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Histopathologic Study ofHistopathologic Study of
SPIO Distribution in MouseSPIO Distribution in Mouse
Introducing our Meth...
Endocytosis and Particle Size
Endocytosis Particle diameter
Phagocytosis 0.1-10µm
Pinocytosis 0.5-100nm
♦ Both phagocytosis and pinocytosis occur in
macrophages
♦ Although internalization of particles less
than 1 µm showed cha...
♦Macrophages are sensitive
to composition, size, and
concentration of the
challenging particles.
phagocytosis.
♦ Particles with surface associated
ligands (such as antibody or
complement) that specifically bind a cell
membrane are mo...
♦ Average diameter of low density
lipoprotein (LDL) is 24.4 nm to more
than 26 nm
♦ Receptor mediated endocytosis is
respo...
Oxidized LDL are recognized
and taken up by:
♦ Common receptor for acetyl LDL (scavenger
receptor)
♦ Specific receptor for...
Macrophages may take up
Oxidized LDL according to its
degree of aggregation
♦ Small aggregated molecules generated
under a...
 
SPIO Endocytosis
♦ Fluid phase endocytosis for tumor cells
♦ Receptor mediated endocytosis
(phagocytosis) for macrophage...
♦Macrophagesand macrophage-like cell
lines had thehighest uptake. Tumor
cells, however, also showed
considerableuptake, ra...
♦After introduction of long-circulating
particles tumoral uptake also increased
particularly whit higher doses
♦The faster...
LCDIO Distribution into Tumor Compartments as
Determined with Fluorescence Microscopy and
Immunohistochemistry Tumor Compa...
Endothelial cells also show iron oxide
uptake; however, it is unclearwhether
the relatively high uptake is related to
cell...
Which Dose Is Better
♦ 3mmolFe/kg is the maximum safe dose?
♦ 1mmolFe/kg is the dose that Reuhem used
for his study
♦ 0.01...
♦ No acute or sub-acute toxic effects were
seen in rats or dogs who received a total of
3000µmolFe/kg,150 times the dose
p...
When We Have The Highest
Concentration of These Particles
in Atherosclerotic Plaque?
Particle Core Size ParticleSize Blood
(nm) (nm) half life
Combidex 5-6 20-30 8h
Feridex 4-6 35-50 2.4±0.2h
MION 4-6 17
Biodistribution 24 Hours after IV Administration of 125
I-labeled LCDIO into Four Rats with 9L-GFP Brain Tumor
Injected do...
What we are going to do
♦We are going to study the
distribution of these particles over
time in 2 extreme doses, in normal...
Method and Material
♦ 20 Apo E-deficient mice >20 months,and 4
normal same age mice
♦ Group 1: 10 Apo-E deficient mice and...
S a m p les fro m h ea rt, lu n g , liver,sp leen , k id n ey,
eso p h a g u s a n d 5 p a rts o f a o rta
fo r H & E ,P e...
Histopathologic study of spio distribution in mice (method)
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Histopathologic study of spio distribution in mice (method)

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Histopathologic study of spio distribution in mice (method)

