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Stanford Cancer Imaging Training Program (SCIT)
Immune-modulating effects of the FDA approved iron oxide nanoparticle ferumoxytol inhibit tumor growth
Saeid Zanganeh, PhD
Stanford Cancer Imaging Training (SCIT) Program
October 14, 2015
Stanford Cancer Imaging Training Program (SCIT
Background: Superparamagnetic Iron Oxide Nanoparticles
Applications and Developments in Diagnostics and Therapy
SPIO in preclinical and experimental applicationMolecular imaging
SPIO in clinical applicationT2/T2* applications: Liver imagingSpleen imagingLymph node imagingTumor imagingBone marrow imagingImaging of the gastrointestinal tractCNS imagingCharacterization of atherosclerotic plaques
SPIO conjugation with antibodies and antibody fragmentsTumor imagingApoptosis imagingCardiovascular imagingCell labeling and cell imaging in MRITransplant diagnostics, imaging of rejection reactions (graft rejection)Inflammation, infection, and adiposity imagingAND…
Stanford Cancer Imaging Training Program (SCIT
Motivation
2.3x106 tumor cells+ USPIO (10 mg Fe/kg)
control: 2.3x106
Tumor Cells
Motivation
Stanford Cancer Imaging Training Program (SCIT
Objective
To evaluate the mechanisms that lead to cancer growth inhibition via local injection of iron oxide nanoparticles into early tumor deposits
Objectives
Stanford Cancer Imaging Training Program (SCIT
1) Evaluating direct toxic effects of ferumoxytol on cancer cells
Low dose ferumoxytol was not cytotoxic
2) Evaluating chemotactic effects of iron oxide nanoparticles
ferumoxytol increased macrophage migration
ferumoxytol induced macrophage-mediated cancer cell apoptosis
3) Ferumoxytol upregulated M1-associated gene expression and downregulated M2-associated gene expretion
4) Effects of iron oxide nanoparticles on tumor growth in vivo
5) In vivo ferumoxytol metabolism and tumor growth
6) in vivo polarization of M1/M2 macrophages and associated gene expression mesurment
Overview
2 Days 14 Days
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HP
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uo
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nce
(arb
itra
ry u
nit
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4
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H2
O2
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microporousmembrane
MMTV-PyMTcancer cells
RAW624.7 macrophage cells
Ferumoxytol
ROS (Hydrogen Peroxide)
ROS (Hydroxyl radical)
Fenton's reaction
Stanford Cancer Imaging Training Program (SCIT
Treatment with anti-colony stimulating factor (CSF)–1 monoclonal antibody
SuperparamagneticIron Oxide
Endorem
Cliavist
Combidex
Supravist
Clariscan
Core
Coating
FDA Approved
150 nm
100 nm
40 nm
30 nm
20 nm
Ferumoxytol (Feraheme , Rienso )
Carboxymethyl Dextran20-30 nm
Superparamagnetic Iron Oxide Nanoparticles
Stanford Cancer Imaging Training Program (SCIT
1) protein corona gives new identity to the nanoparticles which be “seen” by biological species (e.g., cells).Soft corona (reversibly bound proteins)Hard corona (irreversibly bound proteins): Impact on nano particls biodistribution and macrophage uptake
Several reports have demonstrated the composition of protein corona at the surface of SPIONs (with varioussurface chemistries) and their diverse effects on biological species (e.g., cells and biological barriers)
2) The hard corona composition (outer layer structure) at the surface of Ferumoxytol was probed by liquidchromatography tandem mass spectrometry (LC-MS)
In order to obtain the total number of the LC-MS spectra for all of the peptides that are attributed to a matchedprotein, a semi-quantitative assessment of the protein amounts was conducted through application of spectralcounting (SpC) method
Protein Corona and Ferumoxytol
Uniprot accession
number
Protein name NSpC
P01966 Hemoglobin alpha 18.94±1.17
P81644 Apolipoprotein A-II 8.81±0.83
P02081 Hemoglobin beta 6.63±0.81
B0JYN6 Alpha-2-HS-glycoprotein 7.29±0.85
P02768 Serum albumin 6.59±0.85
P15497 Apolipoprotein A-I 6.37±0.31
P34955 Alpha-1-antiproteinase 5.36±0.51
Q03247 Apolipoprotein E 1.58±0.46
P19035 Apolipoprotein C-III 1.27±0.11
P19034 Apolipoprotein C-II 0.99±0.41
Stanford Cancer Imaging Training Program (SCIT
Conclusion
Iron oxide nanoparticles initiate a proinflammatory immune response, based onmacrophage influx into tumors and M1 polarization
This finding has important implications for diagnostic and theranostic applications ofiron oxide nanoparticles
Iron oxide nanoparticle-delivery to tumors may support M1-activatingimmunotherapies, such as the upcoming anti-CD47 therapy at Stanford
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