Array development of anti-inflammatory peptoid-graft polymers for islet delivery

描述(由申请人提供)：使用新材料减少胰岛移植周围的并发症可以改进目前治疗1型糖尿病的策略。到目前为止，新的策略主要集中在限制免疫细胞的激活或防止血液介导的炎症反应，方法是对被包裹的胰岛进行免疫隔离，或者在胰岛上涂上改变表面属性的材料。在这里，我们寻求开发新的模拟肽材料，用于包被/包裹胰岛，不仅抑制炎症反应，而且积极促进抗炎反应，促进移植免疫耐受。我们首先概述了一种新的高通量筛选短肽类序列的阵列方法。类肽是一类模拟多肽的分子，近年来越来越受欢迎，与具有较低免疫原性风险和增加化学构建块多样性的多肽相比，具有潜在的优势。本文提出的制备和筛选类肽化合物的新方法可能对发现新的生物活性序列或评估不同类肽类化合物的生物响应具有重要意义。在这里，阵列将被筛选出不同化学性质的影响 关于巨噬细胞表型，评估同时减少炎症激活和促进抗炎和耐受激活的化学物质。虽然表面化学对经典炎性巨噬细胞激活的影响知道得很多，但对其对这一替代激活表型的影响却知之甚少。还将对阵列的血液接触特性进行筛选，包括限制血清吸附和补体激活的能力。这两个标准(巨噬细胞表型和血清相互作用)将被用于改进类肽文库的设计和识别抗炎信号的有前景的类肽序列。下一步，我们将开发呈现悬垂型类肽序列的类肽接枝聚合物。开发的第一个聚合物将是一种合成的氨基醇，通过二环氧化合物和伯胺在类肽上的逐步生长聚合而成。这种聚合物的主干表现出有限的巨噬细胞活性，人们希望添加类肽接枝将进一步改善对这种聚合物的反应。第二种待开发的材料是类肽接枝海藻酸盐，这是一种广泛用于胰岛包裹和输送的天然生物聚合物。将对这两类聚合物材料进行抗炎巨噬细胞反应以及蛋白质吸附和补体激活的分析。在提案的最后部分，将进一步分析被确定为抗炎的有希望的类肽接枝聚合物，以确定它们在促进胰岛健康和功能的同时包被/包裹猪胰岛的能力。希望该研究计划将产生两类新的抗炎聚合物材料，这些材料可能在未来的表面功能化应用中有用，以改进胰岛移植，并能够在不需要有害的全身免疫抑制的情况下使用同种或异种胰岛。

DESCRIPTION (provided by applicant): Reducing complications surrounding islet transplantation with new materials could improve current strategies to treat type 1 diabetes mellitus. To date, new strategies have focused on limiting the activation of immune cells or preventing blood-mediated inflammatory response through immunoisolation of encapsulated islets or by coating islets with materials to change surface properties. Here, we seek to develop new peptidomimetic materials for use in coating/encapsulating islets that not only inhibit the inflammatory response, but actively promote an anti-inflammatory response and promote immune tolerance to the transplant. We first outline a new array method for high-throughput screening of short peptoid sequences. Peptoids, a peptidomimetic class of molecules, have gained popularity in recent years and have potential advantages when compared to peptides that include less risk for immunogenicity and increased chemical building block diversity. New methods proposed here for the preparation and array screening of peptoids could be important to the discovery of new bioactive sequences or to evaluate the biological response to different peptoid chemistries. Here, arrays will be screened for the effects of different chemical properties on macrophage phenotype, evaluating for chemistries that simultaneously reduce inflammatory activation and promote anti-inflammatory and tolerogenic activation. While a lot is known about the effect of surface chemistry on classical inflammatory macrophage activation, little is known about its effect on this alternative activation phenotype. Arrays will also be screened for blood-contacting properties, inlcuding ability to limit serum adsorption and complement activation. These two criteria (macrophage phenotype and serum interactions) will be used to improve peptoid library design and identify promising peptoid sequences for anti-inflammatory signaling. Next, we will develop peptoid-graft polymers that present pendant peptoid sequences. The first polymer developed will be a synthetic ¿-amino alcohol prepared via step-growth polymerization of diepoxides and primary amines on the peptoid. This polymeric backbone has shown limited macrophage activation, and it is hoped that addition of peptoid grafts will further improve the reaction to this polymer. The second material to be developed is peptoid-grafted alginate, a natural biopolymer that is widely used for islet encapsulation and delivery. Both classes of polymeric materials will be analyzed for an anti-inflammatory macrophage response and for protein adsorption and complement activation. In the final portion of the proposal, promising peptoid- grafted polymers identified to be anti-inflammatory will be further analyzed for their ability to coat/encapsulate porcine islets while promoting islet health and function. It is hoped that the proposed research plan will result in the generation of two new classes of anti-inflammatory polymeric materials that could be useful in future applications toward surface functionalization to improve islet transplantation and enable the use of allogeneic, or even xenogeneic, islets without requiring harmful systemic immune suppression.