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Biomedical technology and innovation
A Shmulewitz and R Langer, Nature Biotechology 24:277-280 (2006)
Nano Tech
Bio Tech Info Tech
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Nanoscale medicinesState of the art of nanoparticles as drug delivery systems
Hans P. MerkleDepartment of Chemistry and Applied BioSciences, D-CHAB
ETH Zurich, CH-8093 Zurich, Switzerland
www.galenik.ethz.ch - [email protected]
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Welcome to Zurich
Welcome to ETH Zurich
ETH Campus Hnggerberg
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Biochemistry
Biophysics
Chemical and Bio-Engineering
Inorganic ChemistryMaterials Science
Microbiology
Organic Chemistry
Pharmaceutical Sciences
Physical Chemistry
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Colloidal silicon dioxide is a widely
established excipient in drug formulation
Particle size ca. 15 nm
Specific surface
50380 m2g-1 (BET)
Tablet disintegrant
Powder flow regulation
agent
Anticaking agent Adsorbent
Suspending agent
Viscosity-increasing agent
1 m
Aerosil A-200
Degussa
Aerosil (Degussa, DE)
Cab-O-Sil (Cabot Corp., USA)
Wacker HDK (Wacker-Chemie, DE)
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TiO2and ZnO nanoparticles in sunscreens
ZnO
TiO2
500 nm
200 nm
AO Gamer et al. Toxicology
in Vitro 20:301
307 (2006)
(Safety) ... would only be of concern inpeople using sunscreens if the ZnO and
TiO2penetrated into viable skin cells.
The weight of current evidence is that
they remain on the surface of the skinand in the outer dead layer
(stratum corneum) of the skin.
http://www.tga.gov.au/npmeds/
sunscreen-zotd.htm
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Superparamagnetic
iron oxide (SPIO)
Fe2O
3or Fe
3O
4
nanoparticles as
contrast agents
for MRI diagnostic
imaging
T1
Gd, T1
SPIO, T2
SPIO + Gd, T2SPIO, true FISP
SPIO, T2 grad
i.v. SPIO nanoparticles
greatly improve visibility
of hepatic metastases from
colon cancer
A Jackson and DA Nicholson
DOI 10.1007/3-540-26420-5_14
http://www.springerlink.com/
content/h1072l0h60326p48/
Springer (2006)
http://www.springerlink.com/content/h1072l0h60326p48/http://www.springerlink.com/content/h1072l0h60326p48/http://www.springerlink.com/content/h1072l0h60326p48/http://www.springerlink.com/content/h1072l0h60326p48/http://www.springerlink.com/content/h1072l0h60326p48/ -
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What makes nanoparticles so attractive
as platform for drug delivery?
Delivery by nanoparticles helps to decouple
the three major functions of drugs ...
- Therapeutic activity
- Biodistribution
- Unwanted side effects
Drug
Nanoparticle
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Agenda
Historical aspects
Nanomedicinesa forward look
Examples and technologies for nanoparticles Biodistribution of nanoparticles
The challengelong circulating
nanoparticles Ligand-mediated delivery
Conclusions
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Birth of nanoparticles as drug delivery
systems at ETH Zurich in 1976
G Birrenbach & PP Speiser, J Pharm Sci 65:1763 (1976)
... the partition of drugs
in such nanoparts
seems to be promisingas a new drug delivery
system for long term
therapy ...
