Nanoparticle scavengers for in vivo sequestration of overdosed drug molecules

DESCRIPTION (provided by applicant): This proposal addresses PHS 2012-02 Omnibus Solicitation of the NIH, CDC, FDA and ACF for Small Business Innovation Research Grant Applications (Parent SBIR [R43/R44]). Chronic wounds affect 6.5 million people in the USeach year, and 1-2% of the population in all developed countries, with treatment costs in the US alone reaching 25 billion annually. The increasing elderly population, in addition to the rising rates of diabetes and obesity, is expected to drive growth in the chronic wound market. Chronic wounds have a high level of inflammatory activity, specifically matrix metalloproteinases (MMPs) that leads to high turnover of the extracellular matrix in a chronic wound. Chronic wounds also are often in an ischemic state, due to decreased vascularity. The increased MMP activity, decreased vascularity, and unstable ECM production in a chronic wound environment all lead to continued skin degradation and subsequent ulceration. Providing an exogenous tissue engineered scaffold, such as a collagen based ECM, has shown some clinical success in treating nonhealing wounds due to their ability to provide a substrate that can bind and increase the activity of resident growth factors. However, existing products can be prematurelydegraded in the caustic environment of the chronic wound, and often do not achieve the necessary cellular infiltration, angiogenesis, and epithelialization to facilitate wound healing. Glytrix has developed a synthetic proteoglycan called DS-SILY. The molecule, inspired by the native proteoglycan decorin, is composed of a dermatan sulfate (DS) backbone with attached collagen binding peptides (SILY). This proteoglycan mimic has been shown to: 1) bind to and protect collagen scaffolds from MMP degradation; 2) promote the proliferation of both endothelial cells and keratinocytes; and 3) decrease granulation tissue and visible scarring and increase tensile strength after incisional wounding in a rat model. These characteristics have led to the hypothesis that augmentation of a collagen scaffold with DS-SILY will lead to slower degradation of the scaffold in the chronic wound environment, and will increase vascularity and epithelialization of the wound by potentiating resident growth factors, resulting in more effective healing of chronic wounds as compared to a collagen scaffold alone. Due to their different biological activities, two DS-SILY molecules with varying molecular weights will be examined in combination with a collagen dressing in a rat model of delayed healing. Wound healing markers will include epithelializaton, inflammation, tissue remodeling, and matrix degradation and deposition. Successful completion of this Phase I SBIR will result in a single DS-SILY molecule that will move forward in development by testing biocompatibility of the molecule as required by the FDA. GMP synthesis, biocompatibility testing, and a small clinical safety study will be the milestones for a Phase II award. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: Chronic wounds, such as diabetic ulcers, do not follow the normal wound-healing pathway, and remain in a perpetual state of increased inflammation and tissue turnover. The proposed work aims to evaluate a new potential therapeutic that can be used in conjunction with approved products to restore normal healing. The novel product works by masking tissue degradation and potentiating natural growth factors that increases wound vascularity and wound closure.