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: 9354476
• 负责人: Andrew Michael Smith
• 金额: $ 39.76万
• 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 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9354476
• 关键词: Adipose tissue; Adverse effects; Animal Model; Animals; Anti-Inflammatory Agents; 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; macrophage; molecular imaging; mouse model; multidisciplinary; nanomaterials; nanoscale; novel strategies; novel therapeutic intervention; novel therapeutics; pre-clinical; prevent; quantitative imaging; research clinical testing; 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.

项目概要 全球肥胖发病率不断上升，给我们的医疗保健系统造成了巨大损失，原因是 2 型糖尿病、心脏病和中风的并发症。最近的证据表明，慢性、低度 炎症是肥胖及其相关病理之间的因果关系。内脏脂肪组织是 起始位点，其中大量存在促炎巨噬细胞。这些细胞释放 细胞因子改变局部和全身生理机能，诱导葡萄糖不耐受、胰岛素抵抗和 心血管功能障碍。因此，脂肪组织中的促炎巨噬细胞呈现出一种 临床干预的明确目标。我们最近开发了一种新的策略来有效地提供治疗 使用通过腹膜递送的多糖将货物运送至脂肪组织巨噬细胞。我们观察到 在肥胖小鼠模型中具有极高的靶向效率（高达注射剂量的 63%）。 值得注意的是，当这些多糖与抗炎前药结合时，单剂量可减少 脂肪组织和血液中促炎细胞因子的基因表达。送货车辆 （多糖）、接头和药物均已获得 FDA 批准，因此这些化合物有可能被用于 迅速转化为临床测试。本提案的目标是彻底、合理地发展这些 通过机制研究基于纳米材料的前药，以了解递送过程和 生理影响。我们将进行定量生物分布、细胞摄取和多尺度成像 研究旨在最大限度地提高递送效率并进一步拓宽治疗窗口。我们将进一步应用蜂窝 在啮齿动物模型中进行基因组学分析，以测试减少局部和全身肥胖的功效 与传统药物相比，炎症、糖尿病表型和脱靶副作用预计会最小化 免费药物对应物。最后，我们将使用化学连接剂和控释来优化递送率 配方以生成先导化合物，为获奖结论前的转化研究做好准备 时期。我们高度跨学科的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（安德鲁·史密斯）、肥胖和糖尿病动物模型方面的专家 （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) 和可翻译的控释材料 （本杰明·凯塞洛斯基）。该提案的成功将特别提供一种可以解耦的新疗法 通过抑制全身炎症来减轻肥胖症的合并症，并更广泛地产生抗- 由于向特定细胞的高递送效率，炎症化合物具有拓宽的治疗窗口 组织。这种预防性治疗策略可能同样有利于患有不断扩大的疾病的患者 与全身炎症有因果关系的疾病列表。