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Drug repurposing offers the chance to explore the full potential of existing drugs while reducing drug development time and costs. For instance, the anticonvulsant drug phenytoin (PHT) has been investigated for its wound healing properties. However, its poor solubility and variability of doses used topically limit its use. Hence, the aim of this study was to improve the properties and wound healing efficacy of PHT for the treatment of diabetic bedsores. PHT was encapsulated, using a modified ionic gelation method, in either positively or negatively charged chitosan-alginate nanoparticles (NPs), which possess previously demonstrated wound healing potential. These NPs were characterized by transmission electron microscopy, differential scanning calorimetry, and Fourier-transform infrared spectroscopy. PHT-loaded NPs were evaluated in vivo for their pressure ulcers’ healing potential using diabetic rats. The prepared NPs, especially the positively charged particles, exhibited superior wound healing efficacy compared to PHT suspension, with respect to healing rates, granulation tissue formation, tissue maturation, and collagen content. The positively charged NPs resulted in a 56.54% wound closure at day 7, compared to 37% for PHT suspension. Moreover, skin treated with these NPs showed a mature dermis structure with skin appendages, which were absent in all other groups, in addition to the highest collagen content of 63.65%. In conclusion, the use of a bioactive carrier enhanced the healing properties of PHT and allowed the use of relatively low doses of the drug. Our findings suggest that the prepared NPs offer an effective antibiotic-free delivery system for diabetic wound healing applications. Graphical Abstract

Phenytoin-loaded bioactive nanoparticles for the treatment of diabetic pressure ulcers: formulation and in vitro/in vivo evaluation