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）是一种慢性全身炎症性疾病，会导致关节破坏。目前，RA 尚无治愈方法。现有的抗风湿药物表现出不同的治疗效果，并且经常与显着的毒性相关，这可能是由于它们的全身分布和缺乏对关节炎关节的组织特异性所致。为了克服这些问题，我们建议开发一种新型水溶性聚合物递送系统，该系统将选择性地在多个炎症关节部位递送和释放药物。这种递送系统将提供优异的治疗功效并大大减少副作用。一种强效糖皮质激素地塞米松 (Dex) 将用作本研究的模型药物。血管生成、血管通透性增加（脉管系统渗漏）、白细胞浸润和滑膜内层增生将促进 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至关节炎关节。 Dex 在关节炎关节组织中的组织特异性释放是通过 pH 敏感的腙键将 Dex 与 HPMA 共聚物载体结合来实现的，该键可以在关节炎关节组织（酸中毒）和酸性溶酶体区室中的酸性条件下特异性裂解滑膜组织细胞。在拟议的实验中，我们将评估各种因素（例如疾病的严重程度、聚合物药物缀合物的理化特征以及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。优化缀合物设计后，将测试递送系统的全部治疗潜力。然后将确定输送系统的详细安全概况。外行语言：这种新型聚合物药物递送系统可以选择性地将地塞米松递送至类风湿性关节炎患者的多个炎症关节。它可以进一步适应其他抗风湿药物，以实现炎症关节特异性。最终，这种新型输送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功效和安全性。

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