Glycemic Control by Glucose-Responsive Hydrogels Based on Synthetic Lectin Mimics

项目摘要/摘要 1型糖尿病约占所有糖尿病病例的10%，并且是不断增长的 患有这种疾病的儿童数量。由于胰腺中释放胰岛素的b细胞被破坏，胰岛素 替代疗法是一线治疗方法。目前，大多数患者每天多次接受胰岛素治疗。 皮下注射。治疗是通过手动监测血糖水平(BGL)和 食物摄入，并可归类为“开环”输送系统，因为胰岛素注射和剂量 不是BGL的直接结果。其结果是胰岛素过多和不足的时期，导致每天的 低血糖和高血糖；BGL的这些变化可能会导致严重的并发症。取而代之的是一个“闭环系统” 递送系统将触发胰岛素释放，以响应外部刺激，在这种情况下，高血糖素值。 许多针对闭环式胰岛素疗法的研究都集中在对葡萄糖的反应上。 聚合物材料或胰岛素结合物。一般的策略是固定化或封装葡萄糖传感器 聚合物基质或颗粒中可因葡萄糖浓度而膨胀或降解的部分，从而 释放包裹的胰岛素。这些材料通常含有葡萄糖专一性的酶，这种酶 可以变性，并遭受反应迟缓，糖结合蛋白或“凝集素”，同样表现出较差 稳定性和免疫原性，或葡萄糖络合苯基硼酸，很容易合成 而且稳定，但结合了许多其他代谢物。这项提议的目标是开发一种对葡萄糖敏感的 避免使用非特异性、不稳定或有毒成分的1型糖尿病的胰岛素疗法。 研究策略详细说明了一种完全合成的葡萄糖特异性受体或 “凝集素模拟”，将这种葡萄糖敏感部分固定在含有胰岛素的水凝胶中，以及 应用所得到的葡萄糖响应材料在体内调节BGLS。分子动力学 已经使用模拟来指导含有形成以下官能团的手性大环的设计 强烈的非共价相互作用，特别是与b-D-葡萄糖的CH和OH基团。模数合成法 建议的化合物将能够有效地评估结合亲和力，以及任何 需要对受体进行设计。该提案的下一个目标涉及铅的共价连接 化合物到聚合物基质；这些水凝胶对葡萄糖浓度的响应性最初将是 在一系列葡萄糖溶液中进行评估。然后，在目标3中将使用葡萄糖响应水凝胶 体内糖尿病小鼠模型中BGLS的调节。如果成功，拟议的研究将允许 葡萄糖反应物质的产生，更容易获得，更稳定，葡萄糖专一性更强，更少 比以前开发的闭环系统有毒。最重要的是，这些材料将提供更安全的 对于依赖胰岛素治疗的糖尿病患者来说，这是更可靠的治疗选择。

Project Summary/Abstract Type 1 diabetes accounts for approximately 10% of all diabetes cases, and is responsible for the growing number of children with the disease. Due to the destruction of insulin-releasing b-cells in the pancreas, insulin replacement therapy is the first-line treatment. Currently, most patients receive insulin by multiple daily subcutaneous injections. The treatment is dictated by manual monitoring of blood glucose levels (BGLs) and food intake, and can be categorized as an “open-loop” delivery system, as insulin injections and dosage are not a direct result of BGLs. The result is periods of insulin excess and deficiency, causing daily episodes of hypo- and hyperglycemia; these changes in BGLs can lead to serious complications. Instead, a “closed-loop” delivery system would trigger insulin release in response to an external stimulus, in this case, high BGLs. Much of the research towards a closed-loop insulin therapy has been focused on glucose-responsive polymeric materials or insulin conjugates. A general strategy is to immobilize or encapsulate a glucose-sensing moiety in a polymer matrix or particle that can swell or degrade in response to glucose concentration, thereby releasing encapsulated insulin. These materials most commonly incorporate glucose-specific enzymes, which can denature and suffer from sluggish response, sugar-binding proteins or “lectins,” which similarly exhibit poor stability and also immunogenicity, or glucose-complexing phenylboronic acids, which are easily synthesized and stable, but bind many other metabolites. The goal of this proposal is to develop a glucose-responsive insulin therapy for type 1 diabetes that circumvents the use of nonspecific, unstable, or toxic components. The Research Strategy details the development of a completely synthetic glucose-specific receptor or “lectin mimic,” the immobilization of this glucose-sensing moiety in insulin-containing hydrogels, and the application of the resulting glucose-responsive materials to regulate BGLs in vivo. Molecular dynamics simulations have been used to guide the design of chiral macrocycles containing functional groups that form strong non-covalent interactions specifically with the CH and OH groups of b-D-glucose. Modular syntheses of the proposed compounds will enable the efficient evaluation of binding affinities, and any modifications that need to be made to receptor design. The next aim of the proposal involves the covalent attachment of the lead compounds to a polymer matrix; the responsiveness of these hydrogels to glucose concentration will be initially evaluated in a series of glucose solutions. Glucose-responsive hydrogels will then be utilized in aim 3 for the regulation of BGLs in an in vivo mouse model of diabetes. If successful, the proposed research will allow for the generation of glucose-responsive materials that are more accessible, stable, glucose-specific, and less toxic than previously developed closed-loop systems. Most importantly, these materials would provide a safer and more reliable treatment option for diabetic patients depending on insulin therapy.