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: 10652269
• 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 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10652269
• 关键词: 3-Dimensional; Affect; Aminosalicylate; Anti-Inflammatory Agents; Antibodies; Antiinflammatory Effect; Antimalarials; Area; Autoimmune; Autoimmune Diseases; Azoles; Biological Availability; Chloroquine; Chronic; Citrobacter rodentium; Colitis; Colon; Colonic Diseases; Colonic inflammation; Development; Diarrhea; Disease model; Drug Kinetics; Engineering; Epithelium; 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; Physiology; Polymers; Property; Public Health; Reactive Oxygen Species; Relapse; Research; Retinal Diseases; Rheumatoid Arthritis; Safety; Signal Pathway; Signal Transduction; Site; T-Cell Activation; TNF gene; Testing; Therapeutic; Therapeutic Effect; United States; absorption; cancer risk; colon cancer risk; copolymer; cost; cytokine; design; dextran sulfate sodium induced colitis; efficacy validation; epithelial injury; epithelial repair; gastrointestinal; gut inflammation; healing; human disease; immune activation; improved; in vitro testing; in vivo; in vivo Model; innovation; mouse model; murine colitis; nano; nanoparticle; novel; palliative; particle; pharmacologic; 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）是一种慢性炎症状况，影响越来越多的人 在美国，无法治愈。 IBD的特征是腹泻，疼痛，氧化应激和 活性氧（ROS）和结肠癌的风险增加。迫切需要更好 IBD的治疗，尤其是在发炎的结肠中局部起作用的治疗，没有全身暴露和 相关的副作用。该提案的目的是开发创新的抗炎珠以改进 治疗IBD。抗炎珠的设计旨在口服给患者，并设计为 查找并优先定位于结肠发炎的部分，在那里他们对与之相关的信号做出响应 结肠炎症和ROS激活其治疗功能。由于其特性，分布 珠子中的珠子仅限于结肠，它们不会像常规的IBD药物那样吸收到整个身体中， 因此，在长期慢性治疗过程中最大程度地减少了不希望的副作用。该项目基于我们最近的 基于广泛使用的抗疟药的新型材料（PCQ）的发现和开发 氯喹。该建议的总体目的是开发和测试口服不可吸收的治疗 颗粒设计为优先积聚并安全地减少IBD中的结肠炎症。中央 该提议的假设是PCQ作为炎症敏感珠的重新构造将导致改善 在结肠的发炎部分中积聚，并改善IBD的抗炎活性。这 假设是基于（i）口服纳米和微粒优先定位在（口服的）证据的（i） IBD炎症部位和（ii）目前的研究，这表明单独PCQ可以增强 小鼠实验IBD。使用炎症响应颗粒传递治疗活性聚合物 （PCQ）代表了IBD局部口服治疗的一种创新方法。我们将完成整体 通过追求三个特定目标来实现目标。在AIM 1中，我们将根据基于ROS响应粒子 治疗性PCQ。在AIM 2中，我们将验证优化的PCQ颗粒在上皮损伤模型中的功效 IBD的IBD感染模型以及由活化T细胞转移引起的慢性IBD模型。目标 3，我们将确定受PCQ治疗影响的细胞和分子方式。

项目成果

Oral Delivery of Nucleic Acid Therapies for Local and Systemic Action.

• DOI: 10.1007/s11095-022-03415-7
• 发表时间: 2023-01
• 期刊: PHARMACEUTICAL RESEARCH
• 影响因子: 3.7
• 作者: Kumari, Neha;Siddhanta, Kasturi;Panja, Sudipta;Joshi, Vineet;Jogdeo, Chinmay;Kapoor, Ekta;Khan, Rubayat;Kollala, Sai Sundeep;Kumar, Balawant;Sil, Diptesh;Singh, Amar B.;Murry, Daryl J.;Oupicky, David
• 通讯作者: Oupicky, David