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

基本信息

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
项目类别：
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

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

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项目摘要

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.

项目摘要全身性红斑狼疮（SLE）是一种令人衰弱的自身免疫性疾病，几乎会影响每个器官在体内。当前对SLE治疗的治疗通常不足，因为它们涉及长期使用非 - 特异性，类固醇和细胞抑制药物与广泛的副作用相关。然而，尽管正在进行开发更好疗法的努力，但只有一种新的，FDA批准的药物对于五十多年来的SLE。在这种情况下，环孢菌素（CSA），两种体液的强大抑制剂细胞介导的免疫反应可能是潜在的候选者，但作为独立治疗的功效因为SLE从未被证明，并且经常用于类固醇篡改。承认缺乏的理由与当前商业CSA公式的成功是由于较差/可变靶（淋巴）组织引起的因此，生物利用度具有不同的生物活性，对肾脏有毒。靶向淋巴组织可能使治疗剂的合理设计能够调节免疫系统，代表由于以下事实，有超过75％的免疫细胞位于肠道相关的淋巴组织（GALT）。此外，与健康相比，狼疮中的galt更大个人，使其成为目标的有吸引力的网站。拟议的研究将产生范式转移，新的使用独特的周期性功能性播种机（P2，与商业不同）末端功能的PLA/PLGA），研究配体密度和成分如何影响 CSA递送到淋巴组织。这项工作是通过以前的发现来实现的，其中高度有效特定于CD71（转铁蛋白受体1，TFR-1）的系统靶向纳米粒子-CSA（称为P2NS-GA-CSA）淋巴样细胞（T和B细胞）的表现优于不含配体的对照和商业CSA产物，导致更好的治疗结果。在该项目中，通过研究如何间隔分子的空间尺寸和组成影响肠受感受器的相互作用和运输纳米颗粒促进定制的剂量调节。该项目包括以下三个目标：目标＃1，以在鼠狼疮和TFR KO模型中建立P2NS-GA-CSA的结构活性关系。目标＃2，以在鼠狼疮模型中定义P2NS-GA-CSA的治疗剂量并建立目标＃3 使用最有效的P2NS-GA-CSA的鼠狼疮模型中的存活率。