Engineering the next generation nanoparticle-cyclosporine A therapy in lupus

设计下一代纳米颗粒环孢素 A 狼疮疗法

• 批准号: 10267718
• 负责人: Meenakshi Arora
• 金额: $ 46.74万
• 依托单位: UNIVERSITY OF ALABAMA IN TUSCALOOSA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-21 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10267718
• 关键词: Affect; Autoimmune Diseases; B-Lymphocytes; Benchmarking; Benefits and Risks; Biological; Biological Availability; Blood flow; CD3 Antigens; CXCL12 gene; CXCR4 gene; Carbon; Cells; Chronic; Clinic; Clinical Research; Complement; Custom; Cyclosporine; Cytostatics; Data; Diagnosis; Disease; Dose; Drug Delivery Systems; Engineering; Evaluation; FDA approved; Formulation; Glomerulonephritis; Goals; Grant; Gut associated lymphoid tissue; Human; Human Characteristics; Immune; Immune system; Immunoglobulin G; Immunologics; Immunosuppressive Agents; Individual; Inflammatory; Intestines; Kidney; Knowledge; Laboratory Finding; Length; Ligands; Lupus; Lupus Nephritis; Lymph; Lymphatic; Lymphatic System; Lymphocyte; Lymphoid; Lymphoid Cell; Lymphoid Tissue; MS4A1 gene; Modeling; Mus; Nucleosome Core Particle; Oral; Organ; Patients; Periodicity; Peripheral Blood Mononuclear Cell; Persons; Pharmaceutical Preparations; Plasma; Polyesters; Portal vein structure; Regimen; Serum; Severities; Signs and Symptoms; Site; Spleen; Steroids; Structure-Activity Relationship; Survival Rate; Symptoms; Systemic Lupus Erythematosus; T-Lymphocyte; TFRC gene; Technology; Testing; Therapeutic; Time; Toxic effect; Translating; Work; capsule; cell mediated immune response; chemokine; chemokine receptor; cytokine; density; design; ds-DNA; effective therapy; human disease; improved; in vivo; innovation; lymph nodes; mouse model; nanomedicine; nanoparticle; nanosystems; nephrotoxicity; next generation; particle; prevent; prophylactic; receptor; side effect; success; therapeutic target; therapy outcome; uptake

Project Summary Systemic lupus erythematosus (SLE) is a debilitating autoimmune disease that can affect almost every organ in the body. Current treatments for SLE are often inadequate because they involve the chronic use of non- specific, steroidal and cytostatic drugs that are associated with a wide spectrum of side-effects. However, notwithstanding ongoing efforts to develop better therapies, there has only been one new, FDA-approved drug for SLE in more than five decades. In this context, cyclosporine (CsA), a powerful suppressor of both humoral and cell-mediated immune responses can be a potential candidate, but its efficacy as a stand-alone treatment for SLE has never been demonstrated and often used to steroid tampering. Acknowledged reason for the lack of success with the current commercial CsA formulations is due to poor/variable target (lymphoid) tissue bioavailability with consequently differing biological activity and toxic to the kidneys. Targeting the lymphoid tissue potentially enables rational design of therapeutics to modulate the immune system, representing an innovative approach to treating lupus due to the fact that more than 75 percent of immune cells reside in the GUT-associated lymphoid tissues (GALT). Moreover, GALT in lupus is larger compared to the healthy individuals, making it an attractive site for targeting. The proposed study will generate paradigm-shifting, new knowledge in the field of nano-medicines using unique periodic-functional-polyesters (P2s, unlike commercial PLA/PLGA that are terminal functional), and investigate how the ligand density and composition influence the CsA delivery to lymphoid tissue. The work is enabled by previous findings, in which highly potent lymphatic system-targeting nanoparticle-CsA (called P2Ns-GA-CsA) specific to CD71 (transferrin receptor 1, TfR-1) on lymphoid cells (T and B-cells) have outperformed ligand-free controls and commercial CsA product, leading to better therapeutic outcomes. In this project, the technology is further developed by investigating how the spatial size and composition of the spacer molecules affect the intestinal-receptor interaction and transport of the nanoparticles facilitating customized dose-regimens. The project comprises of the following three aims, Aim#1, to establish structure-activity relationships for P2Ns-GA-CsA in a murine lupus and TfR KO models. Aim#2, to define the therapeutic dose of P2Ns-GA-CsA in a murine lupus model and Aim#3, to establish survival rates in murine lupus models using the most efficacious P2Ns-GA-CsA.

项目摘要 系统性红斑狼疮（SLE）是一种使人衰弱的自身免疫性疾病，几乎可以影响每个器官 在体内目前的SLE治疗往往是不够的，因为它们涉及长期使用非- 特异性、甾体和细胞生长抑制药物，与广泛的副作用有关。然而，在这方面， 尽管目前正在努力开发更好的治疗方法，但只有一种新的FDA批准的药物 在过去的五十多年里，在这种情况下，环孢素（CsA），一个强大的抑制剂， 和细胞介导的免疫反应可能是一个潜在的候选者，但其作为一个独立的治疗效果， 对SLE的治疗从未被证实，并且经常用于类固醇干预。承认缺乏的原因 目前市售CsA制剂成功的原因是靶（淋巴）组织较差/可变 生物利用度不同，因此具有不同的生物活性和对肾脏的毒性。靶向淋巴 组织潜在地使得能够合理设计治疗剂来调节免疫系统，代表了免疫系统的免疫学特性。 这是一种治疗狼疮的创新方法，因为超过75%的免疫细胞存在于 肠道相关淋巴组织（GALT）。此外，狼疮患者的GALT比健康人大 个人，使其成为一个有吸引力的网站的目标。拟议的研究将产生范式转变，新的 在纳米药物领域的知识，使用独特的双官能聚酯（P2，不像商业 PLA/PLGA是末端功能性的），并研究配体密度和组成如何影响 CsA递送至淋巴组织。这项工作是由以前的发现，其中，高效淋巴 系统靶向纳米粒子-CsA（称为P2 Ns-GA-CsA）对CD 71（转铁蛋白受体1，TfR-1）特异性， 淋巴样细胞（T和B细胞）的表现优于无配体对照和市售CsA产品， 更好的治疗效果。在这个项目中，通过调查如何进一步发展该技术， 间隔分子的空间大小和组成影响药物-受体的相互作用和转运， 所述纳米颗粒促进定制的剂量方案。该项目包括以下三个目标， 目的#1，在鼠狼疮和TfR KO模型中建立P2 Ns-GA-CsA的结构-活性关系。 目的#2，确定P2 Ns-GA-CsA在鼠狼疮模型中的治疗剂量，以及目的#3， 使用最有效的P2 Ns-GA-CsA在鼠狼疮模型中的存活率。