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A Novel Anti-Cancer Strategy Through
Biological Metal Overloading in Cancer Cells via
pH-sensitive Metalo-organic Nanoparticles
Jinhyuk Fred Chung, Ph. D., CEO
NanoMedicine Research Co.
April 18th, 2008
The 5th Nanoforum
Jeju, Korea
Challenges & Limitations in Anti-cancer
Medicines: Seesaw Dillemma
Toxicity /
Selectivity
Efficacy
Cytotoxin
Enzyme Inhibitor
Which side to leverage?
◈ Theory – A lesson from nature
1: Mol Med. 2008 Mar-Apr;14(3-4):98-108. Links
Iron-mediated inhibition of mitochondrial
manganese uptake mediates mitochondrial
dysfunction in a mouse model of
hemochromatosis.
Jouihan HA, Cobine PA, Cooksey RC, Hoagland EA, Boudina S, Abel ED, Winge
DR, McClain DA.
Departments of Medicine and Biochemistry, University of Utah
School of Medicine, Salt Lake City, Utah, USA and.
Benign biological metals can
KILL UPON
OVERLOADING!
“Calcium & Iron Bomb” Strategy
*Source of the depiction unknown
◈ OFeCa-1: The Anti-Cancer Particle
• OFeCa-1
• pH-sensitive organo-metallic
nanoparticles with iron &
calcium as the main therapeutic
components.
• Degrades near neutral pH,
releasing metals.
ICP-MS metal analysis of 11% w/w
OFeCa-1 solution (same concentration
solution as those used for cell & animal
experiments)
Transmission Electron Microscope
(TEM) Image taken near pH 2
◈ OFeCa-1’s Degradation via pH
Mass Distribution at pH 6.4
120
%Mass(Per max peak)
100
pH 6.4
80
60
40
20
78.8
122
190
295
459
712
1110
122
190
295
459
712
1110
122
190
295
459
712
1110
50.7
78.8
78.8
21
32.7
13.5
8.72
5.61
3.62
1.5
2.33
0.97
0.4
0.62
0
Diameter
Mass Distribution at pH 7
120
pH 7.0
%Mass(Per Max Peak)
100
80
60
40
20
50.7
32.7
21
13.5
8.72
5.61
3.62
2.33
1.5
0.97
0.4
0.62
0
Diameter (nm)
Mass Distribution at pH 7.4
120
pH 7.4
80
60
40
20
Diameter (nm)
50.7
32.7
21
13.5
8.72
5.61
3.62
2.33
1.5
0.97
0.4
0
0.62
%Mass(Per Max Peak)
100
• Dynamic light scattering results
on OFeCa-1 at varying pH,
showing pH-dependent
degradation of OFeCa-1 near
physiological ranges (~pH 7).
• Horizontal axis denote
nanoparticle sizes in diameter,
graphs denote mass distribution,
normalized against the norm.
• This degradation property allows
OFeCa-1 to “unload” bound
metals that, in turn, kill target
cancer mass
◈ Human Cancer Cell Screening
Note this occurance of
“critical dosage”, at which
point cancer suddenly
disappear altogether
4.500
4.000
24hr Treated
48
72
3.500
5000 per well
2.500
2.000
1.500
1.000
Hep2 (larynx cancer)
0.500
0.000
0
5
10
20
30
40
50
60
0
5
10
24hrs
4.000
20
30
40
50
60
60
60
48hrs
24
4.500
0
5
72hrs
48
72
3.500
3.000
5000 per well
Cancer Survival
3.000
2.500
2.000
1.500
1.000
293T (kidney cancer)
0.500
0.000
0
5
10
20
24hrs
30
40
50
60
0
5
10
20
30
40
50
60
0
5
10
48hrs
20
30
40
50
60
72hrs
*Cell counting kit-8 (Dojindo, Tokyo) was
used to study cell viability.
