Chloroquine-based polymer particles as oral non-absorbable treatment of inflammatory bowel disease

基于氯喹的聚合物颗粒作为口服不可吸收治疗炎症性肠病

• 批准号: 10356892
• 负责人: David Oupicky
• 金额: $ 51.74万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10356892
• 关键词: 3-Dimensional; Affect; Aminosalicylate; Anti-Inflammatory Agents; Antibodies; Antiinflammatory Effect; Antimalarials; Area; Autoimmune; Autoimmune Diseases; Biological Availability; Chloroquine; Chronic; Citrobacter rodentium; Colitis; Colon; Colonic Diseases; Colonic inflammation; Cytokine Signaling; Development; Diarrhea; Disease model; Drug Kinetics; Engineering; Epithelial; Evaluation; Face; Formulation; Gastrointestinal tract structure; Goals; Health Care Costs; Histologic; Homeostasis; Hydroxychloroquine; Immune; Immunosuppression; Immunosuppressive Agents; Infectious colitis; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Intestinal Mucosa; Liver; Measures; Modality; Modeling; Molecular; Mucous Membrane; Mus; Oral; Oral Administration; Organoids; Oxidative Stress; Pain; Patients; Permeability; Persons; Pharmaceutical Preparations; Pharmacology; Physiology; Polymers; Property; Public Health; Reactive Oxygen Species; Relapse; Research; Retinal Diseases; Rheumatoid Arthritis; Safety; Signal Pathway; Signal Transduction; Site; T-Lymphocyte; TNF gene; Testing; Therapeutic; Therapeutic Effect; Triazoles; United States; absorption; base; cancer risk; colon cancer risk; copolymer; cost; cytokine; design; dextran sulfate sodium induced colitis; efficacy validation; epithelial injury; gastrointestinal; gut inflammation; healing; human disease; immune activation; improved; in vitro testing; in vivo; in vivo Model; injury and repair; innovation; mouse model; murine colitis; nano; nanoparticle; novel; palliative; particle; preclinical safety; public health relevance; side effect; treatment effect

PROJECT SUMMARY Inflammatory bowel disease (IBD) is a chronic inflammatory condition that affects a growing number of people in the United States and for which there is no cure. IBD is characterized by diarrhea, pain, oxidative stress and reactive oxygen species (ROS), and increased risk of colon cancer. There is a great need to develop better treatments for IBD, especially treatments that act locally in the inflamed colon without whole-body exposure and associated side effects. The goal of this proposal is to develop innovative anti-inflammatory beads for improved treatment of IBD. The anti-inflammatory beads are designed to be given orally to the patients and engineered to find and preferentially localize to the inflamed parts of the colon, where they respond to signals associated with the colon inflammation and ROS to activate their therapeutic function. Because of their properties, the distribution of the beads is restricted to the colon and they are not absorbed into the whole body like conventional IBD drugs, thus minimizing undesired side effects during long-term chronic treatment. This project is based on our recent discoveries and development of novel type of materials (PCQ) based on a widely used antimalarial drug chloroquine. The overall objective of this proposal is to develop, and test oral non-absorbable therapeutic particles designed to preferentially accumulate in, and safely reduce, colon inflammation in IBD. The central hypothesis of this proposal is that reformulation of PCQ as inflammation-sensitive beads will lead to improved accumulation in the inflamed parts of the colon and result in improved anti-inflammatory activity in IBD. The hypothesis is based on (i) available evidence that orally given nano- and microparticles preferentially localize at the IBD inflammation sites and (ii) our current studies, which demonstrate that PCQ alone enhances healing of experimental IBD in mice. The use of inflammation-responsive particles to deliver therapeutically active polymer (PCQ) represents an innovative approach to the local oral treatment of IBD. We will accomplish the overall objectives by pursuing three specific aims. In Aim 1, we will prepare ROS-responsive particles based on therapeutic PCQ. In Aim 2, we will validate the efficacy of the optimized PCQ particles in epithelial injury model of IBD, infectious model of IBD, and in a chronic IBD model induced by the transfer of activated T cells. In Aim 3, we will determine the cellular and molecular modalities affected by the PCQ treatment.

项目摘要 炎症性肠病（IBD）是一种慢性炎症性疾病，影响越来越多的人 在美国，没有治愈的方法。IBD的特征在于腹泻、疼痛、氧化应激和炎症。 活性氧（ROS）和结肠癌风险增加。非常需要更好地发展 IBD的治疗，特别是在发炎的结肠中局部作用而不全身暴露的治疗， 相关的副作用。该提案的目标是开发创新的抗炎珠， IBD的治疗抗炎珠被设计成口服给病人， 发现并优先定位于结肠的发炎部分，在那里它们对与结肠炎相关的信号做出反应。 结肠炎症和ROS激活其治疗功能。由于它们的性质， 的珠粒被限制在结肠中，并且它们不像常规IBD药物那样被吸收到全身中， 从而在长期慢性治疗期间最小化不希望的副作用。这个项目是基于我们最近的 基于广泛使用的抗疟疾药物的新型材料（PCQ）的发现和开发 氯喹本提案的总体目标是开发和测试口服非吸收性治疗药物 这些颗粒被设计为优先在IBD中的结肠炎症中积聚并安全地减少IBD中的结肠炎症。中央 该建议假设是将PCQ重新配制为炎症敏感珠将导致改善的 在炎症的结肠部分的积累，并导致改善的抗炎活性在IBD。的 假设是基于（i）现有的证据，即口服给予的纳米颗粒和微粒优先定位于 IBD炎症部位和（ii）我们目前的研究，这表明PCQ单独促进愈合 小鼠实验性IBD。炎症响应性颗粒用于递送治疗活性聚合物的用途 (PCQ)代表了IBD局部口服治疗的创新方法。我们将全面完成 通过实现三个具体目标。在目标1中，我们将基于以下制备ROS响应颗粒： 治疗性PCQ在目标2中，我们将验证优化的PCQ颗粒在上皮损伤模型中的功效 在IBD的感染性模型、IBD的感染性模型和通过转移活化T细胞诱导的慢性IBD模型中。在Aim中 3，我们将确定PCQ治疗影响的细胞和分子模式。