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J. Santamaria Instituto de Nanociencia de Aragon Universidad de Zaragoza

J. Santamaria Instituto de Nanociencia de Aragon ... · • Quantum effects (e.g. plasmonic materials) • Superparamagnetism ... Global market of 339.000 MM $ in 2010, 731.000 MM

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Page 1: J. Santamaria Instituto de Nanociencia de Aragon ... · • Quantum effects (e.g. plasmonic materials) • Superparamagnetism ... Global market of 339.000 MM $ in 2010, 731.000 MM

J. Santamaria

Instituto de Nanociencia de Aragon

Universidad de Zaragoza

Page 2: J. Santamaria Instituto de Nanociencia de Aragon ... · • Quantum effects (e.g. plasmonic materials) • Superparamagnetism ... Global market of 339.000 MM $ in 2010, 731.000 MM

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

Page 3: J. Santamaria Instituto de Nanociencia de Aragon ... · • Quantum effects (e.g. plasmonic materials) • Superparamagnetism ... Global market of 339.000 MM $ in 2010, 731.000 MM

“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

Page 4: J. Santamaria Instituto de Nanociencia de Aragon ... · • Quantum effects (e.g. plasmonic materials) • Superparamagnetism ... Global market of 339.000 MM $ in 2010, 731.000 MM

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?

Page 5: J. Santamaria Instituto de Nanociencia de Aragon ... · • Quantum effects (e.g. plasmonic materials) • Superparamagnetism ... Global market of 339.000 MM $ in 2010, 731.000 MM

• 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

Page 6: J. Santamaria Instituto de Nanociencia de Aragon ... · • Quantum effects (e.g. plasmonic materials) • Superparamagnetism ... Global market of 339.000 MM $ in 2010, 731.000 MM

Nanotechapplications are not a thingof thefuture…

Page 7: J. Santamaria Instituto de Nanociencia de Aragon ... · • Quantum effects (e.g. plasmonic materials) • Superparamagnetism ... Global market of 339.000 MM $ in 2010, 731.000 MM

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

Page 8: J. Santamaria Instituto de Nanociencia de Aragon ... · • Quantum effects (e.g. plasmonic materials) • Superparamagnetism ... Global market of 339.000 MM $ in 2010, 731.000 MM

0

1000000

2000000

3000000

4000000

5000000

2008 2010 2012 2014 2016 2018 2020

Mill

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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

Page 9: J. Santamaria Instituto de Nanociencia de Aragon ... · • Quantum effects (e.g. plasmonic materials) • Superparamagnetism ... Global market of 339.000 MM $ in 2010, 731.000 MM

Nano Stocks

US and European Nanotechnology Graphics

www.behr.nl Holland

Page 10: J. Santamaria Instituto de Nanociencia de Aragon ... · • Quantum effects (e.g. plasmonic materials) • Superparamagnetism ... Global market of 339.000 MM $ in 2010, 731.000 MM
Page 11: J. Santamaria Instituto de Nanociencia de Aragon ... · • Quantum effects (e.g. plasmonic materials) • Superparamagnetism ... Global market of 339.000 MM $ in 2010, 731.000 MM

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):

Page 12: J. Santamaria Instituto de Nanociencia de Aragon ... · • Quantum effects (e.g. plasmonic materials) • Superparamagnetism ... Global market of 339.000 MM $ in 2010, 731.000 MM

• Early and reliable detection of impairments and

conditions that may eventually lead to illness

Diagnosis

Vaso Griego, 480 AC

Luke FIldes, 1891

Page 13: J. Santamaria Instituto de Nanociencia de Aragon ... · • Quantum effects (e.g. plasmonic materials) • Superparamagnetism ... Global market of 339.000 MM $ in 2010, 731.000 MM
Page 14: J. Santamaria Instituto de Nanociencia de Aragon ... · • Quantum effects (e.g. plasmonic materials) • Superparamagnetism ... Global market of 339.000 MM $ in 2010, 731.000 MM

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

Page 15: J. Santamaria Instituto de Nanociencia de Aragon ... · • Quantum effects (e.g. plasmonic materials) • Superparamagnetism ... Global market of 339.000 MM $ in 2010, 731.000 MM

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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Page 16: J. Santamaria Instituto de Nanociencia de Aragon ... · • Quantum effects (e.g. plasmonic materials) • Superparamagnetism ... Global market of 339.000 MM $ in 2010, 731.000 MM

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)

Page 17: J. Santamaria Instituto de Nanociencia de Aragon ... · • Quantum effects (e.g. plasmonic materials) • Superparamagnetism ... Global market of 339.000 MM $ in 2010, 731.000 MM

Hainfield y cols. Br. J. Radiol. (2006)

Wang y cols. Nanolett. (2013)

Gao y cols.

