Probing Cardiovascular Actions of GLP-1 Using Nanoparticles

使用纳米颗粒探索 GLP-1 的心血管作用

• 批准号: 9914122
• 负责人: Andrei Maiseyeu
• 金额: $ 39.63万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9914122
• 关键词: Accounting; Acute; Address; Agonist; Alkynes; Antiatherogenic; Antidiabetic Drugs; Antihypertensive Agents; Antiinflammatory Effect; Arterial Fatty Streak; Artificial nanoparticles; Atherosclerosis; Attenuated; Avidity; Azides; Blood; Blood Glucose; Blood Pressure; Body Weight decreased; CD36 gene; Cadherins; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular system; Cells; Cessation of life; Chemotaxis; Cholesterol; Chronic; Clinic; Clinical; Clinical Research; Data; Dendritic Cells; Detection; Development; Drug Delivery Systems; Eating; Emigrations; Event; Fibrates; Flow Cytometry; Foam Cells; Future; Gadolinium; Gene Expression; Glucose; Goals; Hormones; Hyperglycemia; Hypertension; Image; Immune; Inflammation; Inflammatory; Insulin Resistance; Label; Laboratories; Lesion; Leukocytes; Lipids; Liver; Magnetic Resonance Imaging; Measurable; Messenger RNA; Modality; Modeling; Modernization; Modification; Molecular; Mus; Myeloid Cells; Myocardial Infarction; NTN1 gene; Non-Insulin-Dependent Diabetes Mellitus; OGTT; Organ; Pancreas; Patients; Permeability; Pharmaceutical Preparations; Pharmacologic Substance; Phenotype; Public Health; Regression Analysis; Reporting; Research Personnel; Risk Factors; Safety; Semaphorins; Signal Transduction; Stains; Stroke; Sum; Technology; Testing; Therapeutic; Transcript; Treatment Protocols; base; blood lipid; cardiovascular disorder risk; cell behavior; diabetes mellitus therapy; diabetic; diabetic patient; effective intervention; fluorophore; glucagon-like peptide 1; glycemic control; improved; in vitro Assay; in vivo; insulin sensitivity; laser capture microdissection; liraglutide; macrophage; mimetics; monocyte; mortality; nanoparticle; nanoparticle delivery; non-drug; novel therapeutics; oxidized lipid; particle; peptidomimetics; pleiotropism; receptor; recruit; targeted imaging; tool; treatment effect; treatment strategy; vascular abnormality

Project Summary Hyperglycemia is the hallmark of type 2 diabetes (T2D) and accelerates the development of atherosclerosis, which, in turn, precedes the development of major cardiovascular complications. In people with T2D, cardiovascular disease significantly contributes to mortality, accounting for 65%-to-80% of T2D deaths. The development of pharmaceutical agents that lower glucose while also treating cardiovascular disease is therefore a priority. However, current cardiovascular agents (statins, fibrates, antihypertensives) are only moderately efficacious in T2D, partly because these agents incompletely address certain vascular abnormalities, such as inflammation, foam cell formation and leukocyte recruitment to the arterial wall. Therefore, more effective interventions are needed that treat both hyperglycemia and atherosclerosis. The goal of this proposal is to elucidate the molecular mechanisms of glucagon-like peptide-1 (GLP-1) in cardiovascular disease through the use of nanoparticle probes that target and image atherosclerosis. GLP-1 is an endogenous gut-derived hormone presently used in clinics in the form of peptide mimetics that provide glycemic control in patients with T2D. We and other investigators have demonstrated that GLP-1 exerts a multitude of effects on immune cells and has the potential to reduce atherosclerosis. We posit that GLP-1 may directly regulate immune cell behavior by activating its receptor, GLP-1R, thereby reducing monocyte recruitment to the plaque, potentiating macrophage and cholesterol exit, and resolving inflammation. In order to isolate glucose lowering and systemic effects of GLP-1 from its actions on immune cells in atherosclerosis, an effective drug delivery system would be required that favors accumulation of GLP-1 in lesional leukocytes. We propose to investigate locus-specific actions of GLP-1 with the use of engineered nanoparticles that will image lesional and blood leukocytes simultaneously delivering a payload of a GLP-1 mimetic within plaque. This technology activates the drug release in the plaque following the retention of MRI-visible nanoparticles facilitated by eat-me signals. The underlying mechanisms of the anti-atherogenic effects of GLP-1 will be evaluated by carrying out two specific aims: Specific aim 1 will determine the inflammatory and migratory phenotype of leukocytes that were targeted by nanoparticles or GLP-1 alone. Here we will assess acute effects of GLP-1 on immune cells. Specific aim 2 will define whether lipid or anti-inflammatory effects govern anti-atherogenicity of GLP-1. Here, we will investigate atherosclerosis inhibition depending on the locus of GLP-1 delivery following chronic treatment regimen. Organ-specific actions of GLP-1 will be explored using on-demand nanoparticle delivery via modern pegylation technologies. In sum, the significance of this proposal is that it addresses an urgent clinical need for improved treatment strategies targeting both hyperglycemia and atherosclerosis.

