Synthesis, fluorescence and biodistribution of a bone-targeted near-infrared conjugate

Bisphosphonates (BPs) are non‐hydrolyzable pyrophosphate analogs with high affinity to hydroxyapatite due to their ability to create bidentate or tridentate chelates with calcium ions. Consequently, BP lead to strong interactions with dentin, enamel, and bones. BPs (especially those bearing OH) accelerate osteoblasts action, while strongly inhibiting osteoclasts, thus contributing to enhanced bone formation. Recently, several novel BP non‐biodegradable and biodegradable vinylic monomers were synthesized in our laboratory. This article provides a detailed description regarding the synthesis of a unique biodegradable BP monomer and near infrared (NIR) fluorescent nano/microparticles for diagnosis and therapy of bone malignancy. These particles were prepared by dispersion copolymerization of three monomers: methacrylate polyethylene glycol (PEG) BP, N‐(3‐aminopropyl) methacrylamide, and the crosslinker monomer tetra(ethyleneglycol) diacrylate. The PEG‐BP nanoparticles size was controlled by changing various polymerization parameters. These BP particles possess dual functionality: covalent attachment of a dye (e.g., NIR fluorescent dye) or drug to the nanoparticles through the primary amine groups belonging to the aminopropyl methacrylamide monomeric units and chelation to the bone mineral hydroxyapatite through the BP groups belonging to the methacrylate PEG‐BP monomeric units. Body distribution of the optimal crosslinked BP nanoparticles was tested on a chicken embryo model via intravenous administration. This study indicated that the fluorescence intensity of all the organs except the bones decreased significantly within 48 h (p < 0.05) while that of the bones hardly changed over that time (p > 0.05). In addition, a relatively long half‐life time of these nanoparticles in blood has been demonstrated, probably due to the PEG moiety. Copyright © 2014 John Wiley & Sons, Ltd.

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“…) . This synthesis of various vinylic monomers was the outcome of an ongoing research in the field of biodegradable polymers and molecules …”

Section: Introductionmentioning

confidence: 99%

New biodegradable bisphosphonate vinylic monomers and near infrared fluorescent nanoparticles for biomedical applications

Gluz

Rudnick-Glick

Mizrahi

et al. 2014

Polymers for Advanced Techs

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“…These conditions showed significant improvement over the literature, in terms of both reaction time and purification procedure. Originally, the starting materials were heated to reflux in 1,2-dichlorobenzene for 48 h and isolated by vacuum filtration with ether and later triturated in ether [8]. …”

Section: Resultsmentioning

confidence: 99%

“…Of particular interest are dyes which have widespread applications, some of which are shown in Figure 1. For example, the bone-targeting conjugated compound monocarboxy-ICG ( 1) was found to bind to growing regions of the skeleton and remain visible for two weeks [8]. The prolonged fluorescence could potentially allow for to repeated imaging with a single injection.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Quaternary Heterocyclic Salts

et al. 2013

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“…Briefly, 45 mg MA-PEG-BP [27, 28], 5 mg APMA and 50 mg TTEGDA (5% w/v total monomer concentration) were added to a vial containing 8 mg of the initiator potassium persulfate (8% w/w) and 20 mg of the stabilizer polyvinylpyrrolidone 360 K (1% w/v) dissolved in 2 mL of bicarbonate buffer (0.1 M). For the polymerization, the vial containing the mixture was purged with N 2 to exclude air and then shaken at 83 °C for 8 h. The obtained BP NPs were washed of excess reagents by extensive dialysis cycles (cut-off of 1000 k) with purified water.…”

Section: Methodsmentioning

confidence: 99%

Targeted drug delivery of near IR fluorescent doxorubicin-conjugated poly(ethylene glycol) bisphosphonate nanoparticles for diagnosis and therapy of primary and metastatic bone cancer in a mouse model

et al. 2016

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BackgroundMost primary and metastatic bone tumors demonstrate increased osteoclast activity and bone resorption. Current treatment is based on a combination of surgery, radiotherapy and chemotherapy. Severe side effects are associated with chemotherapy due to use of high dosage and nonspecific uptake. Bisphosphonates have a strong affinity to Ca2+ ions and are widely used in the treatment of bone disorders.ResultsWe have engineered a unique biodegradable bisphosphonate nanoparticle (NPs) bearing two functional surface groups: (1) primary amine groups for covalent attachment of a dye/drug (e.g. NIR dye Cy 7 or doxorubicin); (2) bisphosphonate groups for targeting and chelation to bone hydroxyapatite. In addition, these engineered NPs contain high polyethyleneglycol (PEG) concentration in order to increase their blood half life time. In vitro experiments on Saos-2 human osteosarcoma cell line, demonstrated that at a tenth of the concentration, doxorubicin-conjugated bisphosphonate NPs achieved a similar uptake to free doxorubicin. In vivo targeting experiments using the NIR fluorescence bisphosphonate NPs on both Soas-2 human osteosarcoma xenograft mouse model and orthotopic bone metastases mCherry-labeled 4T1 breast cancer mouse model confirmed specific targeting. In addition, therapeutic in vivo experiments using doxorubicin-conjugated bisphosphonate NPs demonstrated a 40% greater inhibition of tumor growth in Saos-2 human osteosarcoma xenograft mouse model when compared to free doxorubicin.ConclusionsIn this research we have shown the potential use of doxorubicin-conjugated BP NPs for the targeting and treatment of primary and metastatic bone tumors. The targeted delivery of doxorubicin to the tumor significantly increased the efficacy of the anti-cancer drug, thus enabling the effective use of a lower concentration of doxorubicin. Furthermore, the targeting ability of the BP NPs in an orthotopic xenograft mouse model reinforced our findings that these BP NPs have the potential to be used for the treatment of primary and metastatic bone cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12951-016-0233-6) contains supplementary material, which is available to authorized users.

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Synthesis, fluorescence and biodistribution of a bone-targeted near-infrared conjugate

Cited by 26 publications

References 17 publications

New biodegradable bisphosphonate vinylic monomers and near infrared fluorescent nanoparticles for biomedical applications

New biodegradable bisphosphonate vinylic monomers and near infrared fluorescent nanoparticles for biomedical applications

Synthesis of Quaternary Heterocyclic Salts

Targeted drug delivery of near IR fluorescent doxorubicin-conjugated poly(ethylene glycol) bisphosphonate nanoparticles for diagnosis and therapy of primary and metastatic bone cancer in a mouse model

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