  1. 1. Histopathologic Study ofHistopathologic Study of SPIO Distribution in MouseSPIO Distribution in Mouse Introducing our MethodIntroducing our Method
  2. 2. Endocytosis and Particle Size Endocytosis Particle diameter Phagocytosis 0.1-10µm Pinocytosis 0.5-100nm
  3. 3. ♦ Both phagocytosis and pinocytosis occur in macrophages ♦ Although internalization of particles less than 1 µm showed characteristics of both receptor mediated endocytosis and phagocytosis, increasing particle size increases the probability of phagocytosis of readily phagocytosed particles
  4. 4. ♦Macrophages are sensitive to composition, size, and concentration of the challenging particles. phagocytosis.
  5. 5. ♦ Particles with surface associated ligands (such as antibody or complement) that specifically bind a cell membrane are more readily phagocytosed than those without surface receptors. Strong binding between receptors and ligands can lead to fusion if the phagocytosed body is a liposome, virus, or bacterium.
  6. 6. ♦ Average diameter of low density lipoprotein (LDL) is 24.4 nm to more than 26 nm ♦ Receptor mediated endocytosis is responsible for the internalization of low density lipoproteins and for uptake of many substances
  7. 7. Oxidized LDL are recognized and taken up by: ♦ Common receptor for acetyl LDL (scavenger receptor) ♦ Specific receptor for oxidized LDL ♦ Mouse peritoneal macrophages selectively or preferentially ingest aggregated oxidized LDL, but not native oxidized LDL
  8. 8. Macrophages may take up Oxidized LDL according to its degree of aggregation ♦ Small aggregated molecules generated under a mild oxidative condition are recognized via scavenger receptor ♦ Large aggregated particles are taken up by phagocytosis.
  9. 9.   SPIO Endocytosis ♦ Fluid phase endocytosis for tumor cells ♦ Receptor mediated endocytosis (phagocytosis) for macrophages ♦ The later pathway can be dramatically enhanced by opsonization of particles with plasma protein (Schulze )
  10. 10. ♦Macrophagesand macrophage-like cell lines had thehighest uptake. Tumor cells, however, also showed considerableuptake, ranging from 11.9 to 118 ng of iron per million cells(Moore) ♦ With the introduction of smaller and long-circulatingiron oxides, this distribution was shown to be different, withless uptake in liver and spleen and concomitantly more uptakein lymph nodes (Weissleder )
  11. 11. ♦After introduction of long-circulating particles tumoral uptake also increased particularly whit higher doses ♦The faster the growth rate,the greater the Iron oxide uptake, this may be relatedto the higher endocytosis rate in the faster-proliferating cells
  12. 12. LCDIO Distribution into Tumor Compartments as Determined with Fluorescence Microscopy and Immunohistochemistry Tumor Compartment LCDIO Distribution (%) Extracellular Vascular volume fraction 4.5 ± 0.8 Interstitial fraction 19.0 ± 1.8 Intracellular Glioma tumor cells 49.0 ± 4.6 Tumor-associated macrophages 21.0 ± 3.1 Tumor vascular endothelium 6.5 ± 1.4
  13. 13. Endothelial cells also show iron oxide uptake; however, it is unclearwhether the relatively high uptake is related to cellular proliferation
  14. 14. Which Dose Is Better ♦ 3mmolFe/kg is the maximum safe dose? ♦ 1mmolFe/kg is the dose that Reuhem used for his study ♦ 0.01mmolFe/kg is the human dose of Feridex
  15. 15. ♦ No acute or sub-acute toxic effects were seen in rats or dogs who received a total of 3000µmolFe/kg,150 times the dose proposed for MR imaging of the liver ♦ In human and animals it has been shown that these iron particles enter the usual iron metabolism pathway in body
  16. 16. When We Have The Highest Concentration of These Particles in Atherosclerotic Plaque?
  17. 17. Particle Core Size ParticleSize Blood (nm) (nm) half life Combidex 5-6 20-30 8h Feridex 4-6 35-50 2.4±0.2h MION 4-6 17
  18. 18. Biodistribution 24 Hours after IV Administration of 125 I-labeled LCDIO into Four Rats with 9L-GFP Brain Tumor Injected dose per gram of tissue mean ± SD Blood 0.5 ± 0.2 Brain 0.01 ± 0.01 Bone 0.1 ± 0.1 Heart 0.2 ± 0.1 Intestine 0.1 ± 0.1 Lymph node 25.0 ± 3.2 Kidney 0.8 ± 0.1 Liver 1.9 ± 0.3 Lung 0.2 ± 0.1 Muscle 0.1 ± 0.1 Spleen 9.8 ± 0.8 Tumor 0.1 ± 0.1
  19. 19. What we are going to do ♦We are going to study the distribution of these particles over time in 2 extreme doses, in normal and Apo E deficient mice
  20. 20. Method and Material ♦ 20 Apo E-deficient mice >20 months,and 4 normal same age mice ♦ Group 1: 10 Apo-E deficient mice and 2 normal mice,3mmol Fe/kg ♦ Group 2:10 Apo-E deficient mice and 2 normal mice, 0.01mmol Fe/kg
  21. 21. S a m p les fro m h ea rt, lu n g , liver,sp leen , k id n ey, eso p h a g u s a n d 5 p a rts o f a o rta fo r H & E ,P ea rl,M a cro p h a g e S ta in in g In jectio n o f F erid ex 3 m m o l F e/k g S a m p les fro m h ea rt, lu n g , liver,sp leen ,k id n ey, eso p h a g u s a n d 5 p a rts o f a o rta fo r H & E ,P ea rl,M a cro p h a g e S ta in in g In jectio n o f F erid ex 0 .0 1 m m o l F e/k g 2 0 A p o E d eficien t M ice

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