against the herpes simplex viruses type 1 and 2, most likely due to the long-term controlled release of VACV loaded in the ND and an improved delivery of the drug in sub-cellular compartments.

2.1. Materials

All reagents employed used were of analytical grade and purchased from Sigma-Aldrich (St. Louis, MO, USA) unless otherwise stated. Soybean lecithin (Epikuron 200^®) was supplied by Cargill (Hamburg, Germany). Sulfobutyl ether-β-cyclodextrin (Captisol^®, average molecular weight 2163 Da, average degree of substitution 6.5) was a kind gift from Ligand (San Diego, CA, USA). Chitosan low-molecular weight (degree of deacetylation 75–85%, 50–190 KDa, viscosity: 20–300 cps, 1% solution in 1% v/v acetic acid) was used.
Methylcellulose, crystal violet, sodium dodecyl-sulfate (SDS), NP-40, sodium deoxycholate, a cocktail of protease inhibitors, Tween 20, glycine, and Triton X-100 were purchased from Sigma-Aldrich. The anti-HSV-1/2 gD monoclonal antibody (clone 2C10—HA025) was purchased from Virusys Corporation (Taneytown, MD, USA). The anti-actin antibody was from Millipore (Burlington, MA, USA) (clone C4—MAB1501R). The antibodies peroxidase-conjugated AffiniPure F(ab’)2 Fragment goat anti-mouse IgG (H+L) and goat anti-rabbit IgG (H+L) were obtained from Jackson ImmunoResearch Laboratories Inc. (West Grove, PA, USA).

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Argenziano, M.; Arduino, I.; Rittà, M.; Molinar, C.; Feyles, E.; Lembo, D.; Cavalli, R.; Donalisio, M. Enhanced Anti-Herpetic Activity of Valacyclovir Loaded in Sulfobutyl-ether-β-cyclodextrin-decorated Chitosan Nanodroplets. Microorganisms 2023, 11, 2460.
https://doi.org/10.3390/microorganisms11102460