Micellar VIP Nanoparticles for Rheumatoid Arthritis
胶束 VIP 纳米颗粒治疗类风湿关节炎
基本信息
- 批准号:6794264
- 负责人:
- 金额:$ 27.82万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:antiarthritic agentbiological response modifiersbiomaterial development /preparationbiotechnologydisease /disorder modeldrug delivery systemsdrug design /synthesis /productiondrug screening /evaluationinterleukin 1interleukin 10interleukin 4intravenous administrationiodinelaboratory mousemetalloendopeptidasesmicellespharmacokineticsphospholipidsradiotracerrheumatoid arthritissubcutaneous drug administrationtumor necrosis factor alphavasoactive intestinal peptide
项目摘要
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,由于不良事件,相对于不稳定的贵宾单体,由于不良剂量的差异,由于不良剂量的差异,由于不良剂量的差异,因此,由于不稳定的nanoperation sublying drompluity yoursirtions youse y ryaperation thementions y themanter son to缩小了网状内皮系统的吸收。间质空间并随后与这些活跃靶向过程中的免疫和炎症效应细胞表面过表达。类风湿关节炎。该研究的目的是确定低剂量的胶束或皮下摄入的胶束vip会导致胶原蛋白诱导的小鼠关节炎,而无需影响全身性动脉压力的基本宗旨。在胶原蛋白诱导的关节炎的小鼠关节中阐述了某些关键组织修复的细胞因子,反过来。 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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Israel Rubinstein其他文献
Israel Rubinstein的其他文献
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{{ truncateString('Israel Rubinstein', 18)}}的其他基金
LAMb Request for Edstrom PULSE Environmental Monitoring System for Veterinary Medical Unit
LAMb 请求为兽医医疗单位提供 Edstrom PULSE 环境监测系统
- 批准号:
9363532 - 财政年份:2017
- 资助金额:
$ 27.82万 - 项目类别:
Micellar VIP Nanoparticles for Rheumatoid Arthritis
胶束 VIP 纳米颗粒治疗类风湿关节炎
- 批准号:
7076220 - 财政年份:2004
- 资助金额:
$ 27.82万 - 项目类别:
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 - 财政年份:2004
- 资助金额:
$ 27.82万 - 项目类别:
Micellar VIP Nanoparticles for Rheumatoid Arthritis
胶束 VIP 纳米颗粒治疗类风湿关节炎
- 批准号:
7233573 - 财政年份:2004
- 资助金额:
$ 27.82万 - 项目类别:
SMOKELESS TOBACCO--MECHANISMS OF BUCCAL MUCOSA INJURY
无烟烟草——颊粘膜损伤的机制
- 批准号:
2128831 - 财政年份:1994
- 资助金额:
$ 27.82万 - 项目类别:
SMOKELESS TOBACCO--MECHANISMS OF BUCCAL MUCOSA INJURY
无烟烟草——颊粘膜损伤的机制
- 批准号:
2683933 - 财政年份:1994
- 资助金额:
$ 27.82万 - 项目类别:
SMOKELESS TOBACCO--MECHANISMS OF BUCCAL MUCOSA INJURY
无烟烟草——颊粘膜损伤的机制
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2128832 - 财政年份:1994
- 资助金额:
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Micellar VIP Nanoparticles for Rheumatoid Arthritis
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