El martes 10 y el miércoles 11 de abril de 2018 se organizó, en la Fundación Ramón Areces, un Simposio Internacional sobre los Materiales Mesoporosos.

1. Fuyuhiko Tamanoi
Professor
Dept. of Microbio., Immunol. & Molec. Genet.
UCLA
Professor
Institute for Integrated Cell-Material Sciences
Kyoto University
Cancer Therapy using Mesoporous Silica Nanoparticles
iCEMS, Kyoto UniversityUCLA

2. Mesoporous Silica Nanoparticles as a vehicle
for targeted delivery of anticancer drugs
Current
Chemotherapy
Nanoparticle
based therapy
Jeff
Zink

3. Mesoporous Silica Nanoparticles
40 nm
- Homogeneous preparation
- Diameter is 130 nm
- 1400 pores/particle
- Pore diameter is 2 nm
- Large scale preparation
- Well established chemistry can be used to modify
surface or to attach nanomachines

4. Si
O
O
Si
Si
O
Si
O
O
Si
Si
O
O
Si
O
O
O
O
O
O
O
NH3
+
Si
O
-
Si
Si
O
O
P
-
O
O
P
O
-
O
2 nm
F CPT
F
F
FCPT
F = FITC CPT = camptothecin
Si
O
O
Si
Si
O
Si
O
O
Si
Si
O
O
Si
O
O
O
O
O
O
O
NH3
+
Si
O
-
Si
Si
O
O
P
-
O
O
P
O
-
O
2 nm
FF CPT
FF
FF
FFCPT
F = FITC CPT = camptothecin
Apoptosis
MSNs provide valuable delivery
vehicles for hydrophobic, water-
insoluble anticancer drugs
(camptothecin, taxol etc).
Camptothecin
Anticancer drugs can be loaded into the pore
Phosphonate
surface
modification

5. Size of nanoparticles that
can benefit from EPR:
40 - 400 nm
Nanoparticles can accumulate in the tumor
Passive targeting (Enhanced permeability retention)
Active targeting
Surface modification
of NP with targeting
moiety
Normal
tissue Tumor
Folic Acid Silica NanoparticleFolic Acid Silica NanoparticleFolic Acid Silica NanoparticleFolic Acid Silica Nanoparticle

6. Preferential accumulation of MSNs
in the tumor

7. Lung
intestine
tumor
kidney
liver
Lung
intestine
tumor
kidney
liver
Accumulation of MSNs in tumor (tissue section)
24h 72h
Blood circulation
Good tumor
penetration

8. Si
O
O
Si
Si
O
Si
O
O
Si
Si
O
O
Si
O
O
O
O
O
O
O
NH3
+
Si
O
-
Si
Si
O
O
P
-
O
O
P
O
-
O
2 nm
F CPT
F
F
FCPT
F = FITC CPT = camptothecin
Si
O
O
Si
Si
O
Si
O
O
Si
Si
O
O
Si
O
O
O
O
O
O
O
NH3
+
Si
O
-
Si
Si
O
O
P
-
O
O
P
O
-
O
2 nm
FF CPT
FF
FF
FFCPT
F = FITC CPT = camptothecin
Delivering camptothecin by MSNPs

9. Controlled Release
Zero premature release
On-command Release
External
stimuli
Local release
Spatial and temporal
control
Towards
Non-invasive therapy
In collaboration with
Jeffrey Zink
Fraser Stoddart
Light
Magnetic field

10. Development of external signal responsive nanoparticles
NanovalveNanovalve
“Open and Close”
Rotaxanes consist of a
stalk and a moving part
Nanovalve
Nanoimpeller

11. Nanoimpellers
Photo-responsive azobenzene motion in the pores of nanoparticles
CisTrans
Ground state Excited state
Photon
Photon
Motion is generated by light
exposure
Azobenzene
Large conformational change
occurs upon light exposure

12. N N N
N N
N N NN N
457nm
Photo-responsive azobenzene motion in the pores of nanoparticles
= Fluorescent dyes/anticancer drugs
N N
N
N
N
Nanoimpeller

13. Light induced release of
anticancer drug (CPT)
from nanoimpeller in cells
Nucleus
light
release
Cancer cell
MSN
Nucleus
light
release
Cancer cell
MSN
Nucleus
light
release
Cancer cell
MSN
Cell culture chamber
Blue Laser
Cell culture chamber
Blue Laser
0.1 W/cm2
Exposure time dependent release of anticancer drugs.
Power dependent release of anticancer drugs.
Repeated exposure and anticancer release can be achieved.
Cell killing (apoptosis)

14. Magnetic
property
for movement,
recovery
Iron oxide core
Mesoporous
silica
Magnetic nanoparticles
Iron oxide core
MSNs
a b c d ea b c d ea b c d e
H2O MSNs
Iron-oxide MSNs
4 2 1 mg/ml
MRI enhancing effect

15. Magnetic field responsive nanovalves
Superparamagnetic
property of iron oxide
Magnetic nanoparticles heat up when
exposed to oscillating magnetic field.
Magnetic
field

16. No exposure
5 min exposure
Exposure of doxorubicin loaded NPs to oscillating magnetic field
results in drug release and killing of human cancer cells
Release of Dox Cell killing
Doxorubicin-loaded Mag-
MSN is taken up into breast
cancer cells MDA-MB-231.
Frequency 500 KHz
Amplitude 37.4 KAm-1