Nature Biotech. (2004)

Page 18: J. Santamaria Instituto de Nanociencia de Aragon ... · • Quantum effects (e.g. plasmonic materials) • Superparamagnetism ... Global market of 339.000 MM $ in 2010, 731.000 MM

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…

Page 19: J. Santamaria Instituto de Nanociencia de Aragon ... · • Quantum effects (e.g. plasmonic materials) • Superparamagnetism ... Global market of 339.000 MM $ in 2010, 731.000 MM

Delivering drugs

Page 20: J. Santamaria Instituto de Nanociencia de Aragon ... · • Quantum effects (e.g. plasmonic materials) • Superparamagnetism ... Global market of 339.000 MM $ in 2010, 731.000 MM

Maximum desirable concentration

Therapeutic threshold

Maximum desirable concentration

ControlledDrugDelivery: The concept

Page 21: J. Santamaria Instituto de Nanociencia de Aragon ... · • Quantum effects (e.g. plasmonic materials) • Superparamagnetism ... Global market of 339.000 MM $ in 2010, 731.000 MM

• 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…

Page 22: J. Santamaria Instituto de Nanociencia de Aragon ... · • Quantum effects (e.g. plasmonic materials) • Superparamagnetism ... Global market of 339.000 MM $ in 2010, 731.000 MM

Ehrlich + Feynman

Mobile vectors: Intelligent Nps

�Layer for releasecontrol�loading space

�Guiding and monitoring elements

�Functionalelements (e.g. hyperthermia)�Targeting orstealthing elements

Page 23: J. Santamaria Instituto de Nanociencia de Aragon ... · • Quantum effects (e.g. plasmonic materials) • Superparamagnetism ... Global market of 339.000 MM $ in 2010, 731.000 MM

• 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

Page 24: J. Santamaria Instituto de Nanociencia de Aragon ... · • Quantum effects (e.g. plasmonic materials) • Superparamagnetism ... Global market of 339.000 MM $ in 2010, 731.000 MM

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)

Page 25: J. Santamaria Instituto de Nanociencia de Aragon ... · • Quantum effects (e.g. plasmonic materials) • Superparamagnetism ... Global market of 339.000 MM $ in 2010, 731.000 MM

• 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

Page 26: J. Santamaria Instituto de Nanociencia de Aragon ... · • Quantum effects (e.g. plasmonic materials) • Superparamagnetism ... Global market of 339.000 MM $ in 2010, 731.000 MM

• 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

Page 27: J. Santamaria Instituto de Nanociencia de Aragon ... · • Quantum effects (e.g. plasmonic materials) • Superparamagnetism ... Global market of 339.000 MM $ in 2010, 731.000 MM

Nanoscale (2014)

Conde et al.

Biomaterials (2013)

Examplesof deliveryvectorsat INAExamples of deliveryvectors at INA

Page 28: J. Santamaria Instituto de Nanociencia de Aragon ... · • Quantum effects (e.g. plasmonic materials) • Superparamagnetism ... Global market of 339.000 MM $ in 2010, 731.000 MM

How to direct particles towards the target cells:

3) Active Targeting: Cells as Trojan Horse carriers

RSC Adv. (2016)

Page 29: J. Santamaria Instituto de Nanociencia de Aragon ... · • Quantum effects (e.g. plasmonic materials) • Superparamagnetism ... Global market of 339.000 MM $ in 2010, 731.000 MM

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)

Page 30: J. Santamaria Instituto de Nanociencia de Aragon ... · • Quantum effects (e.g. plasmonic materials) • Superparamagnetism ... Global market of 339.000 MM $ in 2010, 731.000 MM

Passive release

J. Mater. Chem. B. (2014)

Control of pore

size + functionalizationDegradation of a

polymer

Page 31: J. Santamaria Instituto de Nanociencia de Aragon ... · • Quantum effects (e.g. plasmonic materials) • Superparamagnetism ... Global market of 339.000 MM $ in 2010, 731.000 MM

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

Page 32: J. Santamaria Instituto de Nanociencia de Aragon ... · • Quantum effects (e.g. plasmonic materials) • Superparamagnetism ... Global market of 339.000 MM $ in 2010, 731.000 MM

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

Page 33: J. Santamaria Instituto de Nanociencia de Aragon ... · • Quantum effects (e.g. plasmonic materials) • Superparamagnetism ... Global market of 339.000 MM $ in 2010, 731.000 MM

