Abstract
Electron paramagnetic resonance (EPR) imaging using nitroxides as molecular probes is potentially a powerful tool for the detection and physiological characterization of micrometastatic lesions. Encapsulating nitroxides in anti-HER2 immunoliposomes at high concentrations to take advantage of the “self-quenching” phenomenon of nitroxides allows generation of robust EPR signals in HER2-overexpressing breast tumor cells with minimal background from indifferent tissues or circulating liposomes. We investigated the in vivo pharmacological properties of nitroxides encapsulated in sterically stabilized liposomes designed for long circulation times. We show that circulation times of nitroxides can be extended from hours to days; this increases the proportion of liposomes in circulation to enhance tumor targeting. Furthermore, nitroxides encapsulated in sterically stabilized anti-HER2 immunoliposomes can be delivered to HER2-overexpressing tumors at micromolar concentrations, which should be imageable by EPR. Lastly, after in vivo administration, liposomally encapsulated nitroxide signal also appears in the liver, spleen, and kidneys. Although these organs are spatially distinct and would not hinder tumor imaging in our model, understanding nitroxide signal retention in these organs is essential for further improvements in EPR imaging contrast between tumors and other tissues. These results lay the foundation to use liposomally delivered nitroxides and EPR imaging to visualize tumor cells in vivo.
Footnotes
This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant GM56481]; and the National Institutes of Health National Institute of Biomedical Imaging and Bioengineering [Grant P41-EB2034].
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.111.039636.
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ABBREVIATIONS:
- EPR
- electron paramagnetic resonance
- HER2
- human epidermal growth factor receptor 2
- Hc7
- HER2-overexpressing breast tumor cell derived from MCF7 cells
- PEG
- polyethylene glycol
- PEG-PE
- ammonium 1,2-distearoyl-sn-glycero-3-phosphatidylethanolamine-N-[polyethylene glycol 2000]
- nitroxide 1
- dipotassium (2,2,5,5-tetramethylpyrrolidin-1-oxyl-3-ylmethyl)amine-N,N-diacetate
- nitroxide 2
- 3-carboxy-2,2,5,5-tetramethyl-1-pyrrolidinyloxyl
- DPBS
- Dulbecco's phosphate-buffered saline
- SNR
- signal-to-noise ratio
- ANOVA
- analysis of variance.
- Received March 18, 2011.
- Accepted July 7, 2011.
- U.S. Government work not protected by U.S. copyright
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