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Noninvasive Imaging of Liposomal Delivery of Superparamagnetic Iron Oxide Nanoparticles to Orthotopic Human Breast Tumor in Mice

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ABSTRACT

Purpose

Magnetic resonance imaging (MRI) is widely used for diagnostic imaging in preclinical studies and in clinical settings. Considering the intrinsic low sensitivity and poor specificity of standard MRI contrast agents, the enhanced delivery of MRI tracers into tumors is an important challenge to be addressed. This study was intended to investigate whether delivery of superparamagnetic iron oxide nanoparticles (SPIONs) can be enhanced by liposomal SPION formulations for either “passive” delivery into tumor via the enhanced permeability and retention (EPR) effect or “active” targeted delivery to tumor endothelium via the receptors for vascular endothelial growth factor (VEGFRs).

Methods

In vivo MRI of orthotopic MDA-MB-231 tumors was performed on a preclinical 9.4 T MRI scanner following intravenous administration of either free/non-targeted or targeted liposomal SPIONs.

Results

In vivo MRI study revealed that only the non-targeted liposomal formulation provided a statistically significant accumulation of SPIONs in the tumor at four hours post-injection. The EPR effect contributes to improved accumulation of liposomal SPIONs in tumors compared to the presumably more transient retention during the targeting of the tumor vasculature via VEGFRs.

Conclusions

A non-targeted liposomal formulation of SPIONs could be the optimal option for MRI detection of breast tumors and for the development of therapeutic liposomes for MRI-guided therapy.

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Abbreviations

DAPI:

4′,6-Diamidino-2-phenylindole

DOPC:

1,2-Dioleoyl-sn-glycero-3-phosphocholine

DOPE:

1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine

DSPC:

1,2-Distearoyl-sn-glycero-3-phosphocholine

DSPE-PEG2000 :

1,2-Distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000

EPR:

Enhanced permeability and retention

GdDTPA-BMA:

Gadolinium-diethylenetriamine pentaacetic acid-bismethylamide

ICG:

Indocynine green

ICP-MS:

Inductively coupled plasma mass spectrometry

IDL:

Interactive data language

Lip(Gd/Fe):

Liposomes encapsulated with GdDTPA-BMA and SPIONs

Lip(ICG):

Liposomes encapsulated with indocynine green

MRI:

Magnetic resonance imaging

PDI:

Polydispersity index

PECAM:

Platelet endothelial cell adhesion molecule

PET:

Positron emission tomography

RARE:

Rapid acquisition with refocusing echoes

ROI:

Region-of-interest

scVEGF:

Single chain vascular endothelial growth factor

scVEGF-Lip(Gd/Fe):

scVEGF-decorated Lip(Gd/Fe)

scVEGF-Lip(ICG):

scVEGF-decorated Lip(ICG)

SDS-PAGE:

Sodium dodecyl sulfate polyacrylamide gel electrophoresis

SPECT:

Single photon emission computed tomography

SPIONs:

Superparamagnetic iron oxide nanoparticles

T 1 :

Spin–lattice relaxation time

T 2 :

Transverse relaxation time

TE:

Echo time

TR:

Repetition time

TSA:

Tyramide signal amplification

VEGFRs:

Vascular endothelial growth factor receptors

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ACKNOWLEDGMENT AND DISCLOSURES

This study was supported by the National Institutes of Health, CA154738 (DA, JMB, and SKS). We are grateful to Ms. Mary McAllister for editing the manuscript.

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Author notes

    Authors and Affiliations

    1. Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, Maryland, 21205, USA

      Yoshinori Kato, Wenlian Zhu, Christopher C. Neoh, Sudath Hapuarachchige & Dmitri Artemov

    2. Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, USA

      Yoshinori Kato & Dmitri Artemov

    3. Life Science Tokyo Advanced Research Center (L-StaR), Hoshi University School of Pharmacy and Pharmaceutical Science, Shinagawa-ku, Tokyo, Japan

      Yoshinori Kato

    4. SibTech, Inc., Brookfield, Connecticut, 06804, USA

      Marina V. Backer & Joseph M. Backer

    5. CadenzaMed LLC, Wayne, Pennsylvania, 19087, USA

      Susanta K. Sarkar

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    1. Yoshinori Kato
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    2. Wenlian Zhu
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    Correspondence to Dmitri Artemov.

    Additional information

    Yoshinori Kato and Wenlian Zhu contributed equally to this work.

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    Kato, Y., Zhu, W., Backer, M.V. et al. Noninvasive Imaging of Liposomal Delivery of Superparamagnetic Iron Oxide Nanoparticles to Orthotopic Human Breast Tumor in Mice. Pharm Res 32, 3746–3755 (2015). https://doi.org/10.1007/s11095-015-1736-9

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    • DOI: https://doi.org/10.1007/s11095-015-1736-9

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