Specific MRI Contrast Media T.

Peyroux February 2005

SuperParamagnetic Iron Oxide Particules (SPIO)

Liver: Endorem GI Tract: Lumirem

Superparamagnetic Iron Oxide particles (SPIO)

Fe3+ Fe2+ O 2-

The active ingredient is a suspension of iron oxide crystals (Fe2O3 and Fe3O4)

Liver MRI contrast medium

Endorem
(Ferumoxides) (Ferumoxides)

Chemical Structure
citric acid iron oxide crystal diameter 5nm

dextran coating The crystals are arranged in a nanoparticle structure (crystal aggregates) with a diameter between 120 and 180 nanometers

Mechanism Of Action Magnetised solid particles Local magnetic field inhomogeneity Nuclear spin dephasing

T2

R2 (signal decrease)

R1 and R2 Relaxivities
Relaxivity (mM-1.s-1) r1 ENDOREM Gd Chelates 25 4.5 r2 100 5.7 r2/ r1 4 1.3

ENDOREM has strong r1 and r2 relaxivities, higher than those of gadolinium chelates

Action of Endorem on the signal

Endorem

T2* T2 effects when particles are concentrated (macrophages, Kpffer cells)

T1 effect when particles are free (vessels, haemangiomas)

Pharmacokinetics
Vascular phase: T1 effect
hepatocytes sinusoids Kpffer cells ENDOREM nanoparticles

Endocytosis: cellular phase with T2* effect

sinusoids Kpffer cells

Pharmacokinetics (cont'd)

ENDOREM particles are rapidly taken up by the reticuloendothelial system (RES) cells and more particularly by the Kpffer cells of the liver Accumulation of ENDOREM in normal liver tissue T2 and Signal intensity

Normal liver: BLACK Malignant lesions: WHITE

Pharmacokinetics (cont'd)
Normally 80% of Endorem is distributed in the liver, 10 to 13% in the spleen and the remainder in the other RES organs. This contrast agent is biodegradable and the iron present in Endorem is incorporated in the normal iron metabolism of the body. Dextran is eliminated in the urine.

Indication

MRI detection of focal lesions of the liver

Focal lesions of the liver

Benign tumors Adenoma Angioma biliary cyst FNH

Primary malignant tumors HCC cholangiocarcinoma vascular tumors Metastases

ENDOREM helps differential diagnosis of focal liver lesions

70 60 50 40 30 20 10 0

liver liver FNH liver

Adenoma

liver

HCC
metastasis

The Product
Presentation:
8 ml ampoule (brown solution) + infusion kit

Administration:
Dosage: 15 mol of Fe/kg bw = 0.075 ml/kg Dilution in 100 ml of 5% glucose Slow IV infusion: 30 min
during 10 min: 2 ml/min or 40 drops/min during 20 min: 4 ml/min or 80 drops/min

Time for imaging: from end of infusion to 6 hours

Colon adenocarcinoma metastasis

T2W Imaging T1W Imaging

Before ENDOREM

After ENDOREM

September

2004

Metastasis
Improves the detection

Before Endorem

After Endorem

Metastasis

Before Endorem

After Endorem

Focal Nodular Hyperplasia

Contributes to detection and characterization of the lesion
Central Scare
Before Endorem After Endorem

Adenoma
Improves the detection of lesions

T1 Gd

T1 Gd + Endorem

Cirrhosis
Cirrhosis : Child A, B Delineation of fibrosis

T2 sequence before Endorem

T2 sequence after Endorem

Cirrhosis
Cirrhosis : Child A, B
Better visualization of the nodules (RN)

T2 before Endorem

T2 after Endorem

Cirrhosis
Cirrhosis : Child A, B Better visualization of the nodules (RN + HCC)

Before Endorem

After Endorem

Tolerance

Back pain Heat sensation Dyspnea Nausea, headache

4.8 1 0.7 0.6

% % % %

Conclusion

MRI + Endorem increase the diagnostic of liver tumors Increase the number of detected lesions Small lesions better visualized Better evaluation of pathologic liver segments Better anatomical delineation

GI Tract MRI Contrast medium

Lumirem

(Ferumoxsil)

Lumirem (Ferumoxsil) SPIO Abdominal and Pelvis MRI Oral and / or rectal route

Characteristics of iron oxide particles

Iron oxide crystals

Coating (siloxane)

Size: 300 nm

r1 and r2 Relaxivities of superparamagnetics products

Relaxivity (mM-1.s-1)
r1 LUMI M M l t , , , r2 r2/r1

Lumirem characteristics
Negative Contrast Medium Lumirem induces a shortening of the T2 relaxation time Signal loss: dark image where the product is present Lumirem masks the fluids of the GI tract

Indications
MR Cholangiopancreatography
(pre-cholecystectomy staging, visualization of Klatskin tumors, visualization of stenosis, assess of pancreatic secretion, cyst)

MR Urography
(ureteral-pelvic junction obstruction)

MR Examination of the intestinal wall

(Rectocolic haemorrhage, Crohns disease)

Oral or rectal route

The Product Presentation Concentration Osmolality Viscosity

300 ml Plastic vial (orange solution and orange flavour) 175 mg Fe/ml

250 mOsm/kg H2O

11-65 mPa.s.

