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的并发症可以改善目前治疗1型糖尿病的策略。到目前为止，新的策略集中在限制免疫细胞的激活或通过免疫隔离包囊胰岛或通过用材料涂覆胰岛以改变表面性质来防止血液介导的炎症反应。在这里，我们寻求开发用于包被/包封胰岛的新的肽模拟物材料，其不仅抑制炎症反应，而且积极促进抗炎反应并促进对移植物的免疫耐受。我们首先概述了一种新的阵列方法，用于短肽序列的高通量筛选。类肽是一类肽模拟物分子，近年来已经流行起来，与肽相比具有潜在的优势，包括免疫原性风险较小和化学结构单元多样性增加。本文提出的用于制备和阵列筛选类肽的新方法对于发现新的生物活性序列或评估对不同类肽化学的生物反应可能是重要的。在这里，阵列将筛选不同的化学性质的影响， 对巨噬细胞表型的影响，评价同时降低炎症活化和促进抗炎和致耐受性活化的化学物质。虽然很多是已知的经典炎症巨噬细胞活化的表面化学的影响，很少有人知道它对这种替代活化表型的影响。还将筛选阵列的血液接触特性，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）将用于改进类肽文库设计和鉴定用于抗炎信号传导的有希望的类肽序列。接下来，我们将开发呈现悬垂类肽序列的类肽接枝聚合物。开发的第一种聚合物将是通过在拟肽上逐步聚合二环氧化物和伯胺制备的合成的氨基醇。该聚合物骨架显示出有限的巨噬细胞活化，并且希望类肽移植物的添加将进一步改善对该聚合物的反应。第二种待开发的材料是类肽接枝藻酸盐，这是一种广泛用于胰岛封装和递送的天然生物聚合物。将分析两类聚合物材料的抗炎巨噬细胞反应以及蛋白质吸附和补体激活。在提案的最后部分，将进一步分析被鉴定为抗炎的有前景的类肽接枝聚合物在促进胰岛健康和功能的同时包覆/包封猪胰岛的能力。希望拟议的研究计划将导致产生两种新的抗炎聚合物材料，它们在未来的表面功能化应用中可能有用，以改善胰岛移植，并使同种异体，甚至异种胰岛的使用不需要有害的全身免疫抑制。

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.