Targeted nanodelivery in T1D

T1D 中的靶向纳米递送

基本信息

批准号：
10202270
负责人：
Reza Abdi
金额：
$ 57.09万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
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：
2020-08-06 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10202270
关键词：
Address Alkynes Antibodies Antibody Therapy Antidiabetic Drugs Attenuated Autoantigens Autoimmune Diabetes Autoimmune Process Autoimmunity Avidity Azides Binding Biodistribution CD3 Antigens Chemistry Clinical Clinical Research Coupling Data Dendritic Cells Development Diabetes Mellitus Disease Dose Drug Delivery Systems Drug Kinetics Effector Cell Encapsulated Endothelial Cells Engineering Ensure Epidemic Equilibrium Family Formulation Glycoproteins Goals Health High Endothelial Venule Home environment Human Immune Immunoglobulin M Immunosuppression Immunotherapeutic agent Inbred NOD Mice Inflammation Insulin-Dependent Diabetes Mellitus Lymphatic Maleimides Malignant Neoplasms Methods Monoclonal Antibodies Morbidity - disease rate Nano delivery Nanotechnology Outcome Pancreas Pathway interactions Patients Peripheral Pharmaceutical Preparations Polymers Process Property Public Health Regulatory T-Lymphocyte Research Research Personnel Site Structure Sulfhydryl Compounds Surface T-Lymphocyte Testing Therapeutic Time Tissues Toxic effect Translations Work autoreactive T cell base biodegradable polymer clinical application clinical efficacy collaborative approach density design diabetic effective therapy experience experimental study human data improved innovation insulin dependent diabetes mellitus onset insulitis interest intravenous administration intravenous injection lymph nodes multidisciplinary nanomedicine nanoparticle pre-clinical preclinical study prevent response side effect spatiotemporal targeted delivery targeted treatment trafficking virtual

项目摘要

With no effective therapy to date, the ongoing Type 1 diabetes (T1D) epidemic continues to be a major health problem. While immune therapeutics (ITs) hold great promise for the treatment of T1D, their inadequacy, serious toxicity, side effects, and morbidity have limited research efforts in the lifelong immunosuppression approach. This shortcoming has prompted investigators to search for alternative approaches. Targeted nanomedicine using polymeric nanoparticles (NPs) holds particular promise to enhance the delivery of ITs to treat T1D. This strategy can minimize the undesirable side effects of ITs by delivering them to diseased tissues, where they can undergo sustained release. In this multidisciplinary project, we aim to develop an innovative, targeted nanodelivery method for ITs for T1D. Although progress has been made in developing new formulations, a method of targeted delivery of NPs to specific tissue sites following systemic administration remains to be developed. The priming and activation of autoreactive T cells occurs in the pancreatic lymph nodes (PLNs), where naive T cells enter through lymph node (LN)-restricted vasculature known as high endothelial venules (HEVs) and encounter autoantigens from the pancreas presented by dendritic cells. Activated T cells traffic subsequently to the pancreas, causing insulitis and autoimmune diabetes. Notably, we have found that HEVs are also formed in the pancreas during the onset of diabetes in NOD mice. Our biodegradable polymeric NPs are coated with MECA79 IgM antibody by using maleimide-thiol chemistry (MECA79-MT-NP); MECA79 binds to peripheral node addressin (PNAd), a glycoprotein family expressed only by endothelial cells of the HEV. Here, we demonstrate for the first time the targeted delivery of MECA79-MT-NPs to the PLNs and pancreata of NOD mice following intravenous administration. We also provide human data that supports the clinical applicability of our delivery platform. Active targeted delivery to these sites has never been achieved in T1D. Moreover, our preliminary data shows that encapsulation of the IT anti-CD3 antibody inside our MECA79-MT-NPs results in more effective reversal of autoimmune diabetes in NOD mice than treatment with free anti-CD3. Our main hypothesis is that targeted delivery of anti-CD3 to the pancreatic lymph nodes (PLNs) and pancreata will increase its efficacy and decrease toxicity by reducing systemic dosing significantly. In Aim 1, we will examine and optimize the stability, binding efficacy, and biodistribution of MECA79-conjugated NPs (MECA79-NPs) by utilizing alkyne-azide chemistry to permit the attachment of the pentameric form of MECA79 to the NP (MECA79-AA-NP). In Aim 2, we will assess the clinical efficacy of encapsulating anti-CD3 inside the formulation of MECA79-NP with the optimized properties from Aim 1 in the reversal of autoimmune diabetes in NOD mice as well as elucidate the mechanisms by which our targeted therapy works. In Aim 3, we plan to test the binding capacity to the PLNs and pancreata of human T1D patients of our optimized MECA79-NPs. This multidisciplinary, collaborative approach will lay the groundwork for the introduction of an innovative, targeted delivery method of ITs for T1D.

