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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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Activity of β-glucosidase in the tumor lesion of the mice administered β-glucosidase (control), β-Glu-MNP, or PEG-β-Glu-MNP. Tumors of magnetically-targeted mice administered PEG-β-Glu-MNP exhibited significantly higher β-glucosidase activity than any other analyzed samples (P<0.01), confirming the selective tumor targeting of PEG-β-Glu-MNP.Abbreviations: PEG, poly(ethylene glycol); β-Glu, β-glucosidase; MNP, magnetic nanoparticles.
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f9-ijn-9-2905: Activity of β-glucosidase in the tumor lesion of the mice administered β-glucosidase (control), β-Glu-MNP, or PEG-β-Glu-MNP. Tumors of magnetically-targeted mice administered PEG-β-Glu-MNP exhibited significantly higher β-glucosidase activity than any other analyzed samples (P<0.01), confirming the selective tumor targeting of PEG-β-Glu-MNP.Abbreviations: PEG, poly(ethylene glycol); β-Glu, β-glucosidase; MNP, magnetic nanoparticles.

Mentions: While the greatly enhanced delivery of MNP to tumors was encouraging, a more important index for evaluating the therapeutic potential of this MDEPT system was the activity of the delivered β-glucosidase in the excised tumors. Tissue samples from control mice, which were not treated with β-glucosidase, showed endogenous background β-glucosidase activity of 17.6 mU/g tissue, which was subtracted for correction of the delivery enzyme activity in tumor lesions. We found 6.07-fold and 3.84-fold higher (P<0.001 for both) β-glucosidase activity in tumor samples excised from the groups targeted with PEG-β-Glu-MNP (32.2±8.0 mU/g tissue) and β-Glu-MNP (20.1±5.0 mU/g tissue), respectively, compared with their nontargeted counterparts (5.3±1.6 mU/g tissue and 5.2±1.5 mU/g tissue, respectively, Figure 9). Enzyme activity in tumor tissues excised from mice injected with free β-glucosidase was also analyzed for comparison. Without the help of MNP and magnetic targeting, only 6.2±2.8 mU/g tissue of enzyme was delivered to these tumor lesions. Conjugation of the enzyme on MNP, PEGylation for better plasma stability, and magnetic targeting together ensured selective delivery of β-glucosidase to the subcutaneous tumor site.


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)

Activity of β-glucosidase in the tumor lesion of the mice administered β-glucosidase (control), β-Glu-MNP, or PEG-β-Glu-MNP. Tumors of magnetically-targeted mice administered PEG-β-Glu-MNP exhibited significantly higher β-glucosidase activity than any other analyzed samples (P<0.01), confirming the selective tumor targeting of PEG-β-Glu-MNP.Abbreviations: PEG, poly(ethylene glycol); β-Glu, β-glucosidase; MNP, magnetic nanoparticles.
© Copyright Policy
Related In: Results  -  Collection

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

f9-ijn-9-2905: Activity of β-glucosidase in the tumor lesion of the mice administered β-glucosidase (control), β-Glu-MNP, or PEG-β-Glu-MNP. Tumors of magnetically-targeted mice administered PEG-β-Glu-MNP exhibited significantly higher β-glucosidase activity than any other analyzed samples (P<0.01), confirming the selective tumor targeting of PEG-β-Glu-MNP.Abbreviations: PEG, poly(ethylene glycol); β-Glu, β-glucosidase; MNP, magnetic nanoparticles.
Mentions: While the greatly enhanced delivery of MNP to tumors was encouraging, a more important index for evaluating the therapeutic potential of this MDEPT system was the activity of the delivered β-glucosidase in the excised tumors. Tissue samples from control mice, which were not treated with β-glucosidase, showed endogenous background β-glucosidase activity of 17.6 mU/g tissue, which was subtracted for correction of the delivery enzyme activity in tumor lesions. We found 6.07-fold and 3.84-fold higher (P<0.001 for both) β-glucosidase activity in tumor samples excised from the groups targeted with PEG-β-Glu-MNP (32.2±8.0 mU/g tissue) and β-Glu-MNP (20.1±5.0 mU/g tissue), respectively, compared with their nontargeted counterparts (5.3±1.6 mU/g tissue and 5.2±1.5 mU/g tissue, respectively, Figure 9). Enzyme activity in tumor tissues excised from mice injected with free β-glucosidase was also analyzed for comparison. Without the help of MNP and magnetic targeting, only 6.2±2.8 mU/g tissue of enzyme was delivered to these tumor lesions. Conjugation of the enzyme on MNP, PEGylation for better plasma stability, and magnetic targeting together ensured selective delivery of β-glucosidase to the subcutaneous tumor site.

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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Related in: MedlinePlus