sPLA2 Selective Degradation of Nanoparticles

描述（由申请人提供）：由脂质体组成的纳米颗粒制剂增加了药物的递送和有效性，否则可能无法渗透到生物屏障中。这些纳米颗粒被证明可以增加几种药物的吸收，包括化疗药物。虽然已经设计了几种配方，可以增加几种药物的全身吸收，但已经确定在特定部位降解的较少。这种能力对于设计在目标组织（如肿瘤）中选择性降解的智能纳米粒子是无价的。脂质体制剂高度由磷脂组成，包括甘油磷脂，如磷脂酰胆碱。甘油磷脂在体内被磷脂酶降解，包括磷脂酶A2 （PLA2）。最近的数据表明，与对照组织相比，人类前列腺癌具有显著更高水平的分泌磷脂酶A2 （sPLA2）活性和表达。在许多情况下，sPLA2的表达和活性比配对对照高20倍。该应用验证了sPLA2在前列腺癌中表达和活性增加的假设，允许设计在这些肿瘤中选择性降解的智能脂质体。验证这一假设的具体目的是：1)确定pla2介导的脂质体体外降解机制；2)设计能够被sPLA2选择性降解的新型纳米粒脂质体；3)确定sPLA2在前列腺癌细胞中脂质体降解机制中的作用；4)确定sPLA2在前列腺癌小鼠模型中脂质体降解、药物释放和疗效机制中的作用。

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.