Micellar VIP Nanoparticles for Rheumatoid Arthritis

胶束 VIP 纳米颗粒治疗类风湿关节炎

• 批准号: 6931961
• 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/6931961
• 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）：尽管治疗疗法最近取得了显着进步，但类风湿关节炎仍然代表了未满足的医疗需求。因此，迫切需要为患有这种疾病的患者开发和测试新的生物相容性，长效和安全的生物反应修饰剂。为此，该探索性/发展研究项目的重点是确定我们实验室中开发的创新策略的功效和安全性，该策略包括将低剂量VIP归为类风湿关节炎的受伤关节。 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因此，网状内皮系统的障碍避免吸收，因此，与不稳定的贵宾单体相似的不良剂量相对于不良剂量，实现其预期生物学效应所需的VIP剂量会显着降低。重要的是，含VIP的纳米颗粒的有益作用被放大，因为它们从损伤组织的漏水微循环中有选择性地外出向间质空间进行渗出，并随后与这些组织中免疫和炎性效应细胞表面过表达过表达的VIP受体结合。微血管内皮细胞的腔侧没有VIP受体，可以放大这种主动靶向过程。在总体上，这些属性表明胶束VIP可以代表一种新型，生物相容性，长效和安全的靶向靶向疾病改良药物，用于类风湿关节炎患者。本研究的目的是确定低剂量胶束胶束vip的静脉内或皮下给药是否减轻了胶原蛋白诱导的小鼠关节炎而不会影响全身动脉压。该提案的基本原则是，低剂量的胶束VIP被积极地针对受伤的关节，在该关节下，它下调了某些关键组织损伤的细胞因子和基质蛋白酶，同时上调某些关键的组织修复细胞因子，从而通过受伤的关节被激活效应细胞阐明的细胞在受伤的关节中，由受伤的关节与粘液collagen-inthistis collagen-inthistis collagen-intytis collagen-intytistity进行。反过来，这将使免疫和炎症级联反应的平衡转移到组织修复上。具体目的是：1）优化用于体内给药的胶束VIP的配方； 2）确定患有胶原蛋白诱导的关节炎的小鼠静脉或皮下胶束VIP的功效和安全性； 3）确定静脉或皮下胶束VIP对胶原蛋白诱导的关节炎的小鼠组织损伤和修复的循环生物标志物的影响； 4）确定具有胶原蛋白诱导的关节炎的小鼠中静脉或皮下胶束125-VIP的药代动力学和生物分布。拟议的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，长效和有效的疾病修饰药物的阶段奠定了基础。