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Enhanced and selective delivery of enzyme therapy to 9L-glioma tumor via magnetic targeting of PEG-modified, β-glucosidase-conjugated iron oxide nanoparticles.

Zhou J, Zhang J, Gao W - Int J Nanomedicine (2014)

Bottom Line: The results showed that the multidomain structure and magnetization properties of these nanoparticles were conserved well throughout the synthesis steps, with an expected diameter increase and zeta potential shifts.Both magnetophoretic mobility analysis and pharmacokinetics showed improved in vitro/in vivo stability of PEG-β-Glu-MNP compared with β-Glu-MNP.In vivo magnetic targeting of PEG-β-Glu-MNP was confirmed by magnetic resonance imaging and electron spin resonance analysis in a mouse model of subcutaneous 9L-glioma.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, Hubei Hospital of Traditional Chinese Medicine, Hubei University of Chinese Medicine, Wuhan, People's Republic of China.

ABSTRACT
The stability of enzyme-conjugated magnetic iron oxide nanoparticles in plasma is of great importance for in vivo delivery of the conjugated enzyme. In this study, β-glucosidase was conjugated on aminated magnetic iron oxide nanoparticles using the glutaraldehyde method (β-Glu-MNP), and further PEGylated via N-hydroxysuccinimide chemistry. The PEG-modified, β-glucosidase-immobilized magnetic iron oxide nanoparticles (PEG-β-Glu-MNPs) were characterized by hydrodynamic diameter distribution, zeta potential, Fourier transform infrared spectroscopy, transmission electron microscopy, and a superconducting quantum interference device. The results showed that the multidomain structure and magnetization properties of these nanoparticles were conserved well throughout the synthesis steps, with an expected diameter increase and zeta potential shifts. The Michaelis constant was calculated to evaluate the activity of conjugated β-glucosidase on the magnetic iron oxide nanoparticles, indicating 73.0% and 65.4% of enzyme activity remaining for β-Glu-MNP and PEG-β-Glu-MNP, respectively. Both magnetophoretic mobility analysis and pharmacokinetics showed improved in vitro/in vivo stability of PEG-β-Glu-MNP compared with β-Glu-MNP. In vivo magnetic targeting of PEG-β-Glu-MNP was confirmed by magnetic resonance imaging and electron spin resonance analysis in a mouse model of subcutaneous 9L-glioma. Satisfactory accumulation of PEG-β-Glu-MNP in tumor tissue was successfully achieved, with an iron content of 627±45 nmol Fe/g tissue and β-glucosidase activity of 32.2±8.0 mU/g tissue.

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Plasma concentration-time profiles of D-MNP, β-Glu-MNP, and PEG-β-Glu-MNP. Inset: corresponding area under the concentration-time curves (AUC) for D-MNP, β-Glu-MNP, and PEG-β-Glu-MNP.Abbreviations: D-MNP, MAG-D magnetic nanoparticles; PEG, poly(ethylene glycol); β-Glu, β-glucosidase; MNP, magnetic nanoparticles; min, minutes.
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f6-ijn-9-2905: Plasma concentration-time profiles of D-MNP, β-Glu-MNP, and PEG-β-Glu-MNP. Inset: corresponding area under the concentration-time curves (AUC) for D-MNP, β-Glu-MNP, and PEG-β-Glu-MNP.Abbreviations: D-MNP, MAG-D magnetic nanoparticles; PEG, poly(ethylene glycol); β-Glu, β-glucosidase; MNP, magnetic nanoparticles; min, minutes.

Mentions: The promising in vitro performance of PEG-β-Glu-MNP encouraged us to evaluate its potential for in vivo application. Electron spin resonance analysis of MNP concentrations in plasma samples following intravenous administration indicated that D-MNP had a short blood circulation time. Less than one fifth (14.4%) of the initial dose (14.78 μg Fe/mL) remained in the systemic circulation at 20 minutes post-administration, and similar results have been reported elsewhere.23 PEG-β-Glu-MNP and β-Glu-MNP showed markedly increased stability in blood, with more than 62% and 34% of the initial blood MNP concentrations, respectively, still remaining in the circulation at 20 minutes post-administration. The area under the curve, equal to the total plasma exposure of MNP for PEG-β-Glu-MNP (8,579±568 μg Fe/mL ⋅ minute) and β-Glu-MNP (2,791±234 µg Fe/mL ⋅ minute) was approximately 8.3-fold and 2.7-fold (P<0.001 for both) greater than that of D-MNP (1,031±123 μg Fe/mL ⋅ minute), (Figure 6).


