Outline
What is nano?
What is cancer?
What is our approach?
at a e t e u d es to a o ed c es?
What are the hurdles to nanomedicines?
How far have we come?
How far do we have to go?
Acknowledgments
Cengage Learning
Hosts in the First Year Program
Hosts in the First Year Program
Department of Chemistry and College of Science at Texas A&M University
Undergrads, Grad students and Post‐docs g
,
over the last ten years
Collaborators from NCI, UTSW, DE, UK
National Institutes of Health, National Science Foundation, DARPA, USDA, Welch Foundation
What is Wh
i
Nano?
Where do you find blood cells?
What is cancer?
The name for a number of diseases in The
name for a number of diseases in
which the body's cells become abnormal and divide without control.
Cancer cells may invade nearby tissues or may spread through the bloodstream and lymphatic system to other parts of
and lymphatic system to other parts of the body… a process called metastasis.
Cancer cells overwhelm organs and C
ll
h l
d
cause failure or secondary diseases. Causes of Death in the United States in 2006
Compiled by the Centers for Disease Control (CDC)
Compiled by the Centers for Disease Control (CDC)
Heart Disease
Cancer
Stroke
Lower respiratory Diabetes
Alzheimer’s
Influenza/pneumonia Kidney disease Septic shock Suicide Liver disease Hypertension Parkinson’s disease Crime All other
All other
26%
23%
6%
5%
3%
3%
2%
2%
1.5%
1.4%
1%
1%
0.8%
0.8%
19%
How is cancer treated? D
Drugs (chemotherapy), Radiation and/or Surgery
( h
h
) R di i
d/ S
Room for improvement: Success rates and quality of life
li
f lif
Where do drugs come from?
Where do drugs come from?
Genetic Engineering,
Vaccines (15%)
Naturally Occurring
(28%)
No Direct Natural
Origin (33%)
Inspired by Nature
(24%)
Sources of the 1031 new potential drugs reported between
1981-2002
How do drugs work?
How do drugs work?
Interfere with metabolism.
Interfere with signaling.
Interfere with mechanical processes.
Paclitaxel ‐ A broad spectrum, hydrophobic FDA‐approved
hydrophobic, FDA
approved (1996) anti‐cancer drug isolated from pine bark (1966) p
that can be readily “attached”.
Design implications:
Design implications: 1. Drug must be released from carrier
2. Drug must get inside target cell
Healthy blood vessels are size‐selective. Tumor vessels are not. l
Dendrimer with ih
Paclitaxel
Human
S
Serum
Albumin
Big Molecules
Dendrimers Cancer
Cell Bacterium Virus Protein
Drugs
1m
1 mm
10o m
10‐3 m
100 μm 10 μm
1 μm
10‐6 m
100 nm
10 nm
1 nm
o
1 A
10‐9 m
Kidneys are similar.
Hypothesis: By attaching toxic, small molecule cancer drugs to a safe, protein‐sized carrier, the drug‐carrier complex will be ,p
,
g
p
selectively deposited in the tumor (instead of healthy cells) where the drugs are slowly released. The carrier has to be big enough to be selectively targeted but small enough to be
enough to be selectively targeted, but small enough to be cleared through the kidneys so that it does not accumulate in the liver (leading to liver toxicity).
Hurdles of Nanomedicines
Hurdles of Nanomedicines
Synthesis – Can it be made?
Scale – Can enough be made?
Drug conjugation – Can drugs be attached and released?
R
Reproducibility
d ibilit – Is it the same each time you make it?
I it th
h ti
k it?
Biodistribution – Does it get to the tumor?
Biocompatibility – Does it accumulate in the body?
Does it accumulate in the body?
Safety/toxicity – Does it cause other problems?
Efficacyy – Does it work?
Therapeutic Advantage – Does it improve treatment and/or quality of life?
…
Making something big benefits from repetitive actions…
ii
i
… like making linear polymers like styrofoam
like making linear polymers like styrofoam or polyethylene.
or polyethylene
But what do we want our nanomedicine to do? d
d ?
Include sites for drug attachment.
Be very well defined in terms of
size and shape.
Branching gives more “ends”…
gg
and a different polymer class called
and
a different polymer class called
dendrimers.
What chemistry do we choose to make tree‐shaped polymers?
k
h
d l
?
Inexpensive.
Proven.
Proven
Scalable.
V
Versatile.
il
“Green.”
What chemistry do we choose to make tree shaped polymers?
make tree‐shaped polymers?
Inexpensive.
Proven.
Proven
Scalable.
V
Versatile.
il
“Green.”
√ Synthesis
√ Scale
√ Reproducibility
Drug conjugation
Biodistribution
Biocompatibility
Safety /toxicity
Efficacy
Th
Therapeutic Advantage
ti Ad t
…
Synthesis.
