J. Santamaria
Instituto de Nanociencia de Aragon
Universidad de Zaragoza
Summary of this talk
• Introduction• Nanotechnology: a true technological revolution
• Nanomedicine, the application of nanotechnology in health-related areas
• Nano-assisted diagnosis
• Nano-assisted drug delivery• Thermal triggering
• Final remarks
“For every equation included in a presentation the
audience will be halved”
Jesus Santamaria corolary to Hawking´s postulate
“For every equation included in a book the sales will
be halved”
Stephen Hawking's A Brief History Of Time
“Never underestimate the joy people derive from
hearing something they already know”
Enrico Fermi
Technological revolutions
• 1. (1600–1740) Financial-agricultural revolution
• 2. (1780–1840) Industrial revolution (steamengine)
• 3. (1880–1920) Second Industrial Revolution (fromBessemer steel to mass production lines)
• 4. (1940–1970) Scientific-technical revolution
• 5. (1985–2000) Information and telecommunicationsrevolution
Wikipedia: A relatively short period when one technology (or set of technologies) is replaced by another. “A technological revolution can be defined as a dramatic change brought about relatively quickly by the introduction of some new technology (Nick Bostrom)
Now: Biotech and Nanotech revolutions?
• QuantitativeChanges
• Higher ability to penetrate
• Extreme surface/volume ratio -- functionalization
• Recognition of nano-objects (includes molecules!)
• QualitativeChanges. New properties emerge:
• Quantum effects (e.g. plasmonic materials)
• Superparamagnetism
• Affinity and reactivity
• …/…
<100 nm: Why?
Nanomaterials: one dimension under 100 nm
Nanotechapplications are not a thingof thefuture…
300 nanoproducts in the market(A. Maynard, Nature, Oct 2006)
Over 1000 nanotech products Woodrow Wilson International Center inventory, July 2009
Current estimation: >3000 products
Breathtaking growth inthe number of commercial productsBreathtaking growth inthe number of commercial products
0
1000000
2000000
3000000
4000000
5000000
2008 2010 2012 2014 2016 2018 2020
Mill
ones
de
dóla
res
LUX RESEARCH
Nanotech products:Global market of 339.000 MM $ in 2010, 731.000 MM $ in 2012. Projection for 2018: > 4.000.000 MM $
Nanotech Product Market
Spectacular economic projections
Nano Stocks
US and European Nanotechnology Graphics
www.behr.nl Holland
NanomedicineThe application of Nanotechnology to health
• Consider the possibility of
builiding objects able to
maneouver at cell level”
• Think of the "weird possibility"
of "swallowing the doctor,”
that would then travel in the
bloodstream inspecting and
repairing defects
Present from the beginning: Feynmann, (1959):
• Early and reliable detection of impairments and
conditions that may eventually lead to illness
Diagnosis
Vaso Griego, 480 AC
Luke FIldes, 1891
Nano-assisted diagnosis
The essential advantage of Nanotechnology:
Dimensions of nano-objects allow a strong
interaction with biomolecules, both outside and
inside cells
Nanodiagnosis: Identify illness or malfunctions as early as possible, ideally at the level of a single malfunctioning cell
in vitro Diagnosis• Real time results
• Highlysensitive(concentration of analytes (e.g. magneticnanoparticles) and signalamplification
• Highly reliable(antibody-functionalized nanoparticles)
• Small size samples
• Lower costs
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in vivo Diagnosis and medical imaging• Aim: Visualize target structures, even if they are of
small dimensions (e.g. a tumor in its initial stages, stillat sub-mm size)• Use especial properties of NPs (optical, magnetic, electrical…) to label the
target cells
Hofmann y cols. Swiss Med. Wkly (2010)
Hainfield y cols. Br. J. Radiol. (2006)
Wang y cols. Nanolett. (2013)
Gao y cols.
