Engineering of new crosslinked near-infrared fluorescent polyethylene glycol bisphosphonate nanoparticles for bone targeting

Gluz, Eran; Grinberg, Igor; Corem-Salkmon, Enav; Mizrahi, Dana M.; Margel, Shlomo

doi:10.1002/pola.26858

Cited by 13 publications

(18 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This was accomplished by replacing the crosslinker monomer EDMA with the crosslinker tetraethyleneglycol diacrylate (TTEGDA) (Fig. ) . EDMA is considerably more hydrophobic than TTEGDA.…”

Section: Synthesis and Characterization Of The Ma‐peg‐bp Monomer And mentioning

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…This was accomplished by replacing the crosslinker monomer EDMA with the crosslinker tetraethyleneglycol diacrylate (TTEGDA) (Fig. ) . EDMA is considerably more hydrophobic than TTEGDA.…”

Section: Synthesis and Characterization Of The Ma‐peg‐bp Monomer And mentioning

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…BP NPs were prepared similarly to that described in the literature [26]. 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).…”

Section: Methodsmentioning

confidence: 99%

“…NIR fluorescent BP NPs were synthesized similarly to that described in the literature [26]. In brief, NIR fluorescent BP NPs were prepared by a reaction of the primary amino groups on the BP NPs with Cy7-NHS ester.…”

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

View full text Add to dashboard Cite

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.

show abstract

“…By dispersion copolymerization of three monomers (methacrylate bisphosphonate 66, N-(3-aminopropyl) methacrylamide 67, and tetra(ethylene glycol) diacrylate 68) (Scheme 33), polymeric nanoparticles 69 were obtained [148]. Their size distribution was controlled by changing various polymerization parameters.…”

Section: Synthesis Of Building Blocks For Polymer Chemistrymentioning

confidence: 99%

Synthetic Procedures Leading towards Aminobisphosphonates

Chmielewska

Kafarski

2016

Molecules

View full text Add to dashboard Cite

Abstract:Growing interest in the biological activity of aminobisphosphonates has stimulated the development of methods for their synthesis. Although several general procedures were previously elaborated to reach this goal, aminobisphosphonate chemistry is still developing quite substantially. Thus, innovative modifications of the existing commonly used reactions, as well as development of new procedures, are presented in this review, concentrating on recent achievements. Additionally, selected examples of aminobisphosphonate derivatization illustrate their usefulness for obtaining new diagnostic and therapeutic agents.

show abstract

Engineering of new crosslinked near-infrared fluorescent polyethylene glycol bisphosphonate nanoparticles for bone targeting

Cited by 13 publications

References 59 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

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

Synthetic Procedures Leading towards Aminobisphosphonates

Contact Info

Product

Resources

About