Bisphosphonate-modified biomaterials for drug delivery and bone tissue engineering

Ossipov, Dmitri

doi:10.1517/17425247.2015.1021679

Cited by 66 publications

(53 citation statements)

References 80 publications

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“…49–53 Most of these studies employ bisphosphonates as the bone-targeting ligands. 54,55 While bisphosphonates have very high bone affinity, they also have potent pharmaceutical activities that can potentially disturb the physiological processes they are supposed to target. 49 More benign types of bone-targeting ligands are receiving increased attention, 56–60 and a probe design based on multiple iminodiacetate groups is a promising new paradigm.…”

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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Section: Resultsmentioning

confidence: 99%

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

et al. 2016

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“…A particularly popular application of HAp is as a drug carrier 6 to deliver drugs such as bisphosphonates 7 , antibiotics 8 and other antimicrobial agents 9,10 , anticancer chemotherapeutics 11,12 , et cetera . HAp also possesses a rare form of stoichiometric flexibility, given that its crystal structure can maintain the characteristic P6 3/m symmetry within a broad range of Ca/P molar ratios (1.3 – 2) and under a very high concentration of defects.…”

Section: Introductionmentioning

confidence: 99%

One ion to rule them all: the combined antibacterial, osteoinductive and anticancer properties of selenite-incorporated hydroxyapatite

Uskoković

Iyer

2017

J. Mater. Chem. B

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Although hydroxyapatite (HAp) has been doped with dozens of different ions, the quest for an ion imparting a combination of properties conducive to bone healing is still ongoing. Because of its protean potency and the similarity in size and shape to the phosphate tetrahedron, selenite ion presents a natural ionic substitute in HAp. The incorporation of selenite into synthetic HAp using two different methods – co-precipitation and ion-exchange sorption - was studied for its effect on crystal properties and on a triad of biological responses: antibacterial, anticancer and osteoinductive. Co-precipitation yielded HAp with higher selenite contents than sorption and the stoichiometry of HAp richest in selenite was represented as Ca9.75(PO4)5.75(SeO3)0.25(OH)1.75. Crystallinity of HAp decreased in direct proportion with the amount of selenite incorporated. Because of their lower selenite content, HAp powders prepared by ion-exchange exhibited a consistently higher crystallinity compared to the co-precipitated ones. Annealing partially recovered the crystallinity, yet the difference in crystallinity between powders prepared by co-precipitation and by ion-exchange remained, suggesting that the amorphization is mainly due to structural incorporation of selenite, not its effect on the crystal growth kinetics. The addition of selenite changed the morphology of HAp nanoparticles from acicular to rounded and affected the crystal lattice parameters in different ways depending on whether the powders were annealed or not. As for the annealed powders, the incorporation of selenite contracted the lattice in both a and c crystallographic directions. In the agar diffusion assay, the effectiveness of HAp was more dependent on the presence or absence of selenite in it than on its concentration and was highest against E. coli and S. aureus, moderately high against S. enteritidis and ineffective against P. aeruginosa. In liquid inoculation tests, on the other hand, the antibacterial activity of HAp was directly proportional to the amount of selenite contained in it. The viability of K7M2 osteosarcoma cells decreased in direct proportion with the amount of selenite in HAp and was significantly different from the untreated control and from pure HAp at contents equal to or higher than 1.9 wt.%. In contrast, no reduction was observed in the viability of primary fibroblasts treated with HAp incorporating different amounts of selenite ions, suggesting their potentially selective anticancer activity: lethal for the cancer cells and harmless for the healthy cells. Finally, mRNA expression of bone gamma-carboxyglutamate protein (BGLAP3) was higher in differentiated MC3T3-E1 osteoblastic cells treated with selenite-incorporated HAp particles than in cells treated with pure HAp. The osteoinductive effect was due to an overall higher metabolic activity of cells treated with the particles and not due to increased proliferation. In such a way, a triad of antibacterial, osteoinductive and anticancer activities was attributed to selenite-incorporated ...

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“…The cleavable carbamate linkage is a key functionality in many drugs designed for target and release in specific tissues 23,24 and confers pharmacokinetic advantages such as stability in serum and lability at infected bone surfaces in the presence of an acidic and enzymatic environment (e.g., inflammation or infection). 25 …”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Antimicrobial Evaluation of a Novel Bone-Targeting Bisphosphonate-Ciprofloxacin Conjugate for the Treatment of Osteomyelitis Biofilms

et al. 2017

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Osteomyelitis is a major problem worldwide and is devastating due to the potential for limb-threatening sequelae and mortality. Osteomyelitis pathogens are bone-attached biofilms, making antibiotic delivery challenging. Here we describe a novel osteoadsorptive bisphosphonate-ciprofloxacin conjugate (BV600022), utilizing a “target and release” chemical strategy, which demonstrated a significantly enhanced therapeutic index versus ciprofloxacin for the treatment of osteomyelitis in vivo. In vitro antimicrobial susceptibility testing of the conjugate against common osteomyelitis pathogens revealed an effective bactericidal profile and sustained release of the parent antibiotic over time. Efficacy and safety were demonstrated in an animal model of periprosthetic osteomyelitis, where a single dose of 10 mg/kg (15.6 µmol/kg) conjugate reduced the bacterial load by 99% and demonstrated nearly an order of magnitude greater activity than the parent antibiotic ciprofloxacin (30 mg/kg, 90.6 µmol/kg) given in multiple doses. Conjugates incorporating a bisphosphonate and an antibiotic for bone-targeted delivery to treat osteomyelitis biofilm pathogens constitute a promising approach to providing high bone-antimicrobial potency while minimizing systemic exposure.

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Bisphosphonate-modified biomaterials for drug delivery and bone tissue engineering

Cited by 66 publications

References 80 publications

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

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

One ion to rule them all: the combined antibacterial, osteoinductive and anticancer properties of selenite-incorporated hydroxyapatite

Design, Synthesis, and Antimicrobial Evaluation of a Novel Bone-Targeting Bisphosphonate-Ciprofloxacin Conjugate for the Treatment of Osteomyelitis Biofilms

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