Self-healable behaviour of dynamic hydrophobized hydrogels as a tool for the design of a delivery system of poorly water-soluble drugs for personalized dual therapy of estrogen-deficiency-related vulvovaginal candidiasis.

Abstract

Vulvovaginal candidiasis (VVC), primarily caused by Candida albicans, significantly impacts women with estrogen deficiency, such as those in menopause. Current treatments often require complex dual-therapy regimens of separate antifungals and hormones. To address this, we developed a dual-drug- hydrogel for a single topical administration. The hydrogel matrix was constructed of reversible boronic ester cross-links using a hyperbranched polyglycidol modified with 1,4-biphenylurethane groups, ensuring the efficient molecular distribution of poorly water-soluble clotrimazole and estrogen. The dynamic nature of cross-links provides both shear-thinning and self-healing properties, allowing for personalized dosing by simply mixing pre-prepared single-drug hydrogels for convenient intravaginal application. The dual-drug formulation exhibited high antifungal and anti-biofilm activity over clotrimazole-only treatments, and effectively inhibited hyphal formation - a critical virulence factor. The carrier demonstrated high cytocompatibility with human fibroblasts and did not adversely affect beneficial Lactobacillus microbiota. Franz cell studies showed a 20-fold and 90-fold increase in clotrimazole and estrogen transport, respectively, compared to aqueous suspensions. Methodologies included rheological characterization, bioadhesion measurements, and in vitro permeability studies. Safety and efficacy were evaluated through cytotoxicity assays and antifungal/anti-biofilm tests against C. albicans. This single-application system can simplify the treatment schedule, minimizing the adverse effects associated with systemic estrogen therapy, and offering a powerful, patient-tailored solution for the targeted management of VVC. STATEMENT OF SIGNIFICANCE: This study introduces a pioneering self-healing hydrogel for the personalized treatment of vulvovaginal candidiasis. By utilizing reversible boronic ester cross-links and a hydrophobized polyglycidol core, the system ensures molecular distribution of poorly water-soluble drugs, preventing crystallization and enhancing bioavailability. We report the first on-demand dosing platform where individual drug-loaded gels are mixed mechanically to create a tailored dual drug carrier. This approach achieves a 20-fold and 90-fold increase in drug permeability for clotrimazole and estrogen, respectively. Beyond simplified administration, the system shows synergistic efficacy against persistent Candida albicans fungal biofilms and hyphae. This work provides a versatile biomaterial platform for personalized multi-drug delivery in clinical practice.