由于迄今为止尚无有效的治疗方法，持续流行的 1 型糖尿病 (T1D) 仍然是一个主要的健康问题问题。虽然免疫疗法（IT）对于治疗 T1D 具有巨大的希望，但它们的不足之处是，严重的毒性、副作用和发病率限制了终身免疫抑制的研究工作方法。这一缺点促使研究人员寻找替代方法。有针对性使用聚合物纳米粒子 (NP) 的纳米医学特别有望增强 IT 的输送治疗 T1D。该策略可以通过将 IT 提供给患病患者来最大程度地减少其不良副作用组织，在那里它们可以持续释放。在这个多学科项目中，我们的目标是开发一个用于 T1D IT 的创新、有针对性的纳米递送方法。尽管在开发方面已经取得了进展新配方，一种在全身给药后将纳米颗粒靶向递送至特定组织部位的方法管理仍有待发展。自身反应性 T 细胞的启动和激活发生在胰腺淋巴结 (PLN)，幼稚 T 细胞通过淋巴结 (LN) 限制的脉管系统进入此处称为高内皮微静脉 (HEV)，并遇到来自胰腺的自身抗原树突状细胞。激活的 T 细胞随后流入胰腺，引起胰岛炎和自身免疫性疾病糖尿病。值得注意的是，我们发现在糖尿病发作期间，胰腺中也会形成 HEV 诺德小鼠。我们的可生物降解聚合物纳米粒子使用马来酰亚胺硫醇涂有 MECA79 IgM 抗体化学（MECA79-MT-NP）； MECA79 与糖蛋白家族外周节点寻址蛋白 (PNAd) 结合仅由 HEV 的内皮细胞表达。在这里，我们首次展示了有针对性的交付静脉注射后 MECA79-MT-NP 进入 NOD 小鼠的 PLN 和胰腺。我们也提供支持我们的交付平台的临床适用性的人体数据。主动定向投放这些站点在 T1D 中从未实现过。此外，我们的初步数据表明，IT 的封装我们的 MECA79-MT-NP 内的抗 CD3 抗体可更有效地逆转自身免疫性糖尿病 NOD小鼠与用游离抗CD3治疗相比。我们的主要假设是将抗 CD3 靶向递送至胰腺淋巴结（PLN）和胰腺将通过减少全身给药显着。在目标 1 中，我们将检查并优化稳定性、结合功效和 MECA79-共轭纳米粒子（MECA79-NPs）的生物分布利用炔烃-叠氮化物化学来允许 MECA79 的五聚体形式与 NP (MECA79-AA-NP) 的连接。在目标 2 中，我们将评估将抗 CD3 封装在具有优化特性的 MECA79-NP 制剂中的临床疗效目的 1 在 NOD 小鼠中逆转自身免疫性糖尿病，并阐明其机制我们的靶向治疗有效。在目标3中，我们计划测试与人类PLN和胰腺的结合能力我们优化的 MECA79-NP 的 T1D 患者。这种多学科、协作的方法将奠定为引入针对 T1D 的创新型、有针对性的 IT 交付方法奠定了基础。