Development of novel bone-targeted chloroquine conjugates to prevent bone resorption.

开发新型骨靶向氯喹结合物以防止骨吸收。

基本信息

批准号：
9355087
负责人：
ROBERT K BOECKMAN
金额：
$ 20.33万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-22 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9355087
关键词：
Adrenal Cortex Hormones Adverse drug effect Adverse effects Adverse event Affect Affinity American Animal Model Anti-Inflammatory Agents Anti-inflammatory Antibiotics Area Arthralgia Arthritis Autoimmune Diseases Benchmarking Binding Biological Assay Blindness Bone Diseases Bone Resorption Bone Surface Bone necrosis Carbamates Cartilage Chemistry Chloroquine Data Development Disease Disease remission Dose Drug Design Drug Targeting Drug usage Enzyme-Linked Immunosorbent Assay Europe Femoral Fractures Frozen Sections Future Generations Human Hydroxychloroquine Hyperparathyroidism Image In Vitro Indocyanine Green Inflammation Injectable Jaw Joints Kidney Knee joint Label Lead Left Limb structure Link Methodology Methods Methotrexate Modeling Monitor Mus Normal tissue morphology Osteoclasts Osteogenesis Osteoporosis Patients Pharmaceutical Preparations Physicians Physiologic calcification Plasticizers Postmenopausal Osteoporosis Property Reporting Rheumatoid Arthritis Risk Route Safety Second lumbar vertebra Serum Site Synovitis TNF gene Technetium Technology Testing Therapeutic Agents Tissues Toxic effect Transgenic Mice Work Wrist joint Zoledronate analog ankle joint base bisphosphonate bone bone imaging bone loss bone turnover design dosage in vivo in vivo imaging system infrared microscopy inhibitor/antagonist joint destruction microCT mouse model novel novel strategies novel therapeutics prevent scale up success tibia willingness

项目摘要

ABSTRACT Rheumatoid arthritis (RA) is a common autoimmune disease, which can cause devastating joint destruction and generalized and localized osteoporosis. Generally, there is no cure for RA, although a variety of drugs can reduce inflammation and joint destruction, including chloroquine (CQ) and hydroxychloroquine (HCQ). Many anti-RA drugs have severe side effects, for example CQ can result in renal toxicity and blindness in up to 0.5- 1% of patients. HCQ has a slightly lower toxicity profile and for this reason it replaced CQ for the treatment of RA in the US and Europe many years ago. We reported recently that CQ, but not HCQ, prevents bone resorption and osteoporosis in mouse models of postmenopausal osteoporosis and hyperparathyroidism. An attractive strategy to minimize side effects of drugs used to treat bone diseases is to administer them in a form that targets them to bone. This could allow drugs to be given to patients at doses with reduced risk of side effects, while also delivering effective concentrations specifically to bone. Based on the high bone affinity of bisphosphonates (BPs) that are currently used to osteoporosis, we have generated a Bone-Targeted CQ (BTCQ) analog using a BP that binds avidly to bone, but does not inhibit bone resorption, which we attached to CQ through degradable carbamate linker chemistry. We have confirmed that BTCQ has high affinity for bone and high potency to inhibit osteoclast formation and bone resorption at 3-10-fold lower concentrations than CQ in vitro. It also inhibited PTH-induced bone resorption in vivo in mice at significantly lower concentrations than CQ. We now plan to: 1) Scale up the existing synthetic route, optimize purification methods to prepare sufficient quantities of BTCQ for examination of its in vivo efficacy in an animal model of RA and test the distribution and cellular localization of fluorescently-labeled bisphosphonates in vivo as an early mechanistic approximation of the PK of BTCQ and potentially of the released CQ; 2) Examine the efficacy of these novel BTCQ conjugates to prevent the development of joint inflammation and destruction in a TNF transgenic mouse model of RA. Success with these studies could then lead to the development of a novel therapy for RA patients and later to the generation of other types of bone-targeted drugs, including chemotherapeutics and antibiotics, using this new conjugation technology.

抽象的类风湿关节炎（RA）是一种常见的自身免疫性疾病，可能造成毁灭性的关节破坏以及广义和局部骨质疏松症。通常，尽管有多种药物可以减少炎症和关节破坏，包括氯喹（CQ）和羟基氯喹（HCQ）。许多抗RA药物具有严重的副作用，例如，CQ可导致肾脏毒性和失明，最高为0.5-- 1％的患者。 HCQ的毒性特征略低，因此，它取代了CQ 多年前在美国和欧洲的RA。我们最近报道了CQ（而不是HCQ）阻止骨头绝经后骨质疏松和甲状旁腺功能亢进的小鼠模型中的吸收和骨质疏松症。一个最大程度地减少用于治疗骨骼疾病的药物的副作用的有吸引力的策略是以一种形式进行治疗这将它们针对骨头。这可以允许药物以剂量降低的剂量给患者提供效果，同时也将有效浓度专门提供给骨骼。基于高骨亲和力当前用于骨质疏松症的双膦酸盐（BPS），我们已经产生了骨靶向的CQ （BTCQ）模拟使用BP与骨相关但不抑制骨吸收的BP，我们将其附加到 CQ通过可降解的氨基甲酸酯接头化学。我们已经确认BTCQ对骨骼具有高亲和力与CQ相比，抑制破骨细胞的形成和骨吸收的高效力高3-10倍体外。它还抑制了小鼠的PTH诱导的小鼠体内骨吸收的浓度明显低于 CQ。现在，我们计划：1）扩展现有的合成路线，优化纯化方法以准备足够数量的BTCQ在RA动物模型中检查其体内功效，并测试荧光标记的双膦酸盐在体内的分布和细胞定位作为早期机械 BTCQ PK的近似以及释放的CQ的可能性； 2）检查这些小说的功效 BTCQ偶联以防止TNF转基因小鼠的关节炎症和破坏的发展 RA模型。这些研究的成功可能会导致为RA患者开发新的疗法后来又产生了其他类型的骨靶向药物，包括化学疗法和抗生素，使用这种新的共轭技术。