Supramolecular hydrogels for localized delivery of immunomodulatory enzymes

用于局部递送免疫调节酶的超分子水凝胶

基本信息

批准号：
9750094
负责人：
Gregory Hudalla
金额：
$ 18.41万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-07 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9750094
关键词：
Address Adenosine Adenosine Triphosphate Anti-inflammatory Apyrase Biocompatible Materials Biological Cell membrane Cells Charge Chimeric Proteins Chronic Clinical Diffuse Diffusion Disease Elements Enzymes Equilibrium Fever Financial Hardship Functional disorder Future Gel Grant Half-Life Homeostasis Hydration status Hydrogels Immune Immune response Immune system Immunocompromised Host Immunologics Immunosuppressive Agents Immunotherapeutic agent In Vitro Individual Inflammation Inflammatory Innate Immune System Lead Lipopolysaccharides Mediating Membrane Modality Modeling Molecular Mus Opportunistic Infections Pain management Pathology Patients Pattern Peptides Pharmaceutical Preparations Play Polymers Pre-Clinical Model Purinergic P2 Receptors Research Resolution Role Route Self-Direction Signal Transduction Site Subcutaneous Injections Therapeutic Uses Time Tissues Wound Healing adaptive immune response base beta pleated sheet cell injury clinical efficacy cost cytokine effective therapy extracellular immune system function immunoregulation in vitro Model in vivo in vivo Model innovation macrophage minimally invasive monocyte nanofiber pathogen preclinical safety programs receptor residence response small molecule standard of care subcutaneous success therapeutic enzyme

项目摘要

Project summary. The innate immune system plays an essential role in protecting host tissue function by eradicating pathogens and other foreign elements, promoting proper wound healing, and maintaining tissue homeostasis. However, dysregulated innate immune system activation resulting from aberrant self-directed immune responses can lead to states of chronic local inflammation that induce tissue damage or dysfunction. Chronic inflammatory diseases are often incurable, and therefore the current standard of care involves managing pain or fever via drugs that inhibit pro-inflammatory cytokines or their receptors. Although effective, these treatment modalities can suppress immune system function and render patients susceptible to opportunistic infections. In contrast, natural resolution of inflammation is mediated in part by enzymes anchored to the cell membrane that convert immunostimulatory signals to an inactive, or in some cases immunosuppressive, form. For example, extracellular ATP (eATP) released by one’s own damaged or dying cells acts as a ‘danger signal’ that activates inflammation, and eATP immunostimulatory activity is locally regulated by membrane-anchored enzymes that dephosphorylate ATP to adenosine (Ado), an immunosuppressive signal. Inspired by these observations, an ATP dephosphorylating enzyme, apyrase, is currently investigated as an immunotherapeutic biologic, and has demonstrated efficacy for suppressing inflammation in pre-clinical models. However, clinical efficacy of soluble apyrase delivered via parenteral routes is likely to be hindered by the short effective half-life typical of biologic drugs. To address this limitation, the proposed research program will develop biomaterials with integrated ATP dephosphorylating enzymes as immunotherapeutics that can be locally delivered to specific tissue sites to suppress aberrant inflammation. Toward this end, the proposed research program will create hydrated polymeric gels (i.e. “hydrogels”) of self- assembled peptide nanofibers with integrated enzymes that dephosphorylate ATP to Ado. Specifically, we will adapt our established platform, Co-Assembly Tags based on CHarge complementarity (“CATCH”), to create hydrogels harboring Adenosine Synthase A (AdsA), an enzyme that dephosphorylates ATP to Ado. Through this grant, we will (i) optimize CATCH-AdsA hydrogel enzymatic activity through material redesign, (ii) assess CATCH-AdsA hydrogel efficacy for immunomodulation using in vitro and in vivo models, and (iii) establish a pre-clinical safety profile for these biomaterials by assessing host innate and adaptive immune responses to CATCH hydrogels and their individual components. Success of the proposed research will lead to new biomaterials that can locally suppress inflammation via presentation of an immunomodulatory enzyme, which will provide the basis for future efforts to develop new immunotherapeutics to resolve chronic inflammation. More generally, a biomaterial platform with interchangeable integrated enzyme components is likely to enable new opportunities to harness natural enzymatic mechanisms to treat various immune-related pathologies.

