Macromolecular Therapy for Improved Treatment of Rheumatoid Arthritis

描述（由申请人提供）：类风湿关节炎（RA）是一种导致腹泻关节破坏的慢性全身性炎症性疾病。目前，尚无治疗类风湿性关节炎的方法。现有的抗风湿药物表现出不同的治疗效果，并且经常与显著的毒性相关，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。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，该系统将选择性地在多个炎症关节部位递送和释放药物。该给药系统具有优越的治疗效果和大大减少的副作用。一种强效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）、白细胞浸润和滑膜内膜增生将促进N-（2-羟丙基）甲基丙烯酰胺（HPMA）共聚物- dex偶联物对关节炎关节的选择性递送和保留。Dex在关节炎关节组织中的组织特异性释放将通过将Dex偶联到HPMA共聚物载体上，通过ph敏感的腙键来实现，该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被特异性地裂解。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，聚合物药物偶联物的物理化学特性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谱的影响。在优化缀合物设计后，将测试该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。外文：这种新型的高分子给药系统可以选择性地将地塞米松输送到类风湿性关节炎患者的多个炎症关节。可进一步适应其他抗风湿药物，达到炎性关节特异性。最终，这种新型的给药系统将提高类风湿关节炎和其他炎症性关节疾病治疗的有效性和安全性。

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.