Macromolecular Therapy for Improved Treatment of Rheumatoid Arthritis

改善类风湿关节炎治疗的大分子疗法

• 批准号: 7456456
• 负责人: Dong Wang
• 金额: $ 22.29万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7456456
• 关键词: Abbreviations; Acetic Acid; Acetic Acids; Acidosis; Acids; Adjuvant Arthritis; Adrenal Glands; Adverse effects; Amides; Amines; Animals; Antirheumatic Agents; Arsanilic Acid; Arthritis; Biodistribution; Biological Markers; Body Weight; Bone Density; Buffers; Characteristics; Chronic; Cleaved cell; Complex; Condition; Control Groups; Data; Daunorubicin; Deposition; Development; Dexamethasone; Dicyclohexylcarbodiimide; Dimethylformamide; Disease; Dose; Drug Delivery Systems; Drug Kinetics; Dual-Energy X-Ray Absorptiometry; End Point; Esters; Evans blue stain; Exhibits; Fluorescein; Fluorescein-5-isothiocyanate; Fluoresceins; Glucocorticoids; Goals; Histologic; Hydrazones; Hydrochloride Salt; Hyperplasia; Image; Incubated; Infiltration; Inflammation; Inflammatory; Isothiocyanates; Joints; Label; Language; Lead; Leukocytes; Liver; Magnetic Resonance Imaging; Microradiography; Modeling; Molecular Weight; Monitor; N-(2-hydroxypropyl)methacrylamide; Object Attachment; Organ; Patients; Pattern; Peripheral; Permeability; Pharmaceutical Preparations; Polyethylene Glycols; Polyglutamic Acid; Polymers; Rattus; Reaction; Research Personnel; Rheumatoid Arthritis; Safety; Serum; Severity of illness; Site; Skeletal system; Specificity; Spleen; Staging; Structure; Synovial Cell; System; Testing; Therapeutic; Thymus Gland; Tissues; Toxic effect; Treatment Efficacy; Treatment Protocols; Trifluoroacetic Acid; Trinitrobenzenesulfonic Acid; Tyrosine; Vascular Permeabilities; Water; X-Ray Computed Tomography; angiogenesis; arthropathies; azobis(isobutyronitrile); base; bone metabolism; cell type; copolymer; cytokine; day; design; digital; fast protein liquid chromatography; hydroxypropyl methacrylate; improved; in vivo; indexing; methacrylamide; monomer; novel; programs; research study; single photon emission computed tomography; size; soft tissue; trafficking

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease that leads to the destruction of diarthrodial joints. Currently, there is no cure for RA. Available antirheumatic drugs exhibit variable therapeutic efficacy and are frequently associated with significant toxicities that may be due to their systemic distribution and lack of tissue-specificity to arthritic joints. To overcome these problems, we propose to develop a novel water-soluble polymeric delivery system that will selectively deliver and release drugs at the sites of multiple inflammatory joints. Such delivery system would provide superior therapeutic efficacy and greatly reduced side effects. A potent glucocorticoid, dexamethasone (Dex), will be used as the model drug in this study. Angiogenesis, increased vascular permeability (leaky vasculature), leukocytes infiltration and synovial lining hyperplasia will facilitate the selective delivery and retention of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-Dex conjugate to arthritic joints. The tissue-specific release of Dex in arthritic joint tissues will be achieved by conjugating Dex to HPMA copolymer carrier via a pH-sensitive hydrazone bond that can be specifically cleaved under the acidic conditions found in arthritis joint tissues (acidosis) and in acidic lysosomal compartments of cells of synovial tissues. In the proposed experiments, we will evaluate the influence of various factors (e.g. severity of the disease, physicochemical characteristics of the polymer drug conjugate and the presence of different synovial cell types) on delivery system selectivity and drug release profiles. The full therapeutic potential of the delivery system will be tested after optimization of the conjugate design. A detailed safety profile of the delivery system will then be determined. Lay language: This novel polymeric drug delivery system can selectively deliver dexamethasone to multiple inflammatory joints of rheumatoid arthritis patients. It could be further adapted to other anti-rheumatic drugs to achieve inflammatory joint specificity. Eventually, this novel delivery system would lead to improved efficacy and safety profiles for treatment of rheumatoid arthritis and other inflammatory joint disorders.

描述(申请人提供)：类风湿性关节炎(RA)是一种慢性全身性炎症性疾病，导致腹泻关节的破坏。目前，类风湿性关节炎还没有治愈方法。现有的抗风湿药物表现出不同的治疗效果，并经常与显著的毒性相关，这可能是由于它们的全身分布和对关节炎关节缺乏组织特异性。为了克服这些问题，我们建议开发一种新型的水溶性聚合物递送系统，它将在多个炎症关节处选择性地递送和释放药物。这样的给药系统将提供更好的治疗效果，并大大减少副作用。一种有效的糖皮质激素，地塞米松(Dex)，将被用作本研究的模型药物。血管生成、血管通透性增加(血管渗漏)、白细胞渗透和滑膜衬里增生将促进N-(2-羟丙基)甲基丙烯酰胺(HPMA)共聚物-地塞米松(HPMA)结合物选择性地输送和保留到关节炎关节。Dex在关节炎关节组织中的组织特异性释放是通过将Dex连接到HPMA共聚载体上来实现的，该载体通过一种对pH敏感的糖苷键进行连接，这种键可以在关节炎关节组织(酸中毒)和滑膜组织细胞的酸性溶酶体室中发现的酸性条件下被特异性切割。在拟议的实验中，我们将评估各种因素(例如疾病的严重性、聚合物药物结合物的物理化学特性以及不同类型滑膜细胞的存在)对给药系统选择性和药物释放情况的影响。在优化了偶联设计后，将测试该输送系统的全部治疗潜力。然后将确定输送系统的详细安全配置文件。外在语言：这种新型的聚合物药物释放系统可以选择性地将地塞米松释放到类风湿关节炎患者的多个炎性关节。它可以进一步与其他抗风湿药物相适应，实现炎症关节的特异性。最终，这种新的给药系统将提高治疗类风湿性关节炎和其他炎症性关节疾病的有效性和安全性。