Applications of Nanotechnology in Healthcare

Leonard Fass Ph.D.GE Healthcare

Journée NanomatériauxEcole des Mines de Paris22/01/09

Nanotechnology: The Future of Medical ScienceThe Ability to Control & Exploit Unique Properties of 1-100 nm Structures

Optical

Structural

Functional

1 (nm)

100 nm

0.1 nm

10-6

10-7

10-8

10-9

10-10

Visible Spectrum

Quantum Dots10-100nm

Red & White

Blood Cells ~2–5 µm

DNA ~2 nm wide

Sub-Atomic

Multiple Applications of Nanotechnology in Medicine

SurgeryCatheters

Endoscopes

Tissue Engineering

MagneticBio-separation

Diagnostic & Stem Cell

Imaging

Body SensorsWireless

DisplaysNano -

electronics

X-Ray Tubes

Low Friction Bearings

MicrofluidicsLab-on-a-Chip

TargetedMolecular &

Thermal Therapy

Pathogen &Contaminant

DetectionSterilization

Oxygen Delivery

ThrombolysisDrug Delivery

Drug DetectionGene Therapy

DeliveryBlood

Brain Barrier Permeability

Bio-MedicineBio Chips

Probes

TransducersDetectors

Factors affecting physical properties

Structure

Size Shape

Surface

Nanomaterial

Why is size important?•Changes in physical properties.

– High thermal and electrical conductivity– High strength to weight ratio– Size dependent Optical, Magnetic and Electrical properties

•Compact devices– MEMS devices as biosensors– High density packing

•Transport across physiological barriers – Blood brain barrier– Cell membranes– Vascular capillary endothelium

•Physiological constraints– Angiogenesis permeability– Osmotic pressure due to lymphangiogenesis– Collagen encapsulation– Agglomeration due to inter-particle forces

Examples of changes in physical properties on the nanoscale

•Paramagnetic Iron Oxide particles become superparamagnetic below 10nm

•Quantum dot fluorescence varies with size when diameter is less than the Exciton Bohr Radius in conditions of 3D confinement

•Nanowires have electron confinement in two dimensions

•Electron hopping replaces tunnelling in short nanowires below 7nm

•Metal nanoshells with dielectric core light absorption wavelength is inversely proportional to shell thickness due to surface plasmon resonance

•Attaching nano-sized biomolecules to cantilevers increases resonance frequency when their thickness is order of nanometres but decreases resonance frequency when their thickness is of order of microns

Small molecules and biological barriers

- Small molecules (< 100nm) pass through capillary membranes

-Small molecules pass through the Blood Brain Barrier, when lipophilic or transport mechanism is available

- Mean free path ∝ √(t/r)

- r ∝ t for fixed diffusion distance

Gustav K. von Schulthess, Zurich

Size dependence of nanoparticle diffusion

Molecule µ / sec Time to radius diffusion diffuse rate 20 µ (sec)

0.1 nm 60 0.11 nm 20 12 nm (FDG) 12 2 4nm nanoparticles 8 4(USPIO‘s) 10 nm (antibody) 6 10 100 nm 2 100 400 nm 1 400

Gustav K. von Schulthess, Zurich

The importance of shape

Bimomimetic nanoparticles have easier access into cells with applications in chemotherapy and as antibacterial agents.

High aspect ratio nanorods pass cell membranes more easily and penetrate deeper into cells than low aspect ratio particles

Reptated polymers and nanorods can enter angiogenic endothelial cells

Nanotube aspect ratio could influence lung toxicity

Enhanced Permeability and Retention(EPR) Effect

Causes accumulation of nanoparticle drugs in tumours due to the increased permeability of angiogenic blood vesselsDrug loaded carbon nanotubes 100nm long and a few nm wide enter angiogenic blood vessels but not normal blood vessels

Angiogenesis Imaging--- Small cross section molecules for PET and MR

interstitium

matrixendothelium

lumen

Agent Endothelium Penetration

coiled molecule

small molecule

linear moleculeParamagnetic ion, Gd

Chelator,DTPA

Backbone polymer,Poly-l-lysine peptide

Agent Synthesis

Agents that penetrate the larger openings in the endothelial layer of blood vessels

Surface effects

Surface Plasmon Resonance

Magnetic Plasmon Resonance

Surface Enhanced Raman Spectroscopy

Dielectric Constant Scaling

Increased Surface to Mass Ratio

Chemical Reactivity

Protein adsorption (Corona effect)