17. Light
Magnetic field
Sound
Electron, photon beams
Harnessing natural energy for cancer therapy

18. Clinical potential to use magnetic field
Apply magnetic coil to generate
oscillating magnetic field
Alternating magnetic field applicator
NanoActivator F100
Targeted magnetic field
Overlay focusing magnetic
effect on top of oscillating
magnetic field

19. We have studied a new type of mesoporous silica
nanoparticles that have enhanced biodegradation
Proteases,
Reducing
conditions
Safety of materials is a paramount concern when
envisioning clinical application

20. Incorporating organic bonds into the framework
Sol-gel synthesis
Pore
CTAB
Alkali
Periodic mesoporous organosilica
Si
OR
OR
OR
RO
Pore
CTAB
Alkali
Pore
Pore
Mesoporous silica NPs
tetraalkoxysilane
Bridged alkoxysilane

21. Sol-gel
S
S
3.5 nm
200 nm
Sol-gel
bis(triethoxysilyl)ethylene
bis(triethoxysilyl)ethane
bis(triethoxysilylpropyl)tetrasulfide
bis(triethoxysilylpropyl)disulfide
Biodegradable PMO NPs
TET
CTAB, NaOH
CTAB, NaOH

22. Biodegradable PMO nanoparticles with
protease sensitive bonds
oxamide
200 nm
Trypsin
48 hr
pH7

23. Biodegradable PMOs are effective in drug delivery
Drug delivery to inhibit
cancer cell growth
Cancer cell uptake Uptake of FITC-labeled NPs
into PANC-1 cells

24. Nature Reviews
Drosophila
Chicken egg
C. elegans

25. Freshly fertilized eggs
are received
Eggs are incubated at 36
degrees. Inside the incubator
needs to be humid.

26. Chorioallantoic
Membrane
(CAM)

27. Chicken Egg Tumor Model experiments
MelanomaOvarian cancer
Teflon ring
Teflon
ring

28. Tumor imaging by transplanting GFP cancer cells
Phase-contrast
Green fluorescence
GFP expressing OVCAR8 cells
transplanted

29. CAM tumor Ovarian patient tumor
The CAM tumor established by using ovarian
cancer cells resembles patient tumor

30. Ovarian
H&E Trichrome Anti-Vimentin
Lung
ECM
Collagen (blue)
Muscle tissue (red)
Mesenchymal stem cells
Intermediate filament
Stromal cells
Macrophage

31. Chicken Egg model vs Mouse Model
Chicken egg Mouse
Short experimental assay (days) Longer observation period
3 days for tumor formation! (weeks to months)
Economical
Expensive
50 yen per egg! 10,000 yen per mouse
High throughput Laborious
Animal protocol not needed! Extensive animal review

32. Doxorubicin loaded biodegradable PMO
administered to the chicken egg tumor
Doxorubicin
loaded

33. Doxo/NP
Tumor elimination by doxorubicin loaded nanoparticles
Doxo/NP

34. Free Dox
100µg
Nanoparticle/Dox
200µg
Lack of organ damage by using doxorubicin
loaded biodegradable PMO
liver
intestine
kidney
heart
spleen
liver
intestine
kidney
heart

35. Lun
g
Live
r
Splee
n
Kidne
y
Intestin
e
Tumo
rHear
t
Doxorubicin is delivered specifically to the tumor,
as revealed by its red fluorescence.
Doxorubicin
loaded
Lung
Control
tumor
Liver
Spleen
Kidney
Intestine
Tumor
Heart

36. Bright field
Brain
Lung
Stomach
Liver
Heart
Small
intestine
Large
intestine
Fluorescence
Non-specific distribution of free doxorubicin

37. Tumor accumulation of Biodegradable MSN
(FITC)
Phase-contrast Green fluorescence
FITC

38. Nanoparticles accumulate in the tumor
Control
tumor Liver
Spleen
Kidney
Intestine
Tumor
Heart
Lung
Phase-contrast Green fluorescence

39. tumor
intestine liver
kidney
heart
Bright field Fluorescence
+
+
+
+
+
+
+
+
+
+ +
+
+
+
+
+
+
+
+
+
PEI-MSN
Doxorubicin
loaded
Positively charged nanoparticles show non-
specific biodistribution

40. 1. Biodegradable PMO nanoparticles provide a
promising type of MSN for cancer therapy.
2. Various biodegradable bridges can be
incorporated.
3. Further animal experiments are being carried
out.

41. Precision medicine
Biobanking
Databank
Patient derived
tumor modelsTumor
organoids
PDX model
PDC model
Patient-derived
xenograft model
Patient-derived
chicken model

42. Chicken egg tumor model provides a valuable
addition to Precision Medicine
Patient derived
tumor model
Identify optimized
Treatment for each patient
Tailor made
treatments
5 days 5 days
Drug screening
Sensitivity screen
Radiation, PDT, hyperthermia

43. Jean-Olivier Durand
Fraser Stoddart
Michael Ambrogio
Fuyuhiko Tamanoi
Kotaro Matsumoto
Tan Doan
Takehiro Harada
Keigo Nakai
Binh Vu
Joel Hayashi
Tammy Yik
Jeff Heard
Northwestern University
University of Montpellier
Jeffrey Zink
Juyao Dong
Angela Hwang
Courtney Thomas
Dan Ferris
City of Hope Cancer Center
Carlotta Glackin
James Finlay
Cai Roberts
Sophia Shahin
King Abdulah University of Science
and Technology
Jonas Croissant
Niveen Khashab
iCEMS, Kyoto University
UCLA