RESUMO
Injectable hydrogel matrices take the shape of a wound cavity and serve as scaffold for tissue repair and regeneration. Yet these materials are generally hydrophilic, limiting the incorporation of poorly water soluble, hydrophobic drugs. Here we show this shortcoming is circumvented through a star-shaped amphiphilic block copolymer comprising poly(ethylene glycol) and poly (propylene sulfide). This star-shaped amphiphilic polymer self-assembles in an aqueous medium into a physically stable hydrogel and effectively dissolves hydrophobic molecules delivering them at therapeutic doses. The self assembled hydrogel is a robust three-dimensional scaffold in vivo effectively promoting cellular infiltration, reducing inflammation, and wound clsoure. When combined with a hydrophobic BRAF inhibitor that promotes paradoxical mitogen-activated protein kinase (MAPK) activation in keratinocytes and wound closure, our self assembled scaffold supported dermal wound closure at a reduced drug dosage compared to administering the drug in dimethyl sulfoxide (DMSO) without a polymeric matrix. This family of star-shaped amphiphilic polymers delivers poorly water soluble active agents at a fraction of generally required dosage for efficacy and supports three-dimensional cell growth at tissue wounds, showing great promise for novel uses of hydrophobic drugs in tissue repair applications.
Assuntos
Portadores de Fármacos/química , Polietilenoglicóis/química , Polímeros/química , Inibidores de Proteínas Quinases/administração & dosagem , Sulfetos/química , Vemurafenib/administração & dosagem , Cicatrização/efeitos dos fármacos , Animais , Portadores de Fármacos/administração & dosagem , Hidrogéis/administração & dosagem , Hidrogéis/química , Interações Hidrofóbicas e Hidrofílicas , Injeções , Camundongos , Polietilenoglicóis/administração & dosagem , Polímeros/administração & dosagem , Inibidores de Proteínas Quinases/uso terapêutico , Solubilidade , Sulfetos/administração & dosagem , Vemurafenib/uso terapêutico , Água/químicaRESUMO
BRAF inhibitors are highly effective therapies for the treatment of BRAF(V600)-mutated melanoma, with the main toxicity being a variety of hyperproliferative skin conditions due to paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway in BRAF wild-type cells. Most of these hyperproliferative skin changes improve when a MEK inhibitor is co-administered, as it blocks paradoxical MAPK activation. Here we show how the BRAF inhibitor vemurafenib accelerates skin wound healing by inducing the proliferation and migration of human keratinocytes through extracellular signal-regulated kinase (ERK) phosphorylation and cell cycle progression. Topical treatment with vemurafenib in two wound-healing mice models accelerates cutaneous wound healing through paradoxical MAPK activation; addition of a mitogen-activated protein kinase kinase (MEK) inhibitor reverses the benefit of vemurafenib-accelerated wound healing. The same dosing regimen of topical BRAF inhibitor does not increase the incidence of cutaneous squamous cell carcinomas in mice. Therefore, topical BRAF inhibitors may have clinical applications in accelerating the healing of skin wounds.