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: 10098822
• 负责人: Meenakshi Arora
• 金额: $ 8.11万
• 依托单位: TEXAS A&M UNIVERSITY
• 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 2021-01-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10098822
• 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; 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.

项目概要 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 在身体里。目前的系统性红斑狼疮治疗方法往往不足，因为它们涉及长期使用非药物 与多种副作用相关的特定类固醇和细胞抑制药物。然而， 尽管不断努力开发更好的疗法，但只有一种新的 FDA 批准的药物 超过 50 年的 SLE 治疗经验。在这种情况下，环孢素（CsA）是一种强大的体液抑制剂 细胞介导的免疫反应可能是一个潜在的候选者，但其作为独立治疗的功效 对于系统性红斑狼疮从未被证实，并且经常被用来类固醇篡改。承认缺失的原因 当前商业 CsA 制剂的成功归因于较差/可变的靶（淋巴）组织 生物利用度因此不同的生物活性和对肾脏的毒性。靶向淋巴组织 组织可能能够合理设计治疗方法来调节免疫系统，这代表了 治疗狼疮的创新方法，因为超过 75% 的免疫细胞位于 GUT 相关淋巴组织 (GALT)。此外，与健康人相比，狼疮患者的 GALT 更大 个人，使其成为有吸引力的目标网站。拟议的研究将产生范式转变、新的 使用独特的周期性功能聚酯（P2s，与商业化不同）的纳米医学领域的知识 PLA/PLGA 是末端功能的），并研究配体密度和组成如何影响 CsA 递送至淋巴组织。这项工作是基于之前的发现，其中高效的淋巴管 CD71（转铁蛋白受体 1，TfR-1）特异性的系统靶向纳米颗粒-CsA（称为 P2Ns-GA-CsA） 淋巴细胞（T 细胞和 B 细胞）的表现优于无配体对照和商业 CsA 产品，导致 更好的治疗效果。在这个项目中，通过研究如何 间隔分子的空间大小和组成影响肠道-受体相互作用和转运 纳米颗粒有助于定制剂量方案。该项目包括以下三个目标， 目标#1，在小鼠狼疮和 TfR KO 模型中建立 P2Ns-GA-CsA 的结构-活性关系。 目标#2，确定小鼠狼疮模型中 P2Ns-GA-CsA 的治疗剂量；目标#3，确定 使用最有效的 P2Ns-GA-CsA 的小鼠狼疮模型的存活率。