Novartis Institutes for Biomedical Research, Center for Proteomic Chemistry, Basel, Switzerland.
ChemMedChem. 2010 May 3;5(5):770-6. doi: 10.1002/cmdc.201000016.
Targeted delivery of drugs to their site of action is a promising strategy to decrease adverse effects and enhance efficacy, but successful applications of this strategy have been scarce. Human bone is a tissue with unique properties due to its high hydroxyapatite mineral content. However, with the exception of bisphosphonates, bone mineral has not been targeted in a successful clinical application of drugs that act on bone, such as anti-resorptive or bone anabolic agents. Herein we present an NMR-based in vitro assay to measure binding affinities of small molecules to hydroxyapatite (HAP) or bone powder. Binding was shown to be specific and competitive, and the assay can be carried out in a direct binding format or in competition mode. A selection of clinically relevant bisphosphonates was ranked by their binding affinity for HAP. The binding affinity decreases in the order: pamidronate > alendronate > zoledronate > risedronate > ibandronate. The differences in binding affinities span a factor of 2.1 between pamidronate and ibandronate, consistent with previous studies. The rank order is very similar with bone powder, although the binding capacity of bone powder is smaller and binding kinetics are slower. A zoledronate derivative that lacks the central hydroxy group binds to HAP with 2.3-fold weaker affinity than zoledronate itself. Any small molecule can be analyzed for its binding to HAP or bone powder, and the binding of common bone-staining agents such as alizarin and its derivatives was confirmed in the new assay. This assay supports a strategy for targeted delivery of drugs to bone by attaching a bone-affinity tag to the active drug substance.
将药物靶向递送到其作用部位是减少不良反应和提高疗效的一种很有前途的策略，但这种策略的成功应用却很少。人骨由于其高羟基磷灰石矿物质含量而具有独特的特性。然而，除了双膦酸盐之外，在作用于骨骼的药物（如抗吸收或骨合成药物）的成功临床应用中，骨矿物质并没有被靶向。本文介绍了一种基于 NMR 的体外测定法，用于测量小分子与羟基磷灰石（HAP）或骨粉的结合亲和力。研究表明，结合是特异性和竞争性的，并且可以在直接结合格式或竞争模式下进行测定。选择了一些具有临床相关性的双膦酸盐，根据它们与 HAP 的结合亲和力进行排序。结合亲和力的顺序为：帕米膦酸盐>阿仑膦酸盐>唑来膦酸盐>利塞膦酸盐>伊班膦酸盐。帕米膦酸盐和伊班膦酸盐之间的结合亲和力差异为 2.1 倍，与之前的研究一致。与骨粉相比，这种排序非常相似，尽管骨粉的结合容量较小，结合动力学较慢。缺乏中心羟基的唑来膦酸盐衍生物与 HAP 的结合亲和力比唑来膦酸盐本身弱 2.3 倍。任何小分子都可以分析其与 HAP 或骨粉的结合，并且在新测定中证实了常见的骨染色剂如茜素及其衍生物的结合。该测定支持通过将骨亲和力标签连接到活性药物物质上来实现药物靶向递送到骨骼的策略。
