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

项目总结/摘要 1型糖尿病占所有糖尿病病例的约10%，并且是导致糖尿病患者不断增加的原因。 患有该病的儿童人数。由于胰腺中释放胰岛素的b细胞的破坏， 替代疗法是第一线治疗。目前，大多数患者每天接受多次胰岛素治疗。 皮下注射治疗通过手动监测血糖水平（BGL）和 食物摄入，并且可以被归类为“开环”递送系统，因为胰岛素注射和剂量是 不是BGL的直接结果其结果是胰岛素过量和不足的时期，导致每日发作， 低血糖和高血糖; BGL的这些变化可能导致严重的并发症。相反，是一个“闭环” 递送系统将响应于外部刺激（在这种情况下，高BGL）而触发胰岛素释放。 大部分针对闭环胰岛素治疗的研究都集中在葡萄糖反应性胰岛素上。 聚合物材料或胰岛素缀合物。一般的策略是将葡萄糖传感微球包封或封装在葡萄糖传感微球中。 聚合物基质或颗粒中的部分，其可以响应于葡萄糖浓度而溶胀或降解，从而 释放包裹的胰岛素。这些材料最常见的是掺入葡萄糖特异性酶， 糖结合蛋白或“凝集素”，它们同样表现出差的 稳定性和免疫原性，或易于合成的葡萄糖络合苯基硼酸 并且稳定，但结合许多其他代谢物。该提案的目标是开发一种葡萄糖响应 避免使用非特异性、不稳定或有毒成分的1型糖尿病胰岛素治疗。 该研究策略详细介绍了完全合成的葡萄糖特异性受体或 “凝集素模拟物”，该葡萄糖敏感部分在含胰岛素的水凝胶中的固定化，以及 将所得葡萄糖响应性材料应用于体内调节BGL。分子动力学 模拟已被用来指导设计手性大环含有官能团， 特别是与b-D-葡萄糖的CH和OH基团的强非共价相互作用。模块化合成 所提出的化合物将能够有效地评价结合亲和力和任何修饰， 需要进行受体设计。该提案的下一个目标涉及铅的共价连接 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价。葡萄糖响应性水凝胶然后将在目标3中用于 在体内糖尿病小鼠模型中BGL的调节。如果成功，拟议的研究将允许 产生更容易获得、稳定、葡萄糖特异性的葡萄糖响应性材料， 比以前开发的闭环系统更有毒性。最重要的是，这些材料将提供更安全的 为依赖胰岛素治疗的糖尿病患者提供更可靠的治疗选择。

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.