Polymer conjugated retinoids for controlled transdermal delivery.

All-trans retinoic acid (ATRA), a derivative of vitamin A, is a common component in cosmetics and commercial acne creams as well as being a first-line chemotherapeutic agent. Today, formulations for the topical application of ATRA rely on creams and emulsions to incorporate the highly hydrophobic ATRA drug. These strategies, when applied to the skin, deliver ATRA as a single bolus, which is immediately taken up into the skin and contributes to many of the known adverse side effects of ATRA treatment, including skin irritation and hair loss. Herein we present a new concept in topical delivery of retinoids by covalently bonding the drug through a hydrolytically degradable ester linkage to a common hydrophilic polymer, polyvinyl alcohol (PVA), creating an amphiphilic nanomaterial that is water-soluble. This PVA bound ATRA can then act as a pro-drug and accumulate within the skin to allow for the sustained controlled delivery of active ATRA. This approach was demonstrated to release active ATRA out to 10days in vitro while significantly enhancing dermal accumulation of the ATRA in explant pig skin. In vivo we demonstrate that the pro-drug formulation reduces application site inflammation compared to free ATRA and retains the drug at the application site at measurable quantities for up to six days.

Nanolayered siRNA delivery platforms for local silencing of CTGF reduce cutaneous scar contraction in third-degree burns.

Wound healing is an incredibly complex biological process that often results in thickened collagen-enriched healed tissue called scar. Cutaneous scars lack many functional structures of the skin such as hair follicles, sweat glands, and papillae. The absence of these structures contributes to a number of the long-term morbidities of wound healing, including loss of function for tissues, increased risk of re-injury, and aesthetic complications. Scar formation is a pervasive factor in our daily lives; however, in the case of serious traumatic injury, scars can create long-lasting complications due to contraction and poor tissue remodeling. Within this report we target the expression of connective tissue growth factor (CTGF), a key mediator of TGFß pro-fibrotic response in cutaneous wound healing, with controlled local delivery of RNA interference. Through this work we describe both a thorough in vitro analysis of nanolayer coated sutures for the controlled delivery of siRNA and its application to improve scar outcomes in a third-degree burn induced scar model in rats. We demonstrate that the knockdown of CTGF significantly altered the local expression of αSMA, TIMP1, and Col1a1, which are known to play roles in scar formation. The knockdown of CTGF within the healing burn wounds resulted in improved tissue remodeling, reduced scar contraction, and the regeneration of papillary structures within the healing tissue. This work adds support to a number of previous reports that indicate CTGF as a potential therapeutic target for fibrosis. Additionally, we believe that the controlled local delivery of siRNA from ultrathin polymer coatings described within this work is a promising approach in RNA interference that could be applied in developing improved cancer therapies, regenerative medicine, and fundamental scientific research.