sPLA2 Selective Degradation of Nanoparticles

sPLA2 纳米颗粒的选择性降解

• 批准号: 7659138
• 负责人: Robert D Arnold
• 金额: $ 18.55万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7659138
• 关键词: Biodistribution; Biological; Blood Circulation; Carbon; Cessation of life; Cholesterol; Cleaved cell; Clinical; Data; Defect; Development; Disease; Doxorubicin Hydrochloride Liposome; Drug Carriers; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Drug toxicity; Effectiveness; Encapsulated; Engineering; Enzymes; Esters; Ethers; Fatty Acids; Fluorescent Probes; Functional disorder; Generations; Glycerophospholipids; Goals; Grant; Half-Life; Head; Heating; Human; Implant; In Vitro; Kinetics; Lead; Lecithin; Light; Lipid Inclusion; Lipids; Liposomes; Location; Lymphatic; Lysophospholipids; Malignant neoplasm of prostate; Measures; Mediating; Membrane; Mus; Neoplasm Metastasis; Normal tissue morphology; PC3 cell line; Penetration; Pharmaceutical Preparations; Phase Transition; Phospholipase; Phospholipase A2; Phospholipids; Physiological; Polyethylene Glycols; Polymers; Positioning Attribute; Prostatic Neoplasms; Role; Solid Neoplasm; Spectrometry, Mass, Electrospray Ionization; Sterically Stabilized Liposome; System; Techniques; Testing; Time; Tissues; Topotecan; Toxic effect; Translating; Treatment Efficacy; Tumor Tissue; absorption; base; cancer cell; cell growth; design; drug efficacy; esterase; improved; in vivo; inhibitor/antagonist; interest; mouse model; nanoparticle; nanoparticulate; novel; preference; public health relevance; subcutaneous; surface coating; tumor; tumor growth; uptake

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.

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传递和有效性，否则可能无法渗透到生物屏障。事实证明，这些纳米颗粒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制剂来增加几种药物的系统吸收，但在特定位置降解的药物较少。这种能力在设计智能纳米粒子方面将是无价的，这种纳米粒子可以选择性地在感兴趣的目标组织(如肿瘤)中降解。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，前列腺癌组织中分泌型磷脂酶A2(SPLA2)的活性和表达水平明显高于正常组织。在许多情况下，sPLA2的表达和活性是配对对照的20倍。这项应用测试了这样一种假设，即前列腺癌中sPLA2表达和活性的增加允许设计在这些肿瘤中选择性降解的智能脂质体。验证这一假说的具体目的是1)确定PLA2介导的脂质体在体外的降解机制，2)设计能够被sPLA2选择性降解的新型纳米颗粒脂质体，3)确定sPLA2在前列腺癌细胞中脂质体降解机制中的作用，以及4)确定sPLA2在前列腺癌小鼠模型中的脂质体降解、药物释放和疗效机制中的作用。 公共卫生相关性：本申请中提出的研究将确定在前列腺癌中选择性降解的药物递送系统。这将通过创造被一种脂肪代谢酶降解的系统来实现，这种酶在前列腺癌中的表达比正常组织高20倍。本质上，这种应用将利用这种选择性酶的表达来增加对前列腺癌的药物输送。