项目摘要 高血糖是2型糖尿病（T2D）的标志，并加速了 动脉粥样硬化，这又是主要心血管并发症的发展。在人中 使用T2D，心血管疾病显着导致死亡率，占T2D的65％至80％ 死亡人数。降低葡萄糖同时还治疗心血管的药物的开发 因此，疾病是优先事项。但是，当前的心血管剂（他汀类药物，纤维化，抗高血压）为 仅在T2D中适度有效，部分是因为这些药物无法完全解决某些血管 异常，例如炎症，泡沫细胞形成和白细胞募集到动脉壁。 因此，需要更有效的干预措施来治疗高血糖和动脉粥样硬化。 该建议的目的是阐明胰高血糖素样肽-1（GLP-1）的分子机制 通过使用靶向动脉粥样硬化的纳米颗粒探针，心血管疾病。 GLP-1是 目前以肽模拟物形式用于诊所中的内源性肠源激素， T2D患者的血糖控制。我们和其他研究人员已经证明GLP-1发挥了A 对免疫细胞的多种影响，有可能减少动脉粥样硬化。我们认为GLP-1可能 通过激活其受体GLP-1R直接调节免疫细胞行为，从而减少单核细胞 招募斑块，增强巨噬细胞和胆固醇出口并解决炎症。为了 GLP-1的分离葡萄糖降低和全身作用，其对动脉粥样硬化中免疫细胞的作用，一种 需要有效的药物输送系统，有利于在病变白细胞中GLP-1的积累。我们 建议通过使用工程纳米颗粒来研究GLP-1的基因座特异性作用，以形象 病变和血清细胞同时提供斑块中GLP-1模拟物的有效载荷。这 在保留MRI-VISIS纳米颗粒之后，技术激活牌匾中的药物释放 由饮食信号促进。 GLP-1的抗动脉生就性作用的基本机制将是 通过执行两个具体目标来评估： 具体目标1将确定白细胞的炎症和迁移表型。 纳米颗粒或GLP-1。在这里，我们将评估GLP-1对免疫细胞的急性影响。 特定的目标2将定义脂质或抗炎作用是否控制GLP-1的抗动脉粥样硬化。这里， 我们将根据慢性后GLP-1递送的轨迹研究动脉粥样硬化的抑制作用 治疗方案。 GLP-1的器官特定作用将使用按需纳米颗粒通过通过点播纳米颗粒通过 现代的Pegylation Technologies。 总而言之，该提议的重要性是它解决了改进治疗的紧急临床需求 针对高血糖和动脉粥样硬化的策略。

项目成果

Low-density lipoprotein nanomedicines: mechanisms of targeting, biology, and theranostic potential.

• DOI: 10.1080/10717544.2021.1886199
• 发表时间: 2021-12
• 期刊: Drug delivery
• 影响因子: 6
• 作者: Di L;Maiseyeu A
• 通讯作者: Maiseyeu A

Facile Cholesterol Loading with a New Probe ezFlux Allows for Streamlined Cholesterol Efflux Assays.

使用新探针 ezFlux 轻松加载胆固醇，可简化胆固醇流出测定。

• DOI: 10.1021/acsomega.0c03112
• 发表时间: 2020
• 期刊: ACS omega
• 影响因子: 4.1
• 作者: Ravodina,AnastasiaM;Badgeley,MarcusA;Rajagopalan,Sanjay;Fedyukina,DariaV;Maiseyeu,Andrei
• 通讯作者: Maiseyeu,Andrei

Non-antigenic regulators of targeting for imaging and therapy.

成像和治疗靶向的非抗原调节剂。

• DOI: 10.1016/j.addr.2016.02.009
• 发表时间: 2016
• 期刊: Advanced drug delivery reviews
• 影响因子: 16.1
• 作者: Maiseyeu,Andrei