Bisphosphonate conjugation for bone specific drug targeting.
Bisphosphonate conjugation for bone specific drug targeting.
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DOI：
10.1016/j.bonr.2018.06.007
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发表时间：
2018-12
期刊：
影响因子：
2.5
通讯作者：
Zinnen S
中科院分区：
文献类型：
--
作者：
Farrell KB;Karpeisky A;Thamm DH;Zinnen S
骨骼提供基本功能，是独特的生物化学和专门细胞的场所，但也可能是疾病的场所。骨疾病和瘤形成的治疗在过去存在困难，并且改善药物向骨的递送仍然是实现有效治疗的重要目标。药物靶向策略通过利用骨羟基磷灰石基质所特有的高矿物质浓度以及组织特异性细胞类型来改善药物在骨中的定位。双膦酸盐分子类特异性结合羟基磷灰石并抑制破骨细胞对骨的再吸收，为退行性骨疾病提供直接治疗，并且如新出现的证据所示，为癌症提供直接治疗。这些骨结合分子还提供了通过双膦酸盐缀合将其他药物特异性递送至骨的机会。双膦酸盐骨靶向治疗已成功治疗骨质疏松症、原发性和转移性骨肿瘤和其他骨疾病，以及改善骨成像。在这篇综述中，我们着重于使用双膦酸盐共轭物与造影剂，并概述双膦酸盐为基础的显像剂，纳米粒子，和其他药物。我们还讨论了连接体设计的潜力和目前的研究进展。正在进行的研究继续扩大骨靶向治疗的可能性，并将其扩展到临床实践中。理想的骨靶向药物治疗疾病并保持正常的骨功能。双膦酸盐对骨矿物质的亲和力是药物骨靶向的理想基础。三个关键要素：（i）药物有效载荷，（ii）双膦酸盐，和（iii）缀合类型决定PK和PD活性。两种有前途的双膦酸盐-缀合物目前正在进行临床肿瘤学试验。需要了解有效载荷、双膦酸盐和缀合物PK/PD指标，以实现该方法的全部潜力。
Bones provide essential functions and are sites of unique biochemistry and specialized cells, but can also be sites of disease. The treatment of bone disorders and neoplasia has presented difficulties in the past, and improved delivery of drugs to bone remains an important goal for achieving effective treatments. Drug targeting strategies have improved drug localization to bone by taking advantage of the high mineral concentration unique to the bone hydroxyapatite matrix, as well as tissue-specific cell types. The bisphosphonate molecule class binds specifically to hydroxyapatite and inhibits osteoclast resorption of bone, providing direct treatment for degenerative bone disorders, and as emerging evidence suggests, cancer. These bone-binding molecules also provide the opportunity to deliver other drugs specifically to bone by bisphosphonate conjugation. Bisphosphonate bone-targeted therapies have been successful in treatment of osteoporosis, primary and metastatic neoplasms of the bone, and other bone disorders, as well as refining bone imaging. In this review, we focus upon the use of bisphosphonate conjugates with antineoplastic agents, and overview bisphosphonate based imaging agents, nanoparticles, and other drugs. We also discuss linker design potential and the current state of bisphosphonate conjugate research progress. Ongoing investigations continue to expand the possibilities for bone-targeted therapeutics and for extending their reach into clinical practice. The ideal bone-targeting drug treats disease and preserves normal bone function. Bisphosphonate affinity for bone mineral is an ideal foundation for specific targeting of drug to the bone. Three critical elements: (i) drug payload, (ii) bisphosphonate, and (iii) type of conjugation determine PK and PD activity. Two promising bisphosphonate-conjugates are currently in clinical oncology trials. Understanding the payload, bisphophonate and conjugate PK/PD metrics is needed to realize the full potential of this approach.