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Nanoparticles for therapeuticsFrequency of scientific publications per year
0
100
200
300
400
500
600
700
800
900
1990 1992 1994 1996 1998 2000 2002 2004 2006
East
up to June 2007
Numberofpublicatio
nsperyear
19902007
(nanoparticle* OR nanocapsul*) AND drug
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Nanomedicine
Scope Analytical tools
Nanoimaging
Nanomaterials and nanodevices
Novel therapeutics andnanodevices
Clinical, regulatory and
toxicological issues
Regulatory issues Guidelines to ensure safe and
reliable transfer of advances in
nanomedicine from laboratory to
bedside
Definitions Size range from 1 nm to
several hundreds ofnanometers
To be included in a micro-
device or a biological
environment
To monitor, control,construct, repair, defend
and improve all human
biological systems
Ultimately to achieve
medical benefit
Concerns To ensure short and long
term safety
http://www.esf.org/
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NCI Alliance for Nanotechnology
in Cancer, 2005
http://nano.cancer.gov/news_center/nanotech_news.asp
Bibliography
2002 - 2007
Website
http://nano.cancer.gov/resource_center/sci_biblio_enabled-therapeutics_abstracts.asp
http://nano.cancer.gov/news_center/nanotech_news.asphttp://nano.cancer.gov/resource_center/sci_biblio_enabled-therapeutics_abstracts.asphttp://nano.cancer.gov/resource_center/sci_biblio_enabled-therapeutics_abstracts.asphttp://nano.cancer.gov/resource_center/sci_biblio_enabled-therapeutics_abstracts.asphttp://nano.cancer.gov/resource_center/sci_biblio_enabled-therapeutics_abstracts.asphttp://nano.cancer.gov/news_center/nanotech_news.asp -
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Clinical potential of nanoparticles
Parenteral and peroral deliveryof drugs of very low aqueous
solubility
Delivery to organs, tissuesand cells of the mononuclear
phagocyte systems, MPS
Extravasation into tumor tissue
Targeted ligand-mediated
delivery
(Mucosal delivery)
- Liver
- Lung
- Lymph nodes
- Macrophages
- APC
Therapeutics
Diagnostics
Vaccines
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Examples and Technologies
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Nanosuspensions of poorly soluble drugs
Unfavorable
energetics leading
to agglomeration
Charge or sterically
stabilized surface
using surfactants
Nanosuspension SolutionCrystal
BE Rabinow, Nat Rev Drug Disc 3:785 (2004)
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Abraxane -
the first nanoparticle
therapeutic on the market:
http://www.abraxane.com/HCP/index.htm
FDA approval of
Abraxane on
January 7, 2005
Taxol
Paclitaxel
Human serum albuminnanoparticles of ca. 150 nm
made by desolvation and
glutardialdehyde crosslinkage.
Vitali Vogel et al. Progr Colloid
Polymer Sci 119:31 (2002)
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Solid lipid nanoparticles, SLN
Excipients Mono-, di- and triglycerides
Fatty acids
Cationic lipids
Surfactants
Manufacturing
High shear homogenisation
Ultrasound Extrusion
Solvent evaporation
DB Chen et al. Chem Pharm Bull
49:1444 (2001)
Long-circulating SLNcontaining paclitaxelt1/2= 10 h (SLP) vs. 1.3 h (PTX)
200 nm
W Mehnert & K Mader, Adv Drug Deliv
Rev 47:165 (2001)
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Nucleic Acid Solutionin Buffer
Free Nucleic AcidRemoval
LB Jeffs et al. Pharm
Res 22:362 (2005)
with DNA
no DNA
200 nm
Liposomes forencapsulation
of nucleic
acids
Scalable, extrusion-
free technology for
stabilized nucleic
acid lipid particles
(SNALP)
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Cellular delivery with micellar core-shell
self-assemblies of amphiphilic polymers
JA Hubbell, Science
300:595 (2003)
Packaging
nucleic acid
Packaging
hydrophobic
drugs
1
2
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Biodistribution of nanoparticles
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Efficient phagocytosis of
human serum albumin
nanoparticles bymacrophages in vitro
0.01 mg/ml HSA
0.025 mg/ml HSA
0.1 mg/ml HSA
1.0 mg/ml HSA
Flow cytometry
C
ounts
FITC intensity
No HSA nanoparticles
Macrophages with
HSA nanoparticles
100 nm
K Langer et al. Int J Pharm
257:169 (2003)
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The Mononuclear
Phagocyte System
MPS
Liver, Kupffer cells
Lungs, macrophages
Spleen, macrophages Lymph nodes,
macrophages
Kidney phagocytes
Blood monocytes
Bone marrow
precursor cells
Brain, microglia
Kupffer cells loaded with
ink particles in liver sinusoids
SV = central vein
Kupffer cells K with
ink nanoparticles in
liver sinusoids. SV:
centrilobular vein
Macrophages M
and erythrocytes E
in spleen tissue
K
M
M
M
E
E
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The liver as a component of the MPS
Liver lobule with portal tract
T and centrilobular vein CV
Centrilobularvein
Lobule
Herpatic vein
Bileduct
Heparticportal vein HPV
Hepaticartery HA
Bile duct HA HPV
T
T
T
CV
From PR Wheather et al.Functional Histology, Churchill
Livingstone, Edinburgh 1987
T
T
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Splenic
accumulation
of NP in the rat
... caused by
filtration at the
interendothelial cell
slits IES or by direct
splenic macrophage
recognition?
SM Moghimi et al.
J Leukoc Biol 54:513 (1993)2 m
Accumulation in lysosomes of rat
splenic red pulp macrophages.
220 nm poly(styrene) nanoparticles.
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Biodistribution of Rhodamin 123 loaded
PGA-PLA nanoparticles in mice
HF Liang et al.
