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An in vitro assay to measure targeted drug delivery to bone mineral

Jahnke, Wolfgang and Henry, Christelle (2010) An in vitro assay to measure targeted drug delivery to bone mineral. ChemMedChem, 5 (5). pp. 770-776. ISSN 1860-7179


Targeted delivery of drugs to their site of action is a promising strategy to reduce side effects and enhance efficacy, but successful application of this strategy has been scarce. Human bone is a tissue with unique properties due to its high hydroxyapatite mineral content. However, with the exception of bisphosphonates, not even bone mineral has been targeted in a successful clinical application of drugs acting on bone, such as anti-resorptive or bone anabolic agents. Here we present an NMR-based in vitro assay to measure binding affinities of small molecules to hydroxyapatite (HAP) or bone powder. Binding has been shown to be specific and competitive, and the assay can be run in direct binding format or competition mode. A selection of clinical bisphosphonates has been ranked by their binding affinity to hydroxyapatite. 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. Zoledronate lacking the central hydroxyl group binds to hydroxyapatite with 2.3-fold weaker affinity than zoledronate itself. Any small molecule can be analyzed for its binding to hydroxyapatite or bone powder, and the binding of common bone-staining agents such as alizarin and derivatives has been 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.

Item Type: Article
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Additional Information: This is a technology paper that describes the design of a novel bone binding assay. Clinical bisphosphonates exemplify the fact that this assay can give rank orders of compounds according to their bone binding affinity. This assay also supports a strategy to enhance the safety and efficacy of drugs acting on bone, by attaching a bone-affinity tag and thus targeting them to bone. NVP-BIU700, an alizarin analog with bone affinity, is cited as an example for a possible bone-affinity tag.
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Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16


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