项目摘要先天免疫系统通过以下方式在保护宿主组织功能中发挥着重要作用。根除病原体和其他外来元素，促进伤口正常愈合并维持组织然而，由于异常的自我导向导致先天免疫系统激活失调。免疫反应可导致慢性局部炎症状态，从而引起组织损伤或功能障碍。慢性炎症性疾病通常无法治愈，因此当前的护理标准包括通过抑制促炎细胞因子或其受体的药物来控制疼痛或发烧虽然有效，但这些治疗方式会抑制免疫系统功能，使患者容易受到感染相反，炎症的自然消退部分是由酶介导的。锚定在细胞膜上，将免疫刺激信号转化为非活性信号，或者在某些情况下免疫抑制，例如，因自身受损或死亡而释放的细胞外 ATP (eATP)。细胞充当激活炎症的“危险信号”，eATP 免疫刺激活性在局部受膜锚定酶调节，该酶将 ATP 去磷酸化为腺苷 (Ado)，受这些观察的启发，ATP 去磷酸化酶腺苷三磷酸双磷酸酶 (apyrase) 被开发出来。目前作为免疫治疗生物制剂进行研究，并已证明能有效抑制然而，临床前模型中的炎症通过肠胃外递送的可溶性腺苷三磷酸双磷酸酶的临床疗效。生物药物典型的有效半衰期短可能会阻碍这些途径。拟议的研究计划将开发具有集成 ATP 去磷酸酶的生物材料可以局部递送到特定组织部位以抑制异常炎症的免疫疗法。为此，拟议的研究计划将创建自体水合聚合物凝胶（即“水凝胶”）组装肽纳米纤维与集成酶，将 ATP 去磷酸化为 Ado。调整我们已建立的平台，基于电荷互补性的联合组装标签（“CATCH”），以创建含有腺苷合酶 A (AdsA) 的水凝胶，腺苷合酶 A 是一种将 ATP 去磷酸化为 Ado Through 的酶。这笔资助，我们将 (i) 通过材料重新设计优化 CATCH-AdsA 水凝胶酶活性，(ii) 评估使用体外和体内模型研究 CATCH-AdsA 水凝胶对免疫调节的功效，以及 (iii) 建立通过评估宿主先天性和适应性免疫反应来了解这些生物材料的临床前安全性 CATCH 水凝胶及其各个成分的研究成功将带来新的成果。生物材料可以通过免疫调节酶的存在来局部抑制炎症，将为未来开发新的免疫疗法来解决慢性炎症奠定基础。更一般地说，具有可互换的集成酶成分的生物材料平台可能使利用天然酶机制治疗各种免疫相关疾病的新机会。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Using Self-Assembling Peptides to Integrate Biomolecules into Functional Supramolecular Biomaterials.

利用自组装肽将生物分子整合到功能性超分子生物材料中。

DOI：
发表时间：
2019-04-12
期刊：
影响因子：
0
作者：
Liu, Renjie;Hudalla, Gregory A
通讯作者：
Hudalla, Gregory A

Injectable nanofibrillar hydrogels based on charge-complementary peptide co-assemblies.

基于电荷互补肽共组装体的可注射纳米纤维水凝胶。

DOI：
发表时间：
2021-04-07
期刊：
影响因子：
6.6
作者：
Soto Morales, Bethsymarie;Liu, Renjie;Olguin, Juanpablo;Ziegler, Abigail M;Herrera, Stephanie M;Backer;Kelley, Karen L;Hudalla, Gregory A
通讯作者：
Hudalla, Gregory A

Harnessing molecular recognition for localized drug delivery.

利用分子识别进行局部药物输送。