Targeted Drug Delivery to Adipose Tissue Macrophages in Obesity

肥胖症中脂肪组织巨噬细胞的靶向药物递送

• 批准号: 9763348
• 负责人: Andrew Michael Smith
• 金额: $ 39.77万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-19 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9763348
• 关键词: Adipose tissue; Animal Model; Animals; Anti-inflammatory; Award; Back; Biodistribution; Biological Assay; Biology; Blinded; Blood; Cardiovascular system; Cells; Chemicals; Chemistry; Chronic; Clinic; Clinical; Comorbidity; Diabetes Mellitus; Disease; Dose; Drug Delivery Systems; Drug Targeting; Effectiveness; Engineering; Ensure; Exhibits; FDA approved; Family; Formulation; Functional disorder; Gene Expression; Genomics; Glucose Intolerance; Goals; Gold; Greater sac of peritoneum; Health; Healthcare Systems; Heart Diseases; Histopathology; Human; Illinois; Incidence; Individual; Inflammation; Inflammatory; Injectable; Insulin Resistance; Intervention; Lead; Link; Liver; Malignant Neoplasms; Measures; Mediator of activation protein; Molecular; Molecular Weight; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Onset of illness; Organ; Pathology; Patients; Peritoneum; Pharmaceutical Preparations; Phenotype; Physiological; Physiology; Polysaccharides; Population; Preventive treatment; Process; Prodrugs; Rodent Model; Site; Societies; Stroke; TNF gene; Testing; Therapeutic; Time; Tissues; Translating; Treatment Efficacy; Universities; Veterinary Pathology; Visceral; Weight; Work; base; clinical translation; controlled release; cytokine; design; diabetic; drug candidate; efficacy testing; feeding; imaging study; improved; innovation; interstitial; lead candidate; macrophage; molecular imaging; mouse model; multidisciplinary; nanomaterials; nanoscale; novel strategies; novel therapeutic intervention; novel therapeutics; pre-clinical; prevent; quantitative imaging; research clinical testing; side effect; small molecule; stem; success; targeted delivery; translational study; uptake

PROJECT SUMMARY The rising worldwide incidence of obesity is inflicting a massive toll on our healthcare system due to complications of type 2 diabetes, heart disease, and stroke. Recent evidence shows that chronic, low-grade inflammation is the causal link between obesity and its associated pathologies. Visceral adipose tissue is the initiating site, where pro-inflammatory macrophages are harbored in large numbers. These cells release cytokines that alter local and systemic physiology, inducing glucose intolerance, insulin resistance, and cardiovascular dysfunction. Therefore, pro-inflammatory macrophage cells in adipose tissue present an obvious target for clinical intervention. We recently developed a novel strategy to efficiently deliver therapeutic cargo to adipose tissue macrophages using polysaccharides delivered through the peritoneum. We observe exceptionally high targeting efficiency (up to 63% of the injected dose) in mouse models of obesity. Remarkably, when these polysaccharides are conjugated to anti-inflammatory prodrugs, a single dose reduces gene expression of pro-inflammatory cytokines both in adipose tissue and blood. The delivery vehicle (polysaccharides), linkers, and drugs are all FDA-approved such that these compounds could potentially be rapidly translated to clinical testing. The goal of this proposal is to thoroughly and rationally develop these nanomaterials-based prodrugs through mechanistic studies to understand the delivery process and the physiological impact. We will perform quantitative biodistribution, cellular uptake, and multiscale imaging studies to maximize delivery efficiency and further widen the therapeutic window. We will further apply cellular and genomics assays in rodent models of obesity to test efficacy toward reducing local and systemic inflammation, diabetic phenotype, and off-target side effects that are expected to be minimized compared with free drug counterparts. Finally, we will optimize the delivery rate using chemical linkers and controlled-release formulations to to generate a lead compound ready for translational studies by the conclusion of the award period. Our highly multidisciplinary team is well suited to succeed in all aspects of this proposed work. Our team includes experts in nanomaterials chemistry (Andrew Smith), animal models of obesity and diabetes (Kelly Swanson), macrophage and obesity biology (Erik Nelson), quantitative imaging and biodistribution (Wawrzyniec Dobrucki), veterinary pathology (Matthew Wallig), and translatable controlled release materials (Benjamin Keselowsky). Success in this proposal will specifically provide a new therapy that can decouple obesity from its comorbidities by inhibiting systemic inflammation, and more broadly yield families of anti- inflammatory compounds with widened therapeutic windows due to high delivery efficiency to specific cells and tissues. This preventative therapeutic strategy may similarly benefit patients suffering from the ever-expanding list of diseases for which systemic inflammation is causally implicated.

项目摘要 肥胖的全球发病率不断上升，这是由于我们的医疗保健系统造成的巨大损失 2型糖尿病，心脏病和中风的并发症。最近的证据表明慢性低级 炎症是肥胖与其相关病理之间的因果关系。内脏脂肪组织是 启动场地，促炎性巨噬细胞大量占有。这些细胞释放 改变局部和全身生理学的细胞因子，诱导葡萄糖不耐症，胰岛素抵抗和 心血管功能障碍。因此，脂肪组织中的促炎性巨噬细胞呈现 明显的临床干预目标。我们最近制定了一种新型策略来有效提供治疗性 使用腹膜传递的多糖到脂肪组织巨噬细胞到脂肪组织巨噬细胞。我们观察到 在肥胖的小鼠模型中，靶向效率极高（高达63％的注射剂量）。 值得注意的是，当将这些多糖与抗炎前药结合在一起时，单剂量减少 脂肪组织和血液中促炎细胞因子的基因表达。送货工具 （多糖），接头和药物均已批准，因此这些化合物可能是可能的 迅速转化为临床测试。该提议的目的是彻底和理性地开发这些 通过机械研究，基于纳米材料的前药，以了解交付过程和 生理影响。我们将执行定量生物分布，蜂窝摄取和多尺度成像 研究以最大化递送效率并进一步扩大治疗窗口。我们将进一步应用细胞 和肥胖模型中的基因组学测定，以测试降低局部和全身性的功效 炎症，糖尿病表型和脱靶副作用，这些副作用预计将最小化 免费药物。最后，我们将使用化学接头和受控释放来优化交付速率 通过奖励的结论来生成铅化合物，准备转化研究 时期。我们高度的多学科团队非常适合在这项拟议工作的各个方面取得成功。我们的 团队包括纳米材料化学（Andrew Smith）的专家，肥胖和糖尿病的动物模型 （Kelly Swanson），巨噬细胞和肥胖生物学（Erik Nelson），定量成像和生物分布 （Wawrzyniec Dobrucki），兽医病理学（Matthew Wallig）和可翻译的受控释放材料 （本杰明·凯塞洛夫斯基）。该建议的成功将专门提供一种新的疗法，可以将 通过抑制系统性炎症，肥胖是由于其合并症，并且更广泛地产生了 由于对特定细胞的递送效率高，炎症化合物具有扩大的治疗窗口，并且 组织。这种预防性治疗策略可能同样受益于不断扩大的患者 系统性炎症的疾病清单是有因果关系的。