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.

项目概要 炎症性肠病 (IBD) 是一种慢性炎症性疾病，影响着越来越多的人 在美国，目前尚无治愈方法。 IBD 的特点是腹泻、疼痛、氧化应激和 活性氧（ROS），并增加患结肠癌的风险。非常需要更好的发展 IBD 治疗，尤其是在发炎结肠局部起作用而无需全身暴露的治疗 相关的副作用。该提案的目标是开发创新的抗炎珠，以改善 治疗炎症性肠病。抗炎珠设计用于患者口服给药，并经过精心设计 找到并优先定位到结肠的发炎部分，在那里它们对与以下相关的信号做出反应 结肠炎症和活性氧激活其治疗功能。由于它们的特性，分布 珠子的作用仅限于结肠，不会像传统的 IBD 药物那样被全身吸收， 从而最大限度地减少长期慢性治疗期间的不良副作用。这个项目是基于我们最近的 基于广泛使用的抗疟药发现和开发新型材料（PCQ） 氯喹。该提案的总体目标是开发和测试口服不可吸收治疗药物 旨在优先积聚并安全减少 IBD 结肠炎症的颗粒。中央 该提案的假设是，将 PCQ 重新配制为炎症敏感珠将导致改善 积聚在结肠发炎部位，从而改善 IBD 的抗炎活性。这 该假设基于 (i) 现有证据表明口服给予的纳米颗粒和微米颗粒优先定位于 IBD 炎症部位和 (ii) 我们目前的研究表明，单独使用 PCQ 可以增强 IBD 炎症部位的愈合 小鼠实验性 IBD。使用炎症反应性颗粒来递送治疗活性聚合物 (PCQ) 代表了 IBD 局部口腔治疗的创新方法。我们将完成总体 通过追求三个具体目标来实现目标。在目标 1 中，我们将基于以下条件制备 ROS 响应颗粒： 治疗性 PCQ。在目标2中，我们将验证优化后的PCQ颗粒在上皮损伤模型中的功效 IBD、IBD 感染模型以及由活化 T 细胞转移诱导的慢性 IBD 模型。瞄准 3，我们将确定受PCQ治疗影响的细胞和分子模式。

项目成果

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

用于局部和全身作用的核酸疗法的口服递送。

• 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