Fluorescent Bisphosphonate and Carboxyphosphonate Probes: A Versatile Imaging Toolkit for Applications in Bone Biology and Biomedicine

Sun, Shuting; Błażewska, K. M.; Kadina, Anastasia P.; Kashemirov, B. A.; Duan, Xuchen; Triffitt, James T.; Dunford, J E; Russell, R. G. G.; Ebetino, Frank H.; Roelofs, Anke J.; Coxon, Fraser P.; Lundy, Mark W.; McKenna, Charles E.

doi:10.1021/acs.bioconjchem.5b00369

Cited by 49 publications

(53 citation statements)

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“…Data from previous studies showed that fluorescently labeled bisphosphonates, e.g. Zol-AF647, mainly accumulate in bones, which is similar to their unlabeled parent bisphosphonates (Junankar et al, 2015; Roelofs et al, 2012; Sun et al, 2015). However, conjugating AF647 onto Zol affects its physicochemical properties.…”

Section: Resultsmentioning

confidence: 90%

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In vivo distribution of zoledronic acid in a bisphosphonate-metal complex-based nanoparticle formulation synthesized by a reverse microemulsion method

Naguib

Cui

2017

International Journal of Pharmaceutics

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Bisphosphonates are used to treat bone diseases such as osteoporosis and cancer-induced bone pain and fractures. It is thought that modifying the pharmacokinetics and biodistribution profiles of bisphosphonates (i.e. rapid renal clearance and extensive bone absorption) will not only reduce their side effects, but also expand their clinical applications to extraskeletal tissues. In the present work, using zoledronic acid (Zol) and calcium as model bisphosphonate and metal molecules, respectively, we prepared DOPA (an anionic lipid)-coated spherical Zol-Ca nanocomposites (Zol-Ca@DOPA) and developed Zol-nanoparticle formulations (i.e. Zol-Ca@bi-lipid NPs) based on the nanocomposites. The influence of the inputted weight ratio of Zol-Ca@DOPA to DSPE-PEG2k on the properties (e.g. size, size distribution, loading efficiency, encapsulation efficiency, zeta potential, and polydispersity) of Zol-Ca@bi-lipid NPs was investigated, and a type of Zol-Ca@bi-lipid NPs with size around 25 nm was selected for further studies. In a mouse model, the Zol-Ca@bi-lipid NPs significantly reduced the bone distribution of Zol, increased the blood circulating time of Zol, and altered the distribution of Zol in major organs, as compared to free Zol. It is expected that similar nanoparticles prepared with bisphosphonate-metal complexes can be explored to expand the applications to bisphosphonates in extraskeletal tissues.

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Section: Resultsmentioning

confidence: 90%

“…To readily detect Zol, 2% (w/w) of the Zol was the fluorescently labeled Zol-AF647. It has been reported that free bisphosphonates and their relative fluorescently labeled bisphosphonates, including Zol and Zol-AF647, have very similar in vivo distributions (Junankar et al, 2015; Roelofs et al, 2012; Sun et al, 2015). C57BL/6 mice were i.v.…”

Section: Resultsmentioning

confidence: 99%

In vivo distribution of zoledronic acid in a bisphosphonate-metal complex-based nanoparticle formulation synthesized by a reverse microemulsion method

Naguib

Cui

2017

International Journal of Pharmaceutics

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“…Inspection of the bone imaging literature indicates increasing community interest in using fluorescent probes for preclinical studies, 44–46 and there are also ongoing efforts to produce multimodality probes for clinical imaging. 47,48 Furthermore, researchers are beginning to develop bone-targeting systems for drug delivery and bone tissue engineering.…”

