Dynamic Hydrogel‐Mediated Co‐Delivery of Clotrimazole and Nifuratel for Safe and Effective In Vivo Cervical Cancer Treatment

Systemic combination chemotherapy for cervical cancer is often limited by poor drug solubility and high toxicity. Over the past decade, there has been growing interest in local therapy using hydrogel-based drug carriers that remain at the site of the lesion, thereby reducing side effects. However, to date, research has been limited mainly to in vitro studies. In this study, we demonstrate the use of dynamic hydrogels to ensure effective delivery of water-insoluble drugs for in vivo anti-cervical cancer therapy in a mouse model. The main structural component of the hydrogel was a non-linear poly(benzyl glycidyl ether)-poly(glyceryl glycerol ether) copolyether, which increases the solubility of the poorly water-soluble clotrimazole and nifuratel and enables reversible cross-linking, confering injectability and self-healing behavior to the hydrogel. Two-dose intratumoral implementation of hydrogel formulations resulted in a superior effect in the reduction of the tumor volume by > 90% within a 14-day therapy. Unexpectedly, 50% of the mice with induced tumors were completely cured with a hydrogel constructed of copolyethers, whose molar ratio of constitutional repeating units of GGE to BGE was equal to 2:1. The drug loading of both drugs can be a key parameter crucial for the achievement of the superior efficacy of this formulation, making it a highly therapeutic delivery system. The use of copolyethers enhanced controlled drug delivery, as evidenced by a statistically significant reduction in tumor volume (p < 0.001) compared to the efficacy of pure drugs (> 0.05). Furthermore, copolyether-based formulations provide a safer therapeutic alternative to pure drugs. This was confirmed by blood biochemical analyses, which showed no increase in LDH or CRP levels, and by histopathological evaluations of mouse livers, which demonstrated that, unlike pure clotrimazole, the formulations do not induce liver damage. The high yield point detected for hydrogel and the strong mucosal adhesion of the synthesized hydrogels up to 18.7 kPa allow the formulation to remain at the target site. Surprisingly, we observed that incorporating clotrimazole into the hydrogel significantly increased mucosal adhesion strength. Permeability investigations performed on ex vivo porcine vaginal mucosa showed a sustained permeation reaching 40% and 25% of permeated nifuratel and clotrimazole, respectively. The presented dual drug-loaded dynamic hydrogels are highly promising for clinical use in cervical cancer treatment.