• 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

Page 34: J. Santamaria Instituto de Nanociencia de Aragon ... · • Quantum effects (e.g. plasmonic materials) • Superparamagnetism ... Global market of 339.000 MM $ in 2010, 731.000 MM

Synthesis of magnetic NPs

Solvothermal,

Polyol-mediated synthesis

Chem. Mater. (2011)

Laser pyrolysis of organic

precursors

Nanotechnol. (2012)

Nanotechnol. (2013)

Page 35: J. Santamaria Instituto de Nanociencia de Aragon ... · • Quantum effects (e.g. plasmonic materials) • Superparamagnetism ... Global market of 339.000 MM $ in 2010, 731.000 MM

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

Page 36: J. Santamaria Instituto de Nanociencia de Aragon ... · • Quantum effects (e.g. plasmonic materials) • Superparamagnetism ... Global market of 339.000 MM $ in 2010, 731.000 MM

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)

Page 37: J. Santamaria Instituto de Nanociencia de Aragon ... · • Quantum effects (e.g. plasmonic materials) • Superparamagnetism ... Global market of 339.000 MM $ in 2010, 731.000 MM

Lab on a Chip (2014)

NIR-responsive nanoparticles

Chem. Engng. J. (2016)

J. Mat. Chem. (2012)

Page 38: J. Santamaria Instituto de Nanociencia de Aragon ... · • Quantum effects (e.g. plasmonic materials) • Superparamagnetism ... Global market of 339.000 MM $ in 2010, 731.000 MM

• “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

Page 39: J. Santamaria Instituto de Nanociencia de Aragon ... · • Quantum effects (e.g. plasmonic materials) • Superparamagnetism ... Global market of 339.000 MM $ in 2010, 731.000 MM

• 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)

Page 40: J. Santamaria Instituto de Nanociencia de Aragon ... · • Quantum effects (e.g. plasmonic materials) • Superparamagnetism ... Global market of 339.000 MM $ in 2010, 731.000 MM

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..

Page 41: J. Santamaria Instituto de Nanociencia de Aragon ... · • Quantum effects (e.g. plasmonic materials) • Superparamagnetism ... Global market of 339.000 MM $ in 2010, 731.000 MM

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)

Page 42: J. Santamaria Instituto de Nanociencia de Aragon ... · • Quantum effects (e.g. plasmonic materials) • Superparamagnetism ... Global market of 339.000 MM $ in 2010, 731.000 MM

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

Page 43: J. Santamaria Instituto de Nanociencia de Aragon ... · • Quantum effects (e.g. plasmonic materials) • Superparamagnetism ... Global market of 339.000 MM $ in 2010, 731.000 MM

Activation through magnetic hypethermia

Nano Letters (2010)

Nano Letters (2011)

Page 44: J. Santamaria Instituto de Nanociencia de Aragon ... · • Quantum effects (e.g. plasmonic materials) • Superparamagnetism ... Global market of 339.000 MM $ in 2010, 731.000 MM

Alternative: NIR-triggerable membranes

In collaboration with D.Kohane, R.

Langer (MIT)

Page 45: J. Santamaria Instituto de Nanociencia de Aragon ... · • Quantum effects (e.g. plasmonic materials) • Superparamagnetism ... Global market of 339.000 MM $ in 2010, 731.000 MM

LASERON

LASERON

LASERON

0 20 40 60 80 100 120 140 160 180 200

37,1

37,8

38,5

39,2

39,9

40,6

41,3

42,0

42,7

Tem

per

atu

re (o

C)

Time (min)

0 20 40 60 80 100 120 140 160 180 200 220

220

Con

cent

ratio

n(µ

g/m

L)

0,4

0,6

0,8

1,0

1,2

1,4

1,6

1,8

2,0

2,2

Proc. Nat. Acad. Sci. (PNAS) (2014)

In collaboration with

D.Kohane, R. Langer

(MIT)

Page 46: J. Santamaria Instituto de Nanociencia de Aragon ... · • Quantum effects (e.g. plasmonic materials) • Superparamagnetism ... Global market of 339.000 MM $ in 2010, 731.000 MM
Page 47: J. Santamaria Instituto de Nanociencia de Aragon ... · • Quantum effects (e.g. plasmonic materials) • Superparamagnetism ... Global market of 339.000 MM $ in 2010, 731.000 MM

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…

Page 48: J. Santamaria Instituto de Nanociencia de Aragon ... · • Quantum effects (e.g. plasmonic materials) • Superparamagnetism ... Global market of 339.000 MM $ in 2010, 731.000 MM

DYNABOOK 1972

“The best way to predict the future

is to invent it”

Alan Kay