Superoxide dismutase (SOD) is an enzyme that can inhibit the production of ROS and has shown tremendous promise for the treatment of acute liver failure in animal models. Unfortunately, SOD has performed poorly in clinical trials because of drug delivery problems. The objective of this R21 application is to develop a new class of polymeric nanoparticles that can deliver SOD in vivo and treat acute liver failure. This new family of nanoparticles are termed the polyketal nanoparticles (PKNs). The central hypothesis of this proposal is that the: The PKNs have the physical and chemical properties needed to deliver SOD to Kupffer cells in vivo, inhibit the production of ROS, and treat acute liver failure. This hypothesis is based upon the unique chemistry of the PKNs and our preliminary findings, which indicate that the PKNs degrade rapidly (1-2 days) under the acidic conditions of the endosomes and lysosomes, target Kupffer cells in vivo, and do not generate acidic degradation products after hydrolysis. The experiments in this proposal will test our central hypothesis; by determining the ability of SOD encapsulated in the PKNs to inhibit ROS generation in liver macrophages and protect mice from Tylenol induced acute liver failure. The successful completion of this R21 application will demonstrate that the PKNs can deliver proteins to macrophages in vivo and will generate a potential treatment for acute liver failure. Furthermore, the PKNs have the potential to deliver small organic molecules, DNA and protein therapeutics. Given the wide range of diseases that macrophages and phagocytic cells are involved in, we anticipate that the PKNs will find widespread use in the field of drug delivery. ? ? ?
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