Micellar VIP Nanoparticles for Rheumatoid Arthritis

胶束 VIP 纳米颗粒治疗类风湿关节炎

• 批准号: 6794264
• 负责人: Israel Rubinstein
• 金额: $ 27.82万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-15 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6794264
• 关键词: antiarthritic agent; biological response modifiers; biomaterial development /preparation; biotechnology; disease /disorder model; drug delivery systems; drug design /synthesis /production; drug screening /evaluation; interleukin 1; interleukin 10; interleukin 4; intravenous administration; iodine; laboratory mouse; metalloendopeptidases; micelles; pharmacokinetics; phospholipids; radiotracer; rheumatoid arthritis; subcutaneous drug administration; tumor necrosis factor alpha; vasoactive intestinal peptide

DESCRIPTION (provided by applicant): Despite remarkable recent advances in therapeutics, rheumatoid arthritis still represents an unmet medical need. Hence, there is an urgent need to develop and test new biocompatible, long-acting and safe biological response modifiers for patients with this condition. To this end, the focus of this exploratory/development research project is on determining the efficacy and safety of an innovative strategy developed in our laboratory consisting of homing low dose VIP to injured joints in rheumatoid arthritis. Our approach exploits the endowed biophysical properties of VIP to self-associate with biocompatible and biodegradable phospholipid nanoparticles (average size, approximately 17 rim) composed of distearoylphosphatidylethanolamine- poly-(ethylene)glycol (PEG; Mr, 2000 (DSPE-PEG2000) that form sterically stabilized micelles. These interactions lead to conformational transition of the VIP molecule from a predominantly random coil in aqueous solution to alpha-helix, the preferred and most stable conformation for ligand-receptor interactions, in the presence of micelles. This process protects VIP from degradation and inactivation in biological fluids and prolongs its circulation time because the PEG molecules grafted on the surface of micelles confer steric hindrance thereby evading uptake by the reticuloendothelial system. Consequently, the dose of VIP required to achieve its intended biological effect is reduced appreciably as are adverse events relative to a similar nominal dose of the unstable VIP monomers. Importantly, the salutary effects of VIP-containing nanoparticles are amplified because they selectively extravasate from the leaky microcirculation of injured tissues into the interstitial space and subsequently bind to VIP receptors overexpressed on the surface of immune and inflammatory effectors cells in these tissues. This active targeting process is amplified by the absence of VIP receptors on the luminal side of microvascular endothelial cells. On aggregate, these attributes indicate that micellar VIP could represent a novel, biocompatible, long-acting and safe targeted disease-modifying drug for patients with rheumatoid arthritis. The purpose this study is to determine whether intravenous or subcutaneous administration of low dose micellar VIP abates collagen-induced arthritis in mice without affecting systemic arterial pressure. The basic tenet of this proposal is that low dose micellar VIP is actively targeted to injured joints where it downregulates certain key tissue injury-promoting cytokines and matrix proteinases while up-regulating certain key tissue repair-promoting cytokines elaborated by activated effector cells in injured joints of mice with collagen-induced arthritis. This, in turn, will shift the balance of the immune and inflammatory cascades toward tissue repair. The specific aims are: 1) Optimize the formulation of micellar VIP for in vivo administration; 2) Determine the efficacy and safety of intravenous or subcutaneous micellar VIP in mice with collagen-induced arthritis; 3) Determine the effects of intravenous or subcutaneous micellar VIP on circulating biomarkers of tissue injury and repair in mice with collagen-induced arthritis; and 4) Determine the pharmacokinetics and biodistribution of intravenous or subcutaneous micellar 125I-VIP in mice with collagen-induced arthritis. The anticipated results of the proposed studies will provide proof of principle and set the stage for testing micellar VIP as a novel, safe, long-acting and efficacious disease modifying drug in patients with rheumatoid arthritis.

描述(由申请人提供)：尽管最近在治疗方面取得了显著的进步，但类风湿性关节炎仍然是一个未得到满足的医疗需求。因此，迫切需要开发和测试新的生物相容、长效和安全的生物反应调节剂来治疗这种疾病。为此，这一探索性/开发性研究项目的重点是确定我们实验室开发的一种创新策略的有效性和安全性，该策略包括将低剂量VIP归巢到类风湿性关节炎的受损关节。我们的方法利用VIP被赋予的生物物理性质来与生物相容和可生物降解的磷脂纳米颗粒(平均尺寸约为17个边)相结合，该纳米颗粒由二硬脂酰磷脂酰磷脂酰乙醇胺-聚乙二醇酯(PEG；MR，2000)组成，形成空间稳定的胶束。这些相互作用导致VIP分子从水溶液中以随机卷曲为主的构象转变为α-螺旋，在胶束存在下，α-螺旋是配体-受体相互作用的首选和最稳定的构象。这一过程保护了VIP在生物液中不被降解和失活，并延长了其循环时间，因为嫁接在胶束表面的聚乙二醇分子提供了空间位阻，从而避免了网状内皮系统的摄取。因此，与不稳定VIP单体的类似标称剂量相比，实现其预期生物效应所需的VIP剂量显著减少，不良反应也明显减少。重要的是，含有VIP的纳米颗粒的有益作用被放大，因为它们选择性地从受损组织渗漏的微循环进入间质空间，随后与这些组织中免疫和炎症效应细胞表面过度表达的VIP受体结合。这种主动的靶向过程被微血管内皮细胞管腔一侧VIP受体的缺失所放大。总体而言，这些属性表明胶束VIP可能代表着一种新型的、生物相容的、长效的、安全的、针对类风湿关节炎患者的靶向疾病修改药物。本研究的目的是确定静脉或皮下注射小剂量胶束VIP是否在不影响体动脉压的情况下减轻胶原蛋白诱导的小鼠关节炎。这一建议的基本原则是，低剂量胶束VIP主动靶向于损伤关节，在胶原性关节炎小鼠损伤关节中，它下调某些关键的组织损伤促进细胞因子和基质蛋白酶，而上调某些由激活的效应细胞所阐述的关键组织修复促进细胞因子。反过来，这将使免疫和炎症级联反应的平衡转向组织修复。具体目的是：1)优化胶束VIP体内给药的处方；2)测定静脉或皮下胶束VIP对胶原性关节炎小鼠的疗效和安全性；3)测定静脉或皮下胶束VIP对胶原性关节炎小鼠组织损伤和修复的循环生物标志物的影响；以及4)测定125I-VIP静脉或皮下胶束在胶原性关节炎小鼠体内的药代动力学和生物分布。拟议研究的预期结果将为测试胶束VIP作为一种新的、安全、长效和有效的类风湿性关节炎患者疾病改良药提供原理证据并奠定基础。