Unimolecular micelles as an effective carrier of poorly water-soluble nifuratel for selective in vivo anticervical cancer therapy via mucoadhesive dynamic hydrogels

Abstract

Cervical cancer remains a significant global health challenge, accounting for over 340,000 deaths annually. Consequently, there is an urgent need for localized drug delivery systems that can effectively eradicate cancer cells while avoiding the systemic toxicity associated with traditional chemotherapy.This study introduces dynamic hydrogels composed of drug-loaded unimolecular micelles, reversibly cross-linked via boronic ester linkages, to provide a safe and effective anticervical cancer in vivo monotherapy using nifuratel. In an animal model, a 14-day regimen of just two doses reduced average tumor volume by up to 95.2% while maintaining stable body weight. Notably, a 60% complete cure rate was achieved in the investigated mice. Comprehensive biochemical analysis (including C-reactive protein, lactate dehydrogenase, creatinine, alkaline phosphatase, ALAT and AST aminotransferases, and total protein, etc.) alongside histopathological examinations confirmed the therapy's safety, showing no systemic toxicity or organ damage. The dynamic nature of the polymer network enabled intratumoral injection of the hydrogel. The unimolecular micelles, based on 3-star-[(poly(benzyl glycidyl ether)-block-(polyglyceryl glycerol ether)], significantly enhanced nifuratel's solubility and bioavailability in aqueous media. Achieving an effective and selective in vivo response was found to be dependent on the precise molar ratio of hydrophilic-to-hydrophobic segments and optimal drug loading.Tensile detachment testing revealed superior mucoadhesive strength of hydrogels at wet conditions up to 11.8 kPa, ensuring stable and controlled drug transport at the tissue site. Furthermore, ex vivo permeability studies using rabbit and porcine membranes demonstrated effective tissue penetration up to 60% after 48 h. This is the first report of a nifuratel carrier providing safe and effective monotherapy of cervical cancer in an in vivo model. These results suggest that nifuratel-loaded dynamic hydrogels constructed of copolyethers constitute a breakthrough delivery system for gynecology, ensuring lowdose, selective therapy of cervical cancer, with significant potential for clinical application.