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

描述（由申请人提供）：利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。迄今为止，新的策略集中在限制免疫细胞的激活或通过免疫隔离被封装的胰岛或通过用材料覆盖胰岛来改变表面特性来预防血液介导的炎症反应。在这里，我们寻求开发新的模拟肽材料，用于覆盖/封装胰岛，不仅抑制炎症反应，而且积极促进抗炎反应和促进对移植的免疫耐受。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（Peptoids）是一类拟肽类分子，近年来越来越受欢迎，与免疫原性风险较小、化学成分多样性增加的肽相比，具有潜在的优势。本文提出的肽类化合物制备和阵列筛选的新方法对于发现新的生物活性序列或评估不同肽类化合物的生物反应具有重要意义。在这里，阵列将被筛选不同化学性质的影响

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.