Protocols of oral administration

MRCP

Without LUMIREM: the duodenal cap superimposes on the common bile duct and the duct of Wirsung is partially masked by the stomach

MRCP

With LUMIREM: the biliary and pancreatic ducts are perfectly visualized

MRCP

LUMIREM facilitates the visualization of Klatskin tumors

Crohns disease: T2W sequence after LUMIREM

Crohns disease: fat suppressed T2w TSE image after LUMIREM

Crohns disease: BH T1w image after LUMIREM and before IV injection of Gd chelate

Crohns disease: BH T1w image after LUMIREM and after IV injection of Gd chelate

The Future

SINEREM

UltraSmall Superparamagnetic Iron Oxide Particles (USPIO)

Sinerem

(Ferumoxtran)

SINEREM

Sinerem

Small Superparamagnetic nanoparticle (30 nm); High T2* efficacy ksk Phagocytosis by macrophages Plasmatic half-life: 36 h Oncology: characterization between inflammatory and metastatic lymph nodes
IRON OXIDE CORE ( 4 nm)

+ + +

+ +

30 nm
DEXTRAN POLYMER

SINEREM

Main Characteristics
ENDOREM Particle size (LLS) R1 (37C, 20 MHz) R2 (37C, 20 MHz) Liver uptake Lymph node uptake 150 nm 23 mmol-1 s-1 100 mmol-1 s-1 82 % <1% SINEREM 30 nm 22 mmol-1 s-1 53 mmol-1 s-1 20 % 11 %

SINEREM

Safety Profile

Acceptable safety profile regarding the clinical indication Safety profile comparable to Endorem

SINEREM

Plain MRI Evaluation Criteria

Normal lymph node: < 10 mm Metastatic lymph node: > 10 mm

SINEREM

Injection Modalities Dosage : 2.6 mg Fe/kg Dilution in 100 ml of normal saline Slow infusion (about 30 minutes) MRI: 24 - 36 hours post injection

Reading guide
= benign = benign = metastasis = metastasis = metastasis

SINEREM

High Resolution Imaging

Nor

l ize ode: iz

Medic re

Medic

st

Benign lymph nodes before Sinerem

M.Mack Frankfurt

Benign lymph nodes after Sinerem

M.Mack Frankfurt

Metastatic lymph node

plain
M.Mack Frankfurt

post Sinerem

Metastatic lymph node

Diagnostic change N0 p N1

Change of therapeutic management Surgery

M.Mack Frankfurt

SINEREM

Sinerem
Lymphotropic contrast Sensitivity and specificity are increased High resolution imaging + Sinerem detection of very small lymph nodes metastases (1-2 mm) q positive false: inflammatory adenopathy q negative false: micromestatases

SINEREM

Sinerem Potential Macrophage imaging

Lymph node Angiography Kidney Atherome plaque

Coronarography with USPIO

C. Klein et al, Improvement of Image Quality of Non-Invasive Coronary Artery Imaging with Magnetic Resonance by the Use of the Intravascular Contrast Agent ClariscanTM (NC100150 Injection) in Patients with Coronary Artery Disease, Journal of Magnetic Resonance Imaging, 2003; 17:656-662

Pre inject.

Post inject. of 2mg Fe/kg NC100150

4mgFe/kg : susceptibility artefacts

Sinerem : kidney and macrophages

Objective: evaluation of intrarenal phagocytosis of Sinerem in 21 patients Glomerulopathies
Important decrease of cortical and medullar T2 signals Important decrease of medullar signals in toxic and acute tubulopathies No variation of signal in non active glomerularpathies (interstitial nephritis, tubular necrosis) Kidney transplant Decrease of cortical and medullar T2 signals

Acute rejection T2*

D0

N.Grenier

D3

Acute GN

D0

D3
N.Grenier

Characterization of atheroma plaque

Composition:
Fibrosis Lipid and necrotic center Calcium Haemorrhage Thrombus Fibrotic cap

Atherosclerotic plaques

Pathologies

% microphages

Stable angina Unstable angina M.I. without Q wave

3.14 1 13.3 5.6 14.6 4.6 p= 0.018

De MORENO & coll.,Circulation, 1994

Image of the plaque

Control: normal rabbits 5 days post Sinerem

WHHL rabbits 5 days post Sinerem

Control of iron deposits (Perls) >0

Ruehm S et al, Circulation 2001; 103:415-422

The use and development of contrast media are linked with technological evolution In MRI: Fast sequences, Magnetic field

The magnet
T1 Relaxation Time

3T 0.2T
Rat brain at 17T S/N

Bo

High Field: internal ear

MIP

Influence of the field on T1

SI

With Gd 1.5T 3T

Time

Summary

SNR Susceptibility TR CM : depends

Non specific products: a few changes Better for particles