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。

• 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
• 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

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.

摘要 类风湿性关节炎（RA）是一种常见的自身免疫性疾病，可导致毁灭性的关节破坏 以及全身性和局限性骨质疏松症。一般来说，没有治愈类风湿关节炎，虽然各种药物可以 减少炎症和关节破坏，包括氯喹（CQ）和羟氯喹（HCQ）。许多 抗RA药物具有严重的副作用，例如CQ可导致肾毒性和失明， 1%的患者。HCQ的毒性略低，因此，它取代CQ用于治疗 在美国和欧洲，很多年前。我们最近报道，CQ，而不是HCQ， 在绝经后骨质疏松症和甲状旁腺功能亢进的小鼠模型中的骨吸收和骨质疏松。一个 最小化用于治疗骨疾病的药物的副作用的有吸引力的策略是以一种形式施用它们， 让它们啃食这可以使药物以降低副作用风险的剂量给予患者 效果，同时也提供了有效的浓度，特别是骨。基于高的骨亲和力， 目前用于骨质疏松症的双磷酸盐（BPs），我们已经产生了骨靶向CQ （BTCQ）类似物，使用与骨强烈结合但不抑制骨吸收的BP，我们将其连接到 CQ通过可降解氨基甲酸酯连接体化学。我们已经证实BTCQ对骨具有高亲和力 在比CQ低3-10倍的浓度下高效抑制破骨细胞形成和骨吸收 体外在小鼠体内，它也能抑制PTH诱导的骨吸收，浓度显著低于 呼叫呼叫我们现在计划：1）扩大现有的合成路线，优化纯化方法，制备 足够量的BTCQ用于检查其在RA动物模型中的体内功效，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制 BTCQ的PK和潜在的释放的CQ的近似值; 2）检查这些新化合物的功效， BTCQ缀合物在TNF转基因小鼠中预防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开发一种新的治疗RA患者的方法 以及后来其他类型的骨靶向药物的产生，包括化疗药物和抗生素， 使用这种新的结合技术。