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进展，但类风湿关节炎仍然代表着未满足的医疗需求。因此，迫切需要开发和测试新的生物相容性，长效和安全的生物反应调节剂。为此，本探索性/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归归类风湿性关节炎损伤关节。我们的方法利用VIP的生物物理特性与生物相容性和可生物降解的磷脂纳米颗粒（平均尺寸，约17圈）自结合，该纳米颗粒由二硬脂酰磷脂酰乙醇胺-聚乙二醇(PEG; Mr, 2000 （DSPE-PEG2000）组成，形成空间稳定的胶束。这些相互作用导致VIP分子的构象从水溶液中的主要随机线圈转变为α -螺旋，在胶束存在的情况下，α -螺旋是配体-受体相互作用的首选和最稳定的构象。这一过程可以防止VIP在生物液体中降解和失活，并延长其循环时间，因为接枝在胶束表面的PEG分子赋予空间位阻，从而避免被网状内皮系统摄取。因此，与不稳定VIP单体的类似标称剂量相比，达到预期生物效应所需的VIP剂量明显减少，不良事件也明显减少。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的渗漏微循环中渗出，进入间隙，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。这种主动靶向过程被微血管内皮细胞管腔侧VIP受体的缺失放大。总的来说，这些特性表明胶束VIP可能代表一种新的、生物相容性的、长效的、安全的靶向类风湿性关节炎药物。本研究的目的是确定静脉注射或皮下注射低剂量胶束VIP是否能在不影响全身动脉压的情况下减轻小鼠胶原诱导的关节炎。本研究的基本原理是低剂量胶束VIP积极靶向损伤关节，在胶原诱导的关节炎小鼠损伤关节中下调某些关键的组织损伤促进细胞因子和基质蛋白酶，同时上调某些关键的组织修复促进细胞因子，这些细胞是由活化的效应细胞产生的。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VIP胶束体内给药配方；2)确定静脉注射或皮下注射胶束VIP治疗小鼠胶原性关节炎的疗效和安全性；3)确定静脉注射或皮下注射胶束VIP对胶原性关节炎小鼠组织损伤和修复循环生物标志物的影响；4)测定125I-VIP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提供原理证明，并为胶束VIP作为一种新型、安全、长效和有效的类风湿性关节炎疾病改善药物进行测试奠定基础。