Nature Biotech. (2004)
Nano-therapy: Ehrlich´s “Magic Bullet”
Paul Ehrlich (Nobel Prize in
Medicine, 1908) coined the term
magische Kugel (magic bullet) for
the ideal therapheutic agent: Able
to selectively kill the malign agent,
leaving healthy cells intact.
Nanotherapy and controlled drug delivery:A highly localized and controlled therapeutic action, withhigh selectivity (ideally at the level of a single cell)
- controlled, highly localized drug delivery- other therapeutic actions: hyperthermia…
Delivering drugs
Maximum desirable concentration
Therapeutic threshold
Maximum desirable concentration
ControlledDrugDelivery: The concept
• Space Precision: The drug will only be delivered to the organs (cells?) that need it.• Avoid damaging side effects• Avoid drug waste
• Time Precision: The drug will only be delivered when needed• On-demand drug delivery. Programmed drug
delivery. Tailored release profiles. • Avoid patience compliance issues. Increased
safety• Drug-free theraphy: Therapeutic alternatives that
employ physical effects• Locally induced hyperthermia
Let us dream…
Ehrlich + Feynman
Mobile vectors: Intelligent Nps
�Layer for releasecontrol�loading space
�Guiding and monitoring elements
�Functionalelements (e.g. hyperthermia)�Targeting orstealthing elements
• How to avoid the detection by RES macrophages?
• How to direct the particles towards the target cells?
• How to regulate drug delivery once the target is reached?
Some (big) problems on the way
I: How to avoid the immune system?
• RES macrophages detect the nanoparticles in blood and remove them
• How to: Stealthing coatings with
hydrophilic polymers (e.g. Poly-ethylene
glycol) to retard (avoid?) detection
Small (2008)
• Enhanced Permeation and Retention (EPR) effectdescribed for proteins in 1986
• Rapid (and defective) angiogenesis leads to leakyblood vessels and poorlymphatic drainage in tumours
• Accumulates nanoparticles in the 100-400 nmrange
• Stealthing is required toachieve sufficient circulationtime
• Already some big successes, e.g. Doxil
Matsumura and MaedaCancer Res. (1986)
II: How to direct particles towards the target cells?1) Passive Targeting - EPR effect
• Active targeting: Surface functionalization with peptides or antibodies that nanoparticle uptake by the target.
• Enough circulation time is required - Stealthing
Target
cell
II: How to direct particles towards the target cells?2) Active Targeting: Antibodies or peptides
Nanoscale (2014)
Conde et al.
Biomaterials (2013)
Examplesof deliveryvectorsat INAExamples of deliveryvectors at INA
How to direct particles towards the target cells:
3) Active Targeting: Cells as Trojan Horse carriers
RSC Adv. (2016)
How to regulate drug delivery once the target is reached?
• Passive release: The process is controlled by drug diffusion or by physical or chemical degradation of the vector
• Simple and inexpensive. BUT: difficulties to avoid early release and to control release rate
• Triggered release: Release started or enhanced by an external signal (e.g. Electromagnetic radiation) or by a local condition (e.g. a different pH)
Passive release
J. Mater. Chem. B. (2014)
Control of pore
size + functionalizationDegradation of a
polymer
Triggered delivery
General triggers:
• Temperature: General (fever, external heating) or local hyperthermia (magnetic, NIR radiation)
• Chemicals (systemically or locally injected)
• Space precision: Avoids “on the way” drug losses
• Time precision: Increased safety by reducing probability of undesired release.
Target-related triggers
• Increased selectivity by tailoring to local environment concentrations: pH, chemical composition
Nanoparticle-mediated Hyperthermia
Localized heating produced when suitable receptors
are reached by external stimuli
-Alternating magnetic field �magnetic NPs
-- NIR radiation �plasmonic (or otherwise NIR-
absorbing) NPs
• Heating achieved when magnetic nanoparticles are subjected to an alternating magnetic field.
