Lipid Nanoparticle Mediated Inhibition and Detection of Matrix Metalloproteinases

脂质纳米颗粒介导的基质金属蛋白酶的抑制和检测

• 批准号: 8255348
• 负责人: Sanku Mallik
• 金额: $ 27.92万
• 依托单位: NORTH DAKOTA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-16 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8255348
• 关键词: Affinity; Amino Acids; Antibodies; Applications Grants; Attention; Binding; Biological Markers; Calorimetry; Cartoons; Charge; Complex; Detection; Developmental Process; Diagnosis; Diagnostic; Disease; Dissociation; Drug Carriers; Drug Delivery Systems; Drug Formulations; Edetic Acid; Ensure; Enzyme Interaction; Enzymes; Evolution; Fatty Acids; Fluorescence; Fluorescence Spectroscopy; Foundations; Gel; Gelatinase A; Gelatinase B; Head; Health; Human; Inhibition of Matrix Metalloproteinases Pathway; Ions; Isoenzymes; Kinetics; Lanthanoid Series Elements; Lead; Life; Ligands; Lipid Bilayers; Lipids; Liposomes; Malignant Neoplasms; Matrilysin; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Mediating; Membrane Proteins; Metals; Methodology; Methods; Molecular; Molecular Biology; Molecular Conformation; Nature; Neoplasm Metastasis; Organic Chemistry; Outcome; Parents; Pathogenesis; Preparation; Process; Proteins; Protocols documentation; Reporter; Research; Role; Scheme; Site; Spectrum Analysis; Structure; Surface; System; Techniques; Testing; Therapeutic; Thermodynamics; Time; Titrations; Transition Elements; Transition Temperature; base; biomaterial compatibility; crosslink; desensitization; design; fluidity; human disease; insight; luminescence; monomer; nanoparticle; novel; polymerization; preference; protein complex; receptor; research study; stromelysin 2; tool; Affinity; Amino Acids; Antibodies; Applications Grants; Attention; Binding; Biological Markers; Calorimetry; Cartoons; Charge; Complex; Detection; Developmental Process; Diagnosis; Diagnostic; Disease; Dissociation; Drug Carriers; Drug Delivery Systems; Drug Formulations; Edetic Acid; Ensure; Enzyme Interaction; Enzymes; Evolution; Fatty Acids; Fluorescence; Fluorescence Spectroscopy; Foundations; Gel; Gelatinase A; Gelatinase B; Head; Health; Human; Inhibition of Matrix Metalloproteinases Pathway; Ions; Isoenzymes; Kinetics; Lanthanoid Series Elements; Lead; Life; Ligands; Lipid Bilayers; Lipids; Liposomes; Malignant Neoplasms; Matrilysin; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Mediating; Membrane Proteins; Metals; Methodology; Methods; Molecular; Molecular Biology; Molecular Conformation; Nature; Neoplasm Metastasis; Organic Chemistry; Outcome; Parents; Pathogenesis; Preparation; Process; Proteins; Protocols documentation; Reporter; Research; Role; Scheme; Site; Spectrum Analysis; Structure; Surface; System; Techniques; Testing; Therapeutic; Thermodynamics; Time; Titrations; Transition Elements; Transition Temperature; base; biomaterial compatibility; crosslink; desensitization; design; fluidity; human disease; insight; luminescence; monomer; nanoparticle; novel; polymerization; preference; protein complex; receptor; research study; stromelysin 2; tool

DESCRIPTION (provided by applicant): Liposomes are one of the best representatives of lipid-based nanoparticles, and they are ideally suited as the drug delivery vehicles due to their ease in formulations as well as biocompatibility. Aside from drug carriers, the liposomal nanoparticles have potentials to form template surfaces against proteins (due to intrinsic mobility of their lipid monomers), and such features can be contrived to develop highly specific diagnostic and desensitization protocols for proteins of biomedical relevance. The proposed research will develop novel liposome-based artificial antibodies , which will find applications in isozyme specific detection and inhibition of four matrix metalloproteinases (viz., MMP-2, MMP-7, MMP-9, and MMP-10), which are known to be involved in the pathogenesis of a variety of human diseases. These fundamental, process developmental , research will be accomplished under the following specific aims: (i) Synthesis of lipid conjugates to serve as the initial anchor sites for MMPs, as well as for interaction at the protein surfaces. (ii) Template polymerization of liposomes in the presence of each of the MMPs (i.e., MMP-2, -7, -9 and -10), and testing the potentials of resultant (polymerized) liposomes in isozyme selective inhibition of their parent MMPs. (iii) Isozyme-selective detection of the MMPs by employing time-resolved luminescence spectroscopy of liposome-incorporated lanthanide ions. (iv) Mechanistic studies on the roles of protein-lipid interactions in isozyme-selective detection and inhibition of MMPs. These research objectives will be accomplished by employing the techniques of synthetic organic chemistry, molecular biology, fluorescence spectroscopy, and kinetic and thermodynamic analyses of enzyme-ligand interactions and enzyme catalyses. The successful completion of this research will provide insights into developing liposomal nanoparticle-based highly specific and facile diagnostic tools for other pathogenic as well as biomarker proteins under diverse pathophysiological conditions. PUBLIC HEALTH RELEVANCE: The outcome of the proposed research will find long term applications in diagnosing and treating various cancers. During this application period, we will focus our attention in designing novel lipid nanoparticles, and in understanding the basic mechanistic principles intrinsic to the detection and inhibition of several enzymes involved in the progression and metastasis of various cancers. The successful completion of this research will establish foundation for developing diagnostic and therapeutic tools for other proteins responsible for causing different human diseases.

描述（由申请人提供）：脂质体是基于脂质的纳米颗粒的最佳代表之一，由于它们易于制剂和生物相容性，因此理想地将其作为药物输送车。除药物载体外，脂质体纳米颗粒具有对蛋白质形成模板表面的潜力（由于其脂质单体的固有迁移率），并且可以为生物医学相关性蛋白质提供高度特定的诊断和脱敏方案而产生这种特征。拟议的研究将开发出新型的基于脂质体的人造抗体，该抗体将在同工酶特异性检测和抑制四种基质金属蛋白酶（viz。，MMP-2，MMP-7，MMP-9，MMP-9和MMP-10）中的应用，已知参与各种人类疾病的发病机制。这些基本的过程发展，研究将以以下特定目的完成：（i）脂质共轭物的合成作为MMP的初始锚固位点以及在蛋白质表面上的相互作用。 （ii）在每个MMP（即MMP -2，-7，-9和-10）存在下脂质体的模板聚合，并测试产生（聚合）脂质体在同工酶选择性抑制其母体MMP中的电势。 （iii）通过使用脂质体掺入的灯笼离子的时间分辨发光光谱来对MMP进行同工酶选择性检测。 （iv）关于蛋白脂相互作用在同工酶选择检测和抑制MMP中的作用的机理研究。这些研究目标将通过采用合成有机化学，分子生物学，荧光光谱以及动力学和热力学分析的技术来实现。这项研究的成功完成将为开发基于脂质体纳米颗粒的高度特异性且功能齐全的诊断工具提供见解，以在多样化的病理生理条件下为其他致病性和生物标志物蛋白质以及生物标志物蛋白。公共卫生相关性：拟议研究的结果将在诊断和治疗各种癌症时找到长期应用。在此应用期间，我们将注意力集中在设计新型的脂质纳米颗粒上，并在理解检测和抑制各种癌症进展和转移的几种酶的基本机理原理上。这项研究的成功完成将为开发诊断和治疗工具的基础，以针对负责引起不同人类疾病的其他蛋白质。