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.

项目概要 高血糖是 2 型糖尿病 (T2D) 的标志，并加速糖尿病的发展 动脉粥样硬化，反过来又先于主要心血管并发症的发生。在人们 对于 T2D，心血管疾病对死亡率有显着影响，占 T2D 的 65% 至 80% 死亡人数。开发降低血糖同时治疗心血管疾病的药物 因此，疾病是当务之急。然而，目前的心血管药物（他汀类药物、贝特类药物、抗高血压药物） 对 T2D 的疗效有限，部分原因是这些药物不能完全解决某些血管问题 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。 该提案的目标是阐明胰高血糖素样肽-1 (GLP-1) 在体内的分子机制。 通过使用针对动脉粥样硬化并对其进行成像的纳米粒子探针来治疗心血管疾病。 GLP-1 是 一种内源性肠源性激素，目前以肽模拟物的形式在临床上使用，可提供 T2D 患者的血糖控制。我们和其他研究人员已经证明 GLP-1 发挥着 对免疫细胞有多种影响，并有可能减少动脉粥样硬化。我们假设 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的排出，并解决炎症。为了 从 GLP-1 对动脉粥样硬化免疫细胞的作用中分离出葡萄糖降低和全身效应，这是一种 需要有效的药物递送系统来促进 GLP-1 在病变白细胞中的积累。我们 提议使用工程纳米颗粒来研究 GLP-1 的位点特异性作用，该纳米颗粒将成像 病变和血液白细胞同时在斑块内传递 GLP-1 模拟物的有效负载。这 保留 MRI 可见纳米颗粒后，技术可激活斑块中的药物释放 通过“吃我”信号来促进。 GLP-1 抗动脉粥样硬化作用的潜在机制是 通过实现两个具体目标进行评估： 具体目标 1 将确定目标白细胞的炎症和迁移表型 纳米颗粒或单独的 GLP-1。在这里，我们将评估 GLP-1 对免疫细胞的急性影响。 具体目标 2 将确定脂质或抗炎作用是否控制 GLP-1 的抗动脉粥样硬化作用。这里， 我们将根据慢性病后 GLP-1 递送的位点来研究动脉粥样硬化的抑制作用 治疗方案。 GLP-1 的器官特异性作用将通过按需纳米颗粒递送进行探索 现代聚乙二醇化技术。 总之，该提案的意义在于它解决了临床对改进治疗的迫切需求 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

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

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