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

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粒子的最佳代表之一，由于其易于配制以及生物相容性，它们非常适合作为药物递送载体。除了药物载体之外，脂质体纳米颗粒还具有形成针对蛋白质的模板表面的潜力（由于其脂质单体的固有流动性），并且可以设计这些特征来开发针对生物医学相关蛋白质的高度特异性的诊断和脱敏方案。拟议的研究将开发新型基于脂质体的人工抗体，该抗体将在四种基质金属蛋白酶（即 MMP-2、MMP-7、MMP-9 和 MMP-10）的同工酶特异性检测和抑制中得到应用，这些酶是已知参与多种人类疾病的发病机制。这些基础的工艺开发研究将在以下具体目标下完成：(i) 合成脂质缀合物，作为 MMP 的初始锚定位点，以及在蛋白质表面相互作用。 (ii) 在每种 MMP（即 MMP-2、-7、-9 和 -10）存在下进行脂质体模板聚合，并测试所得（聚合）脂质体在同工酶选择性抑制其母体 MMP 方面的潜力。 (iii)通过使用脂质体掺入的镧系元素离子的时间分辨发光光谱对MMP进行同工酶选择性检测。 (iv) 蛋白质-脂质相互作用在同工酶选择性检测和 MMP 抑制中作用的机制研究。这些研究目标将通过采用合成有机化学、分子生物学、荧光光谱以及酶-配体相互作用和酶催化的动力学和热力学分析技术来实现。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和简便的诊断工具提供见解，该工具用于不同病理生理条件下的其他病原体以及生物标志物蛋白质。公共健康相关性：拟议研究的结果将在诊断和治疗各种癌症方面找到长期应用。在此应用期间，我们将集中精力设计新型脂质纳米颗粒，并了解检测和抑制多种癌症进展和转移所涉及的几种酶所固有的基本机制原理。这项研究的成功完成将为开发其他引起不同人类疾病的蛋白质的诊断和治疗工具奠定基础。

项目成果

Differential modulation of the active site environment of human carbonic anhydrase XII by cationic quantum dots and polylysine.

• DOI: 10.1016/j.bbapap.2010.02.014
• 发表时间: 2010-06
• 期刊: Biochimica et biophysica acta
• 作者: Manokaran S;Zhang X;Chen W;Srivastava DK
• 通讯作者: Srivastava DK

Stabilization of anionic and neutral forms of a fluorophoric ligand at the active site of human carbonic anhydrase I.

稳定人碳酸酐酶 I 活性位点的阴离子和中性形式的荧光配体。

• DOI: 10.1016/j.bbapap.2010.06.024
• 发表时间: 2010
• 期刊: Biochimica et biophysica acta
• 作者: Manokaran,Sumathra;Banerjee,Jayati;Mallik,Sanku;Srivastava,DK
• 通讯作者: Srivastava,DK

Differentiation of prostate cancer cells using flexible fluorescent polymers.

• DOI: 10.1021/ac202301k
• 发表时间: 2012-01-03
• 期刊: ANALYTICAL CHEMISTRY
• 影响因子: 7.4
• 作者: Scott, Michael D.;Dutta, Rinku;Haldar, Manas K.;Guo, Bin;Friesner, Daniel L.;Mallik, Sanku
• 通讯作者: Mallik, Sanku

Encapsulated microbubbles and echogenic liposomes for contrast ultrasound imaging and targeted drug delivery.

• DOI: 10.1007/s00466-013-0962-4
• 发表时间: 2014-03
• 期刊: COMPUTATIONAL MECHANICS
• 影响因子: 4.1
• 作者: Paul, Shirshendu;Nahire, Rahul;Mallik, Sanku;Sarkar, Kausik
• 通讯作者: Sarkar, Kausik

Fluorescent polymer-based post-translational differentiation and subtyping of breast cancer cells.

基于荧光聚合物的乳腺癌细胞翻译后分化和亚型分析。

• DOI: 10.1039/c2an35877h
• 发表时间: 2012
• 期刊: The Analyst
• 作者: Scott,MichaelD;Dutta,Rinku;Haldar,ManasK;Wagh,Anil;Gustad,ThomasR;Law,Benedict;Friesner,DanielL;Mallik,Sanku
• 通讯作者: Mallik,Sanku