Enhanced and selective delivery of enzyme therapy to 9L-glioma tumor via magnetic targeting of PEG-modified, β-glucosidase-conjugated iron oxide nanoparticles.

Zhou J, Zhang J, Gao W - Int J Nanomedicine (2014)

Plasma concentration-time profiles of D-MNP, β-Glu-MNP, and PEG-β-Glu-MNP. Inset: corresponding area under the concentration-time curves (AUC) for D-MNP, β-Glu-MNP, and PEG-β-Glu-MNP.Abbreviations: D-MNP, MAG-D magnetic nanoparticles; PEG, poly(ethylene glycol); β-Glu, β-glucosidase; MNP, magnetic nanoparticles; min, minutes.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4061166&req=5

f6-ijn-9-2905: Plasma concentration-time profiles of D-MNP, β-Glu-MNP, and PEG-β-Glu-MNP. Inset: corresponding area under the concentration-time curves (AUC) for D-MNP, β-Glu-MNP, and PEG-β-Glu-MNP.Abbreviations: D-MNP, MAG-D magnetic nanoparticles; PEG, poly(ethylene glycol); β-Glu, β-glucosidase; MNP, magnetic nanoparticles; min, minutes.
Mentions: The promising in vitro performance of PEG-β-Glu-MNP encouraged us to evaluate its potential for in vivo application. Electron spin resonance analysis of MNP concentrations in plasma samples following intravenous administration indicated that D-MNP had a short blood circulation time. Less than one fifth (14.4%) of the initial dose (14.78 μg Fe/mL) remained in the systemic circulation at 20 minutes post-administration, and similar results have been reported elsewhere.23 PEG-β-Glu-MNP and β-Glu-MNP showed markedly increased stability in blood, with more than 62% and 34% of the initial blood MNP concentrations, respectively, still remaining in the circulation at 20 minutes post-administration. The area under the curve, equal to the total plasma exposure of MNP for PEG-β-Glu-MNP (8,579±568 μg Fe/mL ⋅ minute) and β-Glu-MNP (2,791±234 µg Fe/mL ⋅ minute) was approximately 8.3-fold and 2.7-fold (P<0.001 for both) greater than that of D-MNP (1,031±123 μg Fe/mL ⋅ minute), (Figure 6).

Bottom Line: The results showed that the multidomain structure and magnetization properties of these nanoparticles were conserved well throughout the synthesis steps, with an expected diameter increase and zeta potential shifts.Both magnetophoretic mobility analysis and pharmacokinetics showed improved in vitro/in vivo stability of PEG-β-Glu-MNP compared with β-Glu-MNP.In vivo magnetic targeting of PEG-β-Glu-MNP was confirmed by magnetic resonance imaging and electron spin resonance analysis in a mouse model of subcutaneous 9L-glioma.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, Hubei Hospital of Traditional Chinese Medicine, Hubei University of Chinese Medicine, Wuhan, People's Republic of China.

ABSTRACT
The stability of enzyme-conjugated magnetic iron oxide nanoparticles in plasma is of great importance for in vivo delivery of the conjugated enzyme. In this study, β-glucosidase was conjugated on aminated magnetic iron oxide nanoparticles using the glutaraldehyde method (β-Glu-MNP), and further PEGylated via N-hydroxysuccinimide chemistry. The PEG-modified, β-glucosidase-immobilized magnetic iron oxide nanoparticles (PEG-β-Glu-MNPs) were characterized by hydrodynamic diameter distribution, zeta potential, Fourier transform infrared spectroscopy, transmission electron microscopy, and a superconducting quantum interference device. The results showed that the multidomain structure and magnetization properties of these nanoparticles were conserved well throughout the synthesis steps, with an expected diameter increase and zeta potential shifts. The Michaelis constant was calculated to evaluate the activity of conjugated β-glucosidase on the magnetic iron oxide nanoparticles, indicating 73.0% and 65.4% of enzyme activity remaining for β-Glu-MNP and PEG-β-Glu-MNP, respectively. Both magnetophoretic mobility analysis and pharmacokinetics showed improved in vitro/in vivo stability of PEG-β-Glu-MNP compared with β-Glu-MNP. In vivo magnetic targeting of PEG-β-Glu-MNP was confirmed by magnetic resonance imaging and electron spin resonance analysis in a mouse model of subcutaneous 9L-glioma. Satisfactory accumulation of PEG-β-Glu-MNP in tumor tissue was successfully achieved, with an iron content of 627±45 nmol Fe/g tissue and β-glucosidase activity of 32.2±8.0 mU/g tissue.

Show MeSH
Related in: MedlinePlus