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

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2008 2010 2012 2014 2016 2018 2020

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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

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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