Hyaluronic acid functionalization improves dermal targeting of polymeric nanoparticles for management of burn wounds: In vitro, ex vivo and in vivo evaluations

Owing to its intricate pathophysiology, impaired wound healing is one of the substantial challenges in the treatment of burn wounds (BWs). Despite the variety of conventional therapies available, morbidities associated with BWs have not subsided. Therefore, aim of the present study was to design an advanced nanotechnology-composited therapy for effectual management of BWs. Hyaluronic acid (HA)-functionalized curcumin (CUR) and quercetin (QUE) co-loaded nanoparticle (HA-CUR-QUE-CSNPs) were fabricated, optimized, characterized and evaluated for successful co-encapsulation of drugs, morphology, stability, drug release, cell proliferation, penetration across the skin, localization in the epidermis and dermis, and in vivo wound healing efficacy. Fabricated HA-functionalized CSNPs exhibited ultra-small size (177 +/- 11 nm), good zeta potential (+37.0 +/- 3.2 mV), high encapsulation efficiency (EE) (QUE-84% and CUR-64%) and loading capacity (LC) (QUE-38% and CUR-43%), and spherical shape with uniformly rough surface. HA-functionalized CSNPs showed a triphasic release pattern with Fickian diffusion kinetics, a time-mannered progression in MC3T3-E1 cells proliferation, improved penetration of CUR (2414 mu g/cm(2)) and QUE (1984 mu g/cm(2)) through stratum corneum, and good localization of drugs in the epidermis and dermis. A superior wound healing efficacy (98% wound closure rate at day 28) with marked histological signs of minimal infiltration of inflammatory cells, re-epithelization, ECM formation, fibroblast infiltration at wound site, granulation tissue formation, angiogenesis, and collagen deposition were also evidenced. This study concludes that HA-functionalization of polymeric NPs could be a promising approach to maximize skin penetration efficiency, localization of drugs in skin tissues, tissue regeneration and BWs healing.