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.

项目总结 由于以下原因，全球肥胖发病率的上升正在给我们的医疗系统造成巨大的损失 2型糖尿病、心脏病和中风的并发症。最近的证据表明，慢性、低度恶性 炎症是肥胖及其相关病理之间的因果联系。内脏脂肪组织是 起始点，大量支持炎症的巨噬细胞藏匿的地方。这些细胞释放 改变局部和全身生理的细胞因子，引起葡萄糖耐受、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一种 临床干预的明显靶点。我们最近开发了一种新的策略来有效地提供治疗 通过腹膜向脂肪组织巨噬细胞运送多糖的货物。我们观察到 在肥胖小鼠模型中极高的靶向效率(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，单次剂量就会减少 促炎症细胞因子在脂肪组织和血液中的基因表达。送货车辆 (多糖)、连接物和药物都是FDA批准的，因此这些化合物可能是 迅速转化为临床测试。这项建议的目标是彻底和合理地开发这些 通过对纳米材料前药的机理研究，了解其给药过程和给药途径 生理上的影响。我们将进行定量生物分布、细胞摄取和多尺度成像 最大限度地提高给药效率和进一步拓宽治疗窗口的研究。我们将进一步应用蜂窝 在肥胖的啮齿动物模型中进行基因组学分析，以测试对减少局部和全身肥胖的效果 炎症、糖尿病表型和非目标副作用，与 免费药物对应物。最后，我们将使用化学连接物和控释来优化递送速度 在获奖结束时生成可用于翻译研究的先导化合物的配方 句号。我们高度多学科的团队非常适合在这项拟议工作的所有方面取得成功。我们的 该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)，巨噬细胞与肥胖生物学(Erik Nelson)，定量成像和生物分布 (Wawrzyniec Dobrucki)、兽医病理学(Matthew Wallig)和可翻译的控制释放材料 (本杰明·凯斯洛夫斯基)这一提议的成功将特别提供一种可以脱钩的新疗法 肥胖通过抑制全身炎症的共病，更广泛地产生抗肥胖的家庭 炎性化合物具有更宽的治疗窗口，这是由于对特定细胞和 纸巾。这一预防性治疗策略同样可能使患有不断扩大的 与全身炎症有因果关系的疾病清单。