Near-infrared-labeled tetracycline derivative is an effective marker of bone deposition in mice

Kovar, Joy L.; Xu, Xiuyuan; Draney, Dan; Cupp, Andrea S.; Simpson, Melanie A.; Olive, D. Michael

doi:10.1016/j.ab.2011.05.011

Cited by 50 publications

(47 citation statements)

References 28 publications

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“…These stains were tetracycline (Sigma-Aldrich) (23) and its analog, Bone-Tag 680 RD (Li-Cor) (24), Alizarin Red S (Sigma-Aldrich) (25), and Xylenol Orange (Sigma-Aldrich) (26). Three of these compounds have differing HAP-binding moieties (Fig.…”

Section: Significancementioning

confidence: 99%

Identification of hydroxyapatite spherules provides new insight into subretinal pigment epithelial deposit formation in the aging eye

Thompson

Reffatto

Bundy³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

108

113

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Accumulation of protein- and lipid-containing deposits external to the retinal pigment epithelium (RPE) is common in the aging eye, and has long been viewed as the hallmark of age-related macular degeneration (AMD). The cause for the accumulation and retention of molecules in the sub-RPE space, however, remains an enigma. Here, we present fluorescence microscopy and X-ray diffraction evidence for the formation of small (0.5–20 μm in diameter), hollow, hydroxyapatite (HAP) spherules in Bruch’s membrane in human eyes. These spherules are distinct in form, placement, and staining from the well-known calcification of the elastin layer of the aging Bruch’s membrane. Secondary ion mass spectrometry (SIMS) imaging confirmed the presence of calcium phosphate in the spherules and identified cholesterol enrichment in their core. Using HAP-selective fluorescent dyes, we show that all types of sub-RPE deposits in the macula, as well as in the periphery, contain numerous HAP spherules. Immunohistochemical labeling for proteins characteristic of sub-RPE deposits, such as complement factor H, vitronectin, and amyloid beta, revealed that HAP spherules were coated with these proteins. HAP spherules were also found outside the sub-RPE deposits, ready to bind proteins at the RPE/choroid interface. Based on these results, we propose a novel mechanism for the growth, and possibly even the formation, of sub-RPE deposits, namely, that the deposit growth and formation begin with the deposition of insoluble HAP shells around naturally occurring, cholesterol-containing extracellular lipid droplets at the RPE/choroid interface; proteins and lipids then attach to these shells, initiating or supporting the growth of sub-RPE deposits.

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Section: Significancementioning

confidence: 99%

Identification of hydroxyapatite spherules provides new insight into subretinal pigment epithelial deposit formation in the aging eye

Thompson

Reffatto

Bundy³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

108

113

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“…Targets hydroxyapatite. 46 Cathepsin-K Targets cathepsin-K, which is expressed in active osteoclasts and involved in the breakdown of the bone matrix. 8 BLI OC (hOC promoter) Targets osteocalcin, which is expressed by osteoblasts and involved in tissue mineralization.…”

Section: Molecular Imaging Modalitiesmentioning

confidence: 99%

“…Using the same concept as with the bisphosphonate-based probes, a tetracycline derivative bound to a fluorophore (IRDye 800CW, LI-COR Biosciences) was recently introduced to image sites of bone remodeling in vivo , using an optical imaging approach. 46 What is interesting about these approaches is that all of these probes are excited at different wave lengths (e.g., green or red), Besides the affinity to hydroxyapatite, other approaches have used different bone proteins as the direct target for the molecular probe. Osteocalcin is such a bone matrix protein, which is expressed by osteoblasts, odontoblasts and hypertrophic chondrocytes at the onset of tissue mineralization.…”

Section: Time-lapsed Imaging Of Bone Remodeling Activitymentioning

confidence: 99%

Advances in multimodality molecular imaging of bone structure and function

2012

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The skeleton is important to the body as a source of minerals and blood cells and provides a structural framework for strength, mobility and the protection of organs. Bone diseases and disorders can have deteriorating effects on the skeleton, but the biological processes underlying anatomical changes in bone diseases occurring in vivo are not well understood, mostly due to the lack of appropriate analysis techniques. Therefore, there is ongoing research in the development of novel in vivo imaging techniques and molecular markers that might help to gain more knowledge of these pathological pathways in animal models and patients. This perspective provides an overview of the latest developments in molecular imaging applied to bone. It emphasizes that multimodality imaging, the combination of multiple imaging techniques encompassing different image modalities, enhances the interpretability of data, and is imperative for the understanding of the biological processes and the associated changes in bone structure and function relationships in vivo .

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“…Near-infrared (NIR) fluorescence imaging of bone minerals, as first introduced in 2001, [1] required that a bisphosphonate or other bone targeting ligand [2][3][4] be conjugated covalently to an NIR fluorophore, creating a bifunctional molecule for biomedical imaging. [4] Although preparative scale synthesis, [5] hybrid optical/nuclear agents, [6] and various clinical applications [7,8] of these molecules were subsequently described, the basis chemical strategy remain unaltered.…”

mentioning

confidence: 99%

“…[2,3] We therefore hypothesized that multiple copies of small substituents (ligands), which singly have low affinity for a target tissue, could be incorporated into the polymethine cyanine core (a fluorophore) in such a way as to generate a final molecule with both high affinity targeting and NIR fluorescence (i.e., a targeted contrast agent). [9][10][11] In this study, we explored this hypothesis by using the phosphonate group as the primary modification, and also studied the ability of other substituents, like sulfonates, to modify performance of the final molecules.…”

mentioning

confidence: 99%

Phosphonated Near‐Infrared Fluorophores for Biomedical Imaging of Bone

Hyun¹,

Wada²,

Bao³

et al. 2014

Angewandte Chemie

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The conventional method for creating targeted contrast agents is to conjugate separate targeting and fluorophore domains. A new strategy is based on the incorporation of targeting moieties into the non‐delocalized structure of pentamethine and heptamethine indocyanines. Using the known affinity of phosphonates for bone minerals in a model system, two families of bifunctional molecules that target bone without requiring a traditional bisphosphonate are synthesized. With peak fluorescence emissions at approximately 700 or 800 nm, these molecules can be used for fluorescence‐assisted resection and exploration (FLARE) dual‐channel imaging. Longitudinal FLARE studies in mice demonstrate that phosphonated near‐infrared fluorophores remain stable in bone for over five weeks, and histological analysis confirms their incorporation into the bone matrix. Taken together, a new strategy for creating ultra‐compact, targeted near‐infrared fluorophores for various bioimaging applications is described.

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Near-infrared-labeled tetracycline derivative is an effective marker of bone deposition in mice

Cited by 50 publications

References 28 publications

Identification of hydroxyapatite spherules provides new insight into subretinal pigment epithelial deposit formation in the aging eye

Identification of hydroxyapatite spherules provides new insight into subretinal pigment epithelial deposit formation in the aging eye

Advances in multimodality molecular imaging of bone structure and function

Phosphonated Near‐Infrared Fluorophores for Biomedical Imaging of Bone

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