√ Synthesis
√ Scale
√ Reproducibility
√ Drug conjugation
Biodistribution
Biocompatibility
Safety /toxicity
Efficacy
Therapeutic Advantage
Therapeutic Advantage
…
Biological data suggests opportunity!
Slow release of drug = safe administration.
Slow clearance by kidneys = tumor uptake.
y
y
p
Increasing T/B; T/M ratios = lower toxicity
… and it is described as one of the safest d it i d
ib d
f th
f t
nanomeds known (NCI)
10
1.0
0.8
06
0.6
0.4
0.2
0.0
fa
t
liv
sp e r
le
e
ki n
dn
st ey
om
sm ach
al
la l int
rg
e
m int
us
cl
e
bo
ne
br
tu ain
m
o
tu r R
m
or
L
0
Tum
mor/Muscle Tissue
e Uptake Ratio
20
bl
oo
d
he
ar
t
lu
ng
%ID//g
30
4h
24h
48h
Tum
mor/Blood Tissue Uptake Ratio
40
0
12
24
Time (h)
36
48
20
15
10
5
0
0
12
24
Time (h)
36
48
Biological data suggests opportunity!
10
0.8
06
0.6
0.4
0.2
0.0
fa
t
liv
sp e r
le
e
ki n
dn
st ey
om
sm ach
al
la l int
rg
e
m int
us
cl
e
bo
ne
br
tu ain
m
o
tu r R
m
or
L
0
Tum
mor/Muscle Tissue
e Uptake Ratio
4h
24h
48h
20
bl
oo
d
he
ar
t
lu
ng
%ID//g
30
Tum
mor/Blood Tissue Uptake Ratio
Slow release of drug = safe administration.
√ Synthesis
√ Scale
Slow clearance by kidneys = tumor uptake.
y
y
p
√ Reproducibility
d ibili
√ Drug conjugation
Increasing T/B; T/M ratios = lower toxicity
√ Biodistribution
√ Biocompatibility
p
y
… and it is described as one of the safest d it i d
ib d
f th
f t
√ Safety /toxicity – National Cancer Institute
nanomeds known (NCI)
Efficacy
Therapeutic Advantage
40
…
20
1.0
0
12
24
Time (h)
36
48
15
10
5
0
0
12
24
Time (h)
36
48
Efficacy in Prostate Cancer Model in Mice
Efficacy in Prostate Cancer Model in Mice
Dose:
100
100 mg/kg or 200 mg/kg)
/k
200
/k )
No treatment
One treatment (Day 4)
Two treatments (Day 4, 10)
Efficacy in Prostate Cancer Model in Mice
Efficacy in Prostate Cancer Model in Mice
√ Synthesis
√ Scale
√ Reproducibility
√ Drug conjugation
√ Biodistribution
√ Biocompatibility
√ Safety /toxicity –
S f t /t i it National Cancer Institute
N ti
lC
I tit t
√ Efficacy
Therapeutic Advantage
…
Dose:
100
100 mg/kg or 200 mg/kg)
/k
200
/k )
No treatment (120x at D70)
(
)
One treatment (10x at D70)
Two treatments (1‐3x at D70)
What’s next? Th
Therapeutic Advantage and …
i Ad
d
Can we achieve lower doses with the “next generation” g
dendrimer? Can we optimize dosing schedule?
Will h
Will these work in additional tumor models like breast, k i ddi i
l
d l lik b
colon, lung, and pancreas?
Will we find a therapeutic advantage over existing therapies
Will we find a therapeutic advantage over existing therapies
(dose size, survival, response)?
… Can we translate to the preclinical and clinical studies?
Better efficacy at lower dose.
Better efficacy at lower dose.
1200
PBS Control
100 mg/kg wklyx1
100 mg/kg wklyx2
200 mg/kg wklyx1
Tumor V
Volume (m
mm3)
1000
800
600
400
200
0
0
10
20
30
40
Day
50
60
70
Conclusion: Evidence for cures…
Conclusion: Evidence for cures…
A
B
C
D
Wk 0
Wk 3
Wk 6
BL
LI Photon Inttensity (10 8 p
p/sec/cm2/sr)
80
60
40
A: PBS
B: 100
00 mg/kg
g/ g wklyx1
y
C: 100 mg/kg wklyx2
D: 200 mg/kg wklyx1
20
Wk 9
0
0
3
6
9
Week
…and a reason to keep working.
Last Bits: Fancy can become reality.
Science takes time.
Science takes money.
Science takes people… like you!
Rewards come in many forms.
2000 2002
2004
National Institutes of Health (NIH)
National Science Foundation (NSF)
United States Department of Agriculture
United States Department of Agriculture
DARPA Welch Foundation
2006 2008 2010 Thank you for your attention.