OFeCa-1 Added (uL/mL Media)
Continued
3.000
24hr
2.500
48hr
72hr
5000 per well
2.000
1.500
1.000
Ramos (Burkitt's lymphoma )
0.500
0.000
0
5
10
20
30
40
50
60
0
5
10
20
30
24hrs
40
50
60
0
5
10
20
30
48hrs
40
50
60
72hrs
5.000
4.500
4.000
3.500
3.000
2.500
2.000
1.500
T98g (brain cancer)
1.000
0.500
0.000
0
5
10
20
30
40
50
60
0
5
10
24hrs
20
30
40
50
60
0
5
10
20
48hrs
30
40
50
60
72hrs
0.900
0.800
0.700
5000 per well
0.600
0.500
0.400
0.300
H460 (lung cancer)
0.200
0.100
0.000
0
5
10
20
30
40
50
60
0
5
10
20
24hr s
30
48hrs
72hr s
40
50
60
0
5
10
20
30
40
50
60
HSC survival (A.U.)
◈ Toxicity Testing against HSC
•
Adult stem cells such as hair
cells & hematopoetic stem cells
(HSC: blood stem cell) are
easily killed by conventional
anti-cancer drugs, leading to hair
loss & bone marrow suppression
during cancer treatment.
•
OFeCa-1, on the other hand,
displays no signs of adverse
1.6
1.4
1.2
1
0.8
0.6
0.4
0.2
0
c
1
2.5
5
10
20
11% OFeCa-1 in Media (uL/mL)
40
effect on mouse HSC’s survival
.
Efficacy against Mouse Cancer Cell
Effect of OFeCa-1 on B16F10
Melanoma & Normal Stromal Cells
% Cell Survival against Control Group
120
•
# of Initial
Melanoma Cells
10^5
100
2.5*10^4
80
1.25*10^4
60
0.6*10^4
40
0.3*10^4
0.15*10^4
20
Normal cell
0
40
20
5
11% w/w OFeCa-1 Added (uL/mL media)
1
•
OFeCa-1 shows
no toxicity
against noncancerous
normal mouse
stromal cells.
Within same
range, OFeCa-1
shows powerful
anti-cancer
activity against
mouse
melanoma
B16F10.
◈ Mouse Model Bearing Metastatic Lung Cancer
Effect of sustained
administration of OFeCa-1 on
intravanous metastatic mouse
model using B16/F10. OFeCa-1
was passively administered as
water-substitute by diluting
11 % OFeCa-1 ten-fold with
dietary water. Quick survey
showed that the mice consumed
roughly 2~3 mL of the diluted
OFeCa-1 daily. (A) B16/F10
control. (B) B16/F10 mice fed
with 1/10 diluted OFeCa-1. (C)
Quantified B16/F10 colonies
found in the lungs of test
subjects. P10 refers to passively
fed 1/10 diluted 11% w/w
OFeCa-1 against water.
A
C
Melanoma Colony Count
B
50
40
30
20
10
0
B16/F10
Control
B16/F10 + P10
Treatment
Experiment terminated before the
extinction of melanoma colonies in the
treatment group for visual
confirmation of successful metastasis
◈ 2W Acute Toxicity Test using SD rats
◈ Replenishment Effect: More Effectiveness
•
Cancer Cell Survival After 72hr Treatment
5
4.5
4
•
3.5
Abs
3
Kept Media
Fresh Media
2.5
2
1.5
1
0.5
0
0
1
10
20
30
O FeCa-1 Added (uL/mL media)
*B16F10 mouse melanoma as model. Media of
appropriate condition were replaced daily for
“fresh media” group.
40
•
The graph left shows clear
evidence of improvement in
anti-cancer efficacy of
OFeCa-1 upon daily
replacement of the media
containing OFeCa-1.
This data indicates that
frequent use of OFeCa-1 is
likely to be recommended in
the future.
Considering the data thus far,
greater dose and more
frequent intake of OFeCa-1
is likely to be highly
recommended, increasing
the demand for OFeCa-1 for
extra assurance in cancer
treatment.
OFeCa-1: Ideal Anti-Cancer Agent
•
•
•
•
•
•
•
•
Ultra-low toxicity*
Composed only of biological metals & organic nanoparticle backbone
that degrades into non-toxic biological metabolites
Displays effectiveness against multiple aggressive cancer cell lines
(both human & mouse origins)
Designed to work in multiple modes, increasing effectiveness &
reducing chances of resistance development
Outlook of good efficacy against Lung cancer
Significantly more effective upon frequent & prolonged use
Expected to be compatible with conventional chemotherapeutic agents.
And many more ideal behaviors & properties that qualify OFeCa-1 as
an ideal candidate for future broad-spectrum cancer treatments.
*Based on toxicity tests against cell-based tests & acute toxicity test using SD rats