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: 7662396
• 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 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7662396
• 关键词: Abbreviations; 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; Control Groups; Data; Daunorubicin; Deposition; Development; Dexamethasone; Dicyclohexylcarbodiimide; Dimethylformamide; Disease; Dose; Drug Delivery Systems; Drug Kinetics; Dual-Energy X-Ray Absorptiometry; 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; Organ; Patients; Pattern; Peripheral; Permeability; Pharmaceutical Preparations; Polyethylene Glycols; Polyglutamic Acid; Polymers; Rattus; Reaction; Research Personnel; Rheumatoid Arthritis; Safety; Serum; Severity of illness; Site; 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; design; digital; fast protein liquid chromatography; improved; in vivo; indexing; methacrylamide; monomer; novel; programs; research study; single photon emission computed tomography; skeletal; skeletal tissue; 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（由申请人提供）：类风湿性关节炎（RA）是一种慢性全身性炎症性疾病，可导致关节破坏。目前还没有治愈RA的方法。现有的抗风湿药物表现出不同的治疗效果，并经常与显着的毒性，这可能是由于他们的全身分布和缺乏组织特异性关节炎关节。为了克服这些问题，我们建议开发一种新的水溶性聚合物递送系统，将选择性地提供和释放药物在多个炎症关节的网站。这种递送系统将提供上级治疗功效和大大减少的副作用。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、增加的血管渗透性（渗漏的脉管系统）、白细胞浸润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-Dex缀合物选择性递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将通过经由pH敏感性腙键将Dex缀合至HPMA共聚物载体来实现，所述PH敏感性腙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区室中发现的酸性条件下特异性裂解。在拟定的实验中，我们将评估各种因素（例如疾病的严重程度、聚合物药物偶联物的理化特性和不同滑膜细胞类型的存在）对递送系统选择性和药物释放曲线的影响。结合物设计优化后，将检测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性特征。外行语言：这种新型的聚合物药物传递系统可以选择性地将地塞米松传递到类风湿关节炎患者的多个炎性关节。它可以进一步适用于其他抗风湿药物，以实现炎症关节特异性。最终，这种新型的输送系统将导致改善治疗类风湿性关节炎和其他炎性关节疾病的疗效和安全性。

项目成果

Early detection and treatment of wear particle-induced inflammation and bone loss in a mouse calvarial osteolysis model using HPMA copolymer conjugates.

• DOI: 10.1021/mp2000555
• 发表时间: 2011-08-01
• 期刊: Molecular pharmaceutics
• 影响因子: 4.9
• 作者: Ren K;Purdue PE;Burton L;Quan LD;Fehringer EV;Thiele GM;Goldring SR;Wang D
• 通讯作者: Wang D

Targeted delivery for musculoskeletal diseases.

肌肉骨骼疾病的靶向给药。

• DOI: 10.1007/s11095-008-9716-y
• 发表时间: 2008
• 期刊: Pharmaceutical research
• 影响因子: 3.7
• 作者: Wang,Dong

The Evaluation of the Therapeutic Efficacy and Side Effects of a Macromolecular Dexamethasone Prodrug in the Collagen-Induced Arthritis Mouse Model.

• DOI: 10.1007/s11095-015-1776-1
• 发表时间: 2016-01
• 期刊: Pharmaceutical research
• 影响因子: 3.7
• 作者: Quan L;Zhang Y;Dusad A;Ren K;Purdue PE;Goldring SR;Wang D
• 通讯作者: Wang D

Development of a macromolecular prodrug for the treatment of inflammatory arthritis: mechanisms involved in arthrotropism and sustained therapeutic efficacy.

• DOI: 10.1186/ar3130
• 发表时间: 2010
• 期刊: Arthritis research & therapy
• 影响因子: 4.9
• 作者: Quan LD;Purdue PE;Liu XM;Boska MD;Lele SM;Thiele GM;Mikuls TR;Dou H;Goldring SR;Wang D
• 通讯作者: Wang D

Syntheses of click PEG-dexamethasone conjugates for the treatment of rheumatoid arthritis.

• DOI: 10.1021/bm100578c
• 发表时间: 2010-10-11
• 期刊: BIOMACROMOLECULES
• 影响因子: 6.2
• 作者: Liu, Xin-Ming;Quan, Ling-dong;Tian, Jun;Laquer, Frederic C.;Ciborowski, Pawel;Wang, Dong
• 通讯作者: Wang, Dong