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，但类风湿性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，用于这种疾病的患者。为此，该探索性/开发研究项目的重点是确定我们实验室开发的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的固有生物物理性质与生物相容性和生物可降解的磷脂纳米颗粒（平均尺寸，约17 μ m）自缔合，所述磷脂纳米颗粒由形成空间稳定胶束的二硬脂酰磷脂酰乙醇胺-聚（乙二醇）（PEG; Mr，2000（DSPE-PEG 2000））组成。这些相互作用导致VIP分子在胶束存在下从水溶液中的主要无规卷曲构象转变为α-螺旋，这是配体-受体相互作用的优选和最稳定的构象。该过程保护VIP免于在生物流体中降解和失活，并延长其循环时间，因为接枝在胶束表面上的PEG分子赋予空间位阻，从而避免网状内皮系统的摄取。因此，相对于不稳定VIP单体的类似标称剂量，实现其预期生物学效应所需的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渗出到间质空间中，随后结合到这些组织中免疫和炎症效应细胞表面上过表达的VIP受体。这种主动靶向过程由于微血管内皮细胞的管腔侧上不存在VIP受体而放大。总的来说，这些属性表明，胶束VIP可以代表一种新的，生物相容性，长效和安全的靶向疾病改善类风湿关节炎患者的药物。本研究的目的是确定静脉或皮下注射低剂量胶束VIP是否减轻小鼠胶原诱导的关节炎而不影响全身动脉压。该提议的基本原则是低剂量胶束VIP主动靶向损伤关节，在损伤关节中其下调某些关键组织损伤促进细胞因子和基质蛋白酶，同时上调由患有胶原诱导的关节炎的小鼠的损伤关节中的活化效应细胞产生的某些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。具体目标是：1）优化胶束VIP的体内给药处方; 2）确定静脉或皮下注射胶束VIP对胶原诱导的关节炎小鼠的有效性和安全性; 3）确定静脉或皮下注射胶束VIP对胶原诱导的关节炎小鼠组织损伤和修复的循环生物标志物的影响;（4）测定~（125）I-VIP胶束静脉注射或皮下注射在胶原诱导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，并为测试胶束VIP作为类风湿关节炎患者的新型、安全、长效和有效的疾病改善药物奠定基础。