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Magnetic Targeting of Novel Heparinized Iron Oxide Nanoparticles Evaluated in a 9L-glioma Mouse Model

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ABSTRACT

Purpose

A novel PEGylated and heparinized magnetic iron oxide nano-platform (DNPH) was synthesized for simultaneous magnetic resonance imaging (MRI) and tumor targeting.

Methods

Starch-coated magnetic iron oxide nanoparticles (“D”) were crosslinked, aminated (DN) and then simultaneously PEGylated and heparinized with different feed ratios of PEG and heparin (DNPH1-4). DNPH products were characterized by Fourier transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM) and superconducting quantum interference device (SQUID). The magentic targeting of DNPH3, with appropriate amounts of conjugated PEG and heparin, in a mouse 9L-glioma subcutaneous tumor model was confirmed by magnetic resonance imaging (MRI)/electron spin resonance (ESR).

Results

DNPH3 showed long circulating properties in vivo (half-life >8 h, more than 60-fold longer than that of parent D) and low reticuloendothelial system (RES) recognition in liver and spleen. Protamine, a model cationic protein, was efficiently loaded onto DNPH3 with a maximum loading content of 26.4 μg/mg Fe. Magnetic capture of DNPH3 in tumor site with optimized conditions (I.D. of 12 mg/kg, targeting time of 45 min) was up to 29.42 μg Fe/g tissue (12.26% I.D./g tissue).

Conclusion

DNPH3 showed the potential to be used as a platform for cationic proteins for simultaneous tumor targeting and imaging.

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Abbreviations

CPP:

Cell penetrating peptide

D:

Starch-coated magnetic iron oxide nanoparticles

DLS:

Dynamic light scattering

DN:

Aminated D

DNPH:

Aminated, PEGylated and heparinized D

EPR:

Enhanced penetration effect

ESR:

Echo spin resonance

FTIR:

Fourier transform infrared spectroscopy

ICP-OES:

Inductively coupled plasma optical emission spectroscopy

MNP:

Magnetic nanoparticles

MRI:

Magnetic resonance imaging

MWCO:

Molecular weight cut-off

PBE:

Protamine binding effiency

PK:

Pharmacokinetics

PLC:

Protamine loading content

siRNA:

Small interfering RNA (siRNA)

SQUID:

Superconducting quantum interference device

TEM:

transmission electron microscopy

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Acknowledgments And Disclosures

This work was supported in part by the National Institutes of Health (NIH) R01 Grants CA114612 and NS066945, and a Hartwell Foundation Biomedical Research Award. This work was also partially sponsored by Grant R31-2008-000-10103-01 from the World Class University (WCU) project of South Korea. In addition, the project was partially sponsored by the National Basic Research Program of China (973 Program) 2013CB932502.

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Authors and Affiliations

  1. Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnosis School of Pharmacy, Tianjin Medical University, Tianjin, 300070, China

    Jian Zhang, Meong Cheol Shin & Victor C. Yang

  2. Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, Michigan, 48109, USA

    Jian Zhang, Meong Cheol Shin & Victor C. Yang

  3. College of Pharmacy, The University of Michigan, Ann Arbor, Michigan, 48109-1065, USA

    Victor C. Yang

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  1. Jian Zhang
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  2. Meong Cheol Shin
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Correspondence to Victor C. Yang.

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Zhang, J., Shin, M.C. & Yang, V.C. Magnetic Targeting of Novel Heparinized Iron Oxide Nanoparticles Evaluated in a 9L-glioma Mouse Model. Pharm Res 31, 579–592 (2014). https://doi.org/10.1007/s11095-013-1182-5

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  • DOI: https://doi.org/10.1007/s11095-013-1182-5

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