Section: Resultsmentioning

confidence: 99%

Pre-Assembly of Near-Infrared Fluorescent Multivalent Molecular Probes for Biological Imaging

et al. 2016

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A programmable pre-assembly method is described and shown to produce near-infrared fluorescent molecular probes with tunable multivalent binding properties. The modular assembly process threads one or two copies of a tetralactam macrocycle onto a fluorescent PEGylated squaraine scaffold containing a complementary number of docking stations. Appended to the macrocycle periphery are multiple copies of a ligand that is known to target a biomarker. The structure and high purity of each threaded complex was determined by independent spectrometric methods and also by gel electrophoresis. Especially helpful were diagnostic red-shift and energy transfer features in the absorption and fluorescence spectra. The threaded complexes were found to be effective multivalent molecular probes for fluorescence microscopy and in vivo fluorescence imaging of living subjects. Two multivalent probes were prepared and tested for targeting of bone in mice. A pre-assembled probe with twelve bone-targeting iminodiacetate ligands produced more bone accumulation than an analogous pre-assembled probe with six iminodiacetate ligands. Notably, there was no loss in probe fluorescence at the bone target site after 24 hours in the living animal, indicating that the pre-assembled fluorescent probe maintained very high mechanical and chemical stability on the skeletal surface. The study shows how this versatile pre-assembly method can be used in a parallel combinatorial manner to produce libraries of near-infrared fluorescent multivalent molecular probes for different types of imaging and diagnostic applications, with incremental structural changes in the number of targeting groups, linker lengths, linker flexibility, and degree of PEGylation.

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“…To determine whether the ZA was internalized by the macrophages, the BMDMs were treated with 10 µM of the fluorescent‐labeled ZA analog 5‐FAM‐ZOL (BV111001; BioVinc, Los Angeles, CA, USA) (30). After treatment for the indicated time, the cells were thrice washed with PBS and fixed for 10 min in 4% paraformaldehyde.…”

Section: Methodsmentioning

confidence: 99%

Zoledronic acid promotes TLR‐4‐mediated M1 macrophage polarization in bisphosphonate‐related osteonecrosis of the jaw

Zhu

et al. 2019

FASEB j.

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Bisphosphonate‐related osteonecrosis of the jaw (BRONJ) is a detrimental side effect of the long‐term administration of bisphosphonates. Although macrophages were reported to be an important mediator of BRONJ, the detailed potential mechanism of BRONJ remains unclear. Here, we reported an elevated TLR‐4 expression in macrophages under action of zoledronic acid (ZA), resulting in enhanced M1 macrophage polarization and decreased M2 macrophage polarization both in vitro and in vivo. After inhibiting the TLR‐4 signaling pathway, the activation of the TLR‐4/NF‐κB signaling pathway and the induction of NF‐κB nuclear translocation and production of proinflammatory cytokines by ZA were suppressed in macrophages, thereby inhibiting M1 macrophage polarization. By utilizing the TLR‐4−/− mice, development of BRONJ was markedly ameliorated, and M1 macrophages were significantly attenuated in the extraction socket tissues in the TLR‐4−/− mice. Importantly, the systemic administration of the TLR‐4 inhibitor TAK‐242 improved the wound healing of the extraction socket and decreased the incidence rate of BRONJ. Taken together, our findings suggest that TLR‐4‐mediated macrophage polarization participates in the pathogenesis of BRONJ in mice, and TLR‐4 may be a potential target for the prevention and therapeutic treatment of BRONJ.—Zhu, W., Xu, R., Du, J., Fu, Y., Li, S., Zhang, P., Liu, L., Jiang, H. Zoledronic acid promotes TLR‐4‐mediated M1 macrophage polarization in bisphosphonate‐related osteonecrosis of the jaw. FASEB J. 33, 5208–5219 (2019). http://www.fasebj.org

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Fluorescent Bisphosphonate and Carboxyphosphonate Probes: A Versatile Imaging Toolkit for Applications in Bone Biology and Biomedicine

Cited by 49 publications

References 50 publications

In vivo distribution of zoledronic acid in a bisphosphonate-metal complex-based nanoparticle formulation synthesized by a reverse microemulsion method

In vivo distribution of zoledronic acid in a bisphosphonate-metal complex-based nanoparticle formulation synthesized by a reverse microemulsion method

Pre-Assembly of Near-Infrared Fluorescent Multivalent Molecular Probes for Biological Imaging

Zoledronic acid promotes TLR‐4‐mediated M1 macrophage polarization in bisphosphonate‐related osteonecrosis of the jaw

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