(591d) Targeting, Delivery, and Immobilization of Therapeutic Factors with Native Free Radicals

Elevated concentrations of free radicals are characteristic of a wide variety of tissue injuries and disease states, such as inflammatory diseases, neurological disorders, ischemia, burn wounds, and traumatic brain injuries. Free radicals are extremely reactive and can cause significant damage to proteins, lipid membranes, and nucleic acids. Left unchecked, these free radicals can perpetuate inflammatory states, induce the continued generation of further free radicals, and overall serve as an obstacle to healing. Delivery of exogenous compounds, such as antioxidants, to scavenge or otherwise detoxify these free radicals has been frequently investigated, but typically antioxidants alone are insufficient in remediating complex injury environments. Drugs or growth factors that promote healing through other mechanisms in these conditions and have similarly shown promise, but are often cleared too rapidly from the injury site to have a prolonged effect. Although the heightened reactivity of free radicals is deleterious in vivo, it is of great benefit in polymer chemistry, propagating polymerization reactions, and initiating crosslinking reactions between specific functional groups. We hypothesized that free radicals generated through injury and disease can be leveraged to induce crosslinking of acrylated groups on polymers. The advantages of this reaction are two-fold: 1) sufficient crosslinking of acrylated polymers will reduce their diffusivity, thereby localizing them to the target tissue and providing a vehicle for delivery of therapeutic factors; and 2) the crosslinking reaction may reduce or sequester radicals, reducing their ability to damage the tissue. Acrylated PEGs reduced the concentration of a radical used in standard scavenging assays (DPPH) as well as with reactive oxygen species (ROS) and reactive nitrogen species (RNS) commonly found in vivo. Further, in cellular assays, acrylated PEGs provided a measure of protection to cultures from hydrogen peroxide injury. These ROS also induced acrylate-acrylate crosslinking. Together these results strongly support our hypothesis and indicate that acrylated PEGs can be used to target and sustain the presentation of therapeutic factors within injured or diseased tissues and also sequester the free radicals to protect the tissue from further damage. Current efforts aim to identify optimal sizes and configurations of the acrylated carrier polymers and to test these polymers in a tissue explant model. Ultimately, this proposed acrylated PEG based system represents a versatile drug delivery platform that targets regions of injured or diseased tissue and can be amended to carry nearly endless therapeutic payloads.

This work is supported by a pilot research grant (CBIR16PIL015) and a graduate fellowship (CBIR14FEL004) generously provided by the New Jersey Commission on Brain Injury Research (NJCBIR).