sPLA2 Selective Degradation of Nanoparticles

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Nanoparticle formulations consisting of liposomes increase the delivery and effectiveness of drugs that may not otherwise be permeable to biological barriers. These nanoparticles are proven to increase absorption of several drugs classes, including chemotherapeutics. While several formulations have been designed that increase the systemic absorption of several drugs, less have been identified that degrade at specific locations. Such ability would be invaluable in the design of smart nanoparticles that selectively degrade in the target tissues of interest, such as tumors. Liposome formulations are highly composed of phospholipids including glycerophospholipids such as phosphatidylcholine. Glycerophospholipids are degraded in the body by phospholipases, including phospholipase A2 (PLA2). Recent data demonstrates that human prostate cancers have significantly higher levels of secretory phospholipase A2 (sPLA2) activity and expression compared to control tissue. In many cases the expression and activity of sPLA2 is 20-fold higher than paired controls. This application tests the hypothesis that increased expression and activity of sPLA2 in prostate cancers allows for the design of smart liposomes that are selectively degraded in these tumors. The Specific Aims designed to test this hypothesis are 1) Determine the mechanisms of PLA2-mediated degradation of liposomes in vitro, 2) Design novel nanoparticulate liposomes capable of being selectively degraded by sPLA2, 3) Identify the role of sPLA2 in the mechanism of degradation of liposomes in prostate cancer cells, and 4) Determine the role of sPLA2 in the mechanisms o liposomal degradation, drug release and efficacy in mouse models of prostate cancer. PUBLIC HEALTH RELEVANCE: Studies proposed in this application will identify drug delivery systems that are selectively degraded in prostate tumors. This will be done by creating systems that are degraded by a lipid-metabolizing enzyme whose expression is 20-fold higher in prostate tumors, compared to normal tissues. In essence, this application will make use of this selective enzyme expression to increase drug delivery to prostate tumors.