Biomaterials
27:2051 (2006)
100 nm nanoparticles
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Extravasation into tumor tissueEnhanced permeability and retention (EPR) effect
TM Allen & PR Cullis Science 303:1818 (2004)
Y Matsumura et al. Gan To Kagaku Ryoho 14:821 (1987)T Inai et al. Am J Pathol
165:32 (2004))
Endothelial
fenestrations
to tumor tissue
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Passage of nanoparticles across the BBB
is mediated by binding of ApoE
Blood
vessel
Neuron
Endothelium
AstrocyteBasement
membrane
PericyteTight junction
ApoE
receptor
Release
of drug
Endotheli
um
ApoE
ApoEcoated NP
Polysorbate 80
coated NP
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Long-circulating "stealth"
nanoparticles
... how to avoid clearance by the MPS?
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Toward protein resistant "stealth" surfaces
Adsorption of hydrophilic block-co-polymers onhydrophobic surfaces
Poloxamines a 20; b 120
Poloxamers a 60; b 100120
Covalent conjugation of PEGa a 40 - 100 SMMoghimi
etal.Pharmaco
lRev53:283(20
01)
PEGb PPGa PPGa PEGb
PEGb PPGa PPGa PEGb
NCH2CH2N
PEGb PPGa PEGb
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The surface makes the difference
Polystyrene nanospheres of 200 nm.
Due to surface hydrophobicityuncoated particles tend to aggregate.
Upon iv injection uncoated particles
are cleared within minutes by the
hepatic Kupffer cells.
SM Moghimi et al. FASEB J 19:311 (2005)
Polystyrene nanospheres of 200 nm
with poloxamine 908 coating of 8 nm.Coating prevents aggregation, and
results in ordered stacking. Upon iv
injection, coated particles circulate for
extended periods of time. Eventual
clearance by spleen is due to filtration.
Uncoated nanoparticles Poloxamine 908 coated
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Paclitaxel loaded core-shell
assemblies extend circulation
and antitumor activityin tumor-bearing mice
JA Hubbell, Science
300:595 (2003)
Negative
control
T Hamaguchi et al.
Brit J Cancer 92:1240 (2005)
25, 50 and 100 mg kg-1
Paclitaxel alone
Paclitaxel micelles
Paclitaxel
Control
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Breakthrough in
siRNA delivery
K Whalley, Nature Rev Drug Discov 4:1 (2006)
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4040
LiposomesStabilized nucleic acid
lipid particles (SNALP)for DNA and RNA delivery
Lipid excipients
H
+
PEG-lipid
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SNALP for systemic
siRNA mediated
ApoB gene silencingto lower LDL
TS Zimmermann et al.
Nature 441:111 (2006)
siRNA delivery throughSNALP can lower both
ApoB and LDL levels in
cynomolgus monkeys
RelativeAp
oBlevel
RelativeLDLlevel
ApoB
LDL
LDL particle ApoB
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Ligand mediated deliveryof nanoparticles
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Gal-PLA-PGA nanoparticles
HF Liang et al.
Bioconj Chem
17:291-299 (2006)
Poly(L-lactic acid)
PLA
Activated PLA
Carbodiimid
Poly(-glutamic acid)
Amphiphilic
block copolymer
NanoparticleGalactosylated nanoparticle
Galactosamine
Galactosamine
Targeted nanoparticles
for paclitaxel delivery
Hydrophilic,
anionic shell
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Tumor
Liver
Spleen
Gal-Rhod-NPRhod-NP
Liver and tumor targeted localization of
galactosamin modified nanoparticles
HF Liang et al.
Biomaterials
27:2051 (2006)
Partial reduction of
spleenic acculation
in mice
Increased liver uptake
Increased tumor uptake
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Targeted organdistribution ofgalactosamin
modifiedpaclitaxel NPs
HF Liang et al.
Biomaterials
27:2051 (2006)
Galactosamin
negative control
Galactosamin
modified NPs
Intensity
counts/mg
Inten
sity
counts/mg
Rhodamin 123loaded Gal-NPs in
hepatoma-tumor-
bearing nude mice
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Superior tumor volume response of
galactosamin modified paclitaxel NPs
HFLianget
al.Biomaterials
27:2051(2006)
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Conclusions
The future of nanomedicines has alreadybegun.
Nanomedicines raise novel prospects for
diagnosis and drug delivery.
Nanomedicines can decouple the delivery of
drugs from their normal biodistribution.
Scientific challenges are long circulation
("stealth") and ligand-mediated delivery
Laboratory-to-clinic is demanding, but niches
are about to come up.
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Thank you for your attention