Targeted Drug Delivery to Adipose Tissue Macrophages in Obesity

项目摘要 全球范围内肥胖症发病率的上升正在对我们的医疗保健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、低水平的 炎症是肥胖和其相关病理之间的因果联系。内脏脂肪组织是 起始位点，其中大量存在促炎性巨噬细胞。这些细胞释放 改变局部和全身生理学，诱导葡萄糖耐受不良、胰岛素抵抗的细胞因子， 心血管功能障碍因此，脂肪组织中的促炎性巨噬细胞呈现一种 临床干预的明显目标。我们最近开发了一种新的策略， 货物脂肪组织巨噬细胞使用多糖通过腹膜传递。我们观察 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，单剂量减少了 脂肪组织和血液中促炎细胞因子的基因表达。递送交通工具 （多糖）、连接体和药物都是FDA批准的，使得这些化合物可以潜在地用于治疗。 迅速转化为临床试验。该提案的目标是彻底合理地发展这些 纳米材料为基础的前药通过机制研究，以了解交付过程和 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，以最大限度地提高输送效率，并进一步扩大治疗窗口。我们将进一步应用细胞 和基因组学分析，以测试对减少局部和全身性肥胖的功效。 炎症、糖尿病表型和脱靶副作用，与 免费的药物同行。最后，我们将使用化学连接剂和控释剂优化递送速率。 配方，以产生一个先导化合物准备转化研究的结论，该奖项 期我们高度多学科的团队非常适合在这一拟议工作的各个方面取得成功。我们 研究小组包括纳米材料化学专家（安德鲁·史密斯）、肥胖和糖尿病动物模型专家 （Kelly Swanson），巨噬细胞和肥胖生物学（Erik纳尔逊），定量成像和生物分布 （Wawrzyniec Dobrucki）、兽医病理学（Matthew Wallig）和可翻译控释材料 （Benjamin Keselowsky）.这项提案的成功将特别提供一种新的疗法， 肥胖从其合并症通过抑制全身炎症，更广泛地产生家庭的抗- - 由于对特定细胞的高递送效率而具有加宽的治疗窗的炎性化合物， 组织中这种预防性治疗策略可能同样有益于患有不断扩大的 与全身炎症有因果关系的疾病列表。

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.