immune-modulating effects of the fda approved iron … · stanford cancer imaging training program...

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…


Motivation

2.3x106 tumor cells+ USPIO (10 mg Fe/kg)

control: 2.3x106

Tumor Cells

Motivation


Objective

To evaluate the mechanisms that lead to cancer growth inhibition via local injection of iron oxide nanoparticles into early tumor deposits

Objectives


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


What is Special About Ferumoxytol ?

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12

16

20

HP

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4

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H2

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microporousmembrane

MMTV-PyMTcancer cells

RAW624.7 macrophage cells

Ferumoxytol

ROS (Hydrogen Peroxide)

ROS (Hydroxyl radical)

Fenton's reaction


ROS and Apoptosis


Treatment with anti-colony stimulating factor (CSF)–1 monoclonal antibody


In vivo polarization of M1/M2 macrophages

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


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


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


Thank you

DAPI + CD 80

immune-modulating effects of the fda approved iron … · stanford cancer imaging training program...

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