• Superparamagnetism (avoid agglomeration)
• Nanoparticles generate heat via:
• Neel relaxation (related to displacement of magnetic domain boundaries)
• Brownian loss (rotation of nanoparticles against viscous forces)
Hyperthermia with magnetic NPs
Synthesis of magnetic NPs
Solvothermal,
Polyol-mediated synthesis
Chem. Mater. (2011)
Laser pyrolysis of organic
precursors
Nanotechnol. (2012)
Nanotechnol. (2013)
1989 Neeves y Birnboim
(theoretical development)
Naomi Halas
1997 Halas et al.
( “nanoshells” with plasmon
resonance in the water window)
2003 Halas et. Al.
(tumor ablation in mice)
Several clinical trials
ongoing
NIR hyperthermia
Nanostructures capable of NIR response
A variety of such
structures are made in
our lab:
- Core/shell silica/gold
- Hollow gold
nanoshells
- Gold nanorods
- CuS nanoparticles
- …/…
Penetration:
Tailor structures to
absorb in the so-
called “water
window”
Minimal absorption by water and tissues-Penetration up to 8-12 cm (soft tissue)-Penetration up to 4-5 cm (through skull)
Lab on a Chip (2014)
NIR-responsive nanoparticles
Chem. Engng. J. (2016)
J. Mat. Chem. (2012)
• “Conventional” approach:
NPs capable of producing
hyperthermia are used for cell killing.
SiO2
Au
• Our approach: use suitable
structures to host the drug and
the triggering nanoparticle.
Heating accelerates drug release
Temperature-Triggered Delivery
Combine thermal ablation and triggered delivery
• Use temperature increase to activate (and tune)
enhanced drug release
Same concept applied in biodegradable
nanoparticles
Collaborations with E. Reverchon, U.
Salerno (Italy) and M. Blanco, U. Navarra
(Spain)
J. Mat. Chem. B (2014) Nanoscale (2016)
Drug Delivery from fixed platforms
• Prosthesis
• Insertable medical
devices
• Permanent implants
• External devices (e.g.
Skin patches)
• Delivery of antibiotics,
chemotherapics,
growth factors,
analgesics cosmetics..
Triggered release using NP- actuated valves
(magnetic/NIR hyperthermia)
Delivery at a fixed location
�Drug reservoir limited by a
thermally sensitive membrane
�Membrane includes
elements that can be remotely
heated
Collaboration with Daniel
Kohane (Harvard Ch. H.) and
Robert Langer (MIT, USA)
Thermally sensitive gel membrane
Hydrogel:
A copolymer of N-isopropylacrylamide
(NIPAM) and
N-isopropylmethacrylamide (NIPMAM)
and acrylamide (AAm)
Matrix:
Ethylcellulose
A Reversible Process – Allows multiple dosing cycles
Activation through magnetic hypethermia
Nano Letters (2010)
Nano Letters (2011)
Alternative: NIR-triggerable membranes
In collaboration with D.Kohane, R.
Langer (MIT)
LASERON
LASERON
LASERON
0 20 40 60 80 100 120 140 160 180 200
37,1
37,8
38,5
39,2
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40,6
41,3
42,0
42,7
Tem
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C)
Time (min)
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Proc. Nat. Acad. Sci. (PNAS) (2014)
In collaboration with
D.Kohane, R. Langer
(MIT)
Final Remarks• Nanomaterials are at the core of a new
technological revolution. All fields are involved: food, environment, defense,
consumer applications, health…• “Intelligent” nanoparticles:
• Drug load + Monitoring/Guiding/Recognition elements +
remote activation
• “Intelligent” Drug reservoirs:
• Capable of multiple drug loading and release
• A markedly multidisciplinary field: Success requires cooperation of scientists in different fields: synthetic chemistry, medicine, advanced fabrication, materials engineering, crystal growth, magnetism, photonics…
DYNABOOK 1972
“The best way to predict the future
is to invent it”
Alan Kay