Jam-packed

Segregated

Preventing nanoparticle agglomeration

Structure and Physical PropertiesStructural properties of nanomaterials lead to advanced physical characteristics----increased mechanical strength, low coefficient of friction, high electrical & thermal conductivity etc. Applications

– Nanowire--- superconducting magnets for MRI– Nanocomposites---X-Ray tube anodes – Carbon nanotube, Spindt electrodes--- field emitters for

X-Ray tube cathodes, displays for point of care devices– Nanolayers---low friction bearings for X-Ray tube

anodes – Nanomaterials---high density electronics, thermal

expansion compensation for miniature medical devices– Nanoneedles--- biosensors– Block copolymers---tissue engineering.

~ 1µ

• Contrast agents for Medical Imaging and Pathogen Detection– MRI Magnetic Resonance Imaging– Optical imaging– Ultrasound– CT Computerized Tomography with X Rays– PET Positron Emission Tomography– PAT Photo-Acoustic Tomography– SERS Surface Enhanced Raman Spectroscopy– SPRI Surface Plasmon Resonance Imaging

• Microfluidics synthesis of PET molecules • Targeted agents for molecular imaging• Targeted image guided therapy• Magnetic heating of nanoparticles during therapy• Infra-red heating of nanoshells/nanotubes during therapy• Convection enhanced delivery with liposomes

Nanotechnology in Imaging and Therapy

Biomarker Imaging

Payload BiomarkerLigand

BiomarkersBiomarkers identified from studies of the Human Genome & Proteome

Targeted ChemistryTargeted chemistry that selectively binds to Biomarkers and amplifies their imaging signal

Ligands include •Viruses•Small molecules •Peptides •Antibodies•DARPINS•Aptamers•Dual recognition

Validation versus gold standard will be key

Nanotechnology Molecular Imaging Agents

Diseased CellSignal Target

Ligand Enhanced Sensitivity (SNR) Targeting Capability

10 nm

SPIO (MR)

• Iron oxidenanoparticles• 10 – 100 nm

Liposomes/Emulsions (MR, CT)

• Gd or I laden liposomesor lipid emulsions• 10K to 100K atoms/nanoparticle• 100 – 300 nm

Dendrimers (MR,CT)

• Iodinated dendrimers•Gadolinium dendrimers• 5 – 30 nm

Fullerenes (MR)

• Gd filled buckyballs• 1 - 5 nm

Quantum Dots (Optical)

• CdSe/Te/SiC nanoparticles• 4 – 20 nm

Nanotubes (MR)

• Gd filled Carbon nanotubes• 10 Gd atom clusters• 10X Sensitivity

Core/Shell nanoparticles(CT)

• Metal or metal oxide core • Shell of I, Gd, Ca • 10nm

Fluorescence microscopy3.0T Scanning time ~ 13 minutesresolution 39 × 48 × 100 µm3

MRI living SPIO labeled HUVECs

• HUVECs – human umbilical vein endothelial cells• Repair of vessel walls & tracking of vessel growth (oncology) • SPIO labelling ---- viability of cells & cell division?

Multiplexed Imaging with Quantum Dots

Image of mouse intestine showing two types of protein and the cell nucleus(blue)

Mark Ellison, Tom Deenink NCMIR

Emerging Targeted Interventional Therapies

Imaging Guidance

Targeted Contrast

Targeted Treatment

• Metal nano-particles• Radio markers• Fluorescent markers

• Quantum dots

Medical Applications

• EM navigation• 3D X-ray• Intra-vascular U/S• Optical imaging• MR

• Chemo-embolization• Magnetic and IR thermal therapy with nanoparticles

• X-Ray activation• Focused ultrasound• Light-activated therapy• Carriers: nano-particles, liposomes, polymers

• Colorectal cancer• Melanoma• Kidney cancer• Bladder cancer• Breast cancer• Brain cancer• Prostate cancer

Nanotechnology Drug Delivery SystemsLiposomesMicellesLiquid CrystalsPorous SiliconDendrimersHydrogelsMolecular Imprinted PolymersConjugation of polymers to peptides or proteinsIn-situ forming implantsControlled release microchipsNanoparticles, Nanocells, Nanocontainers, Nanorods, Nanotubes, Nanopipettes, Nanobubbles

• Ultrasound imaged and activated drugs• Focused ultrasound for thermal or mechanical activation• Photo-acoustic activation• Liposomes• Non lipid based

• Magnetically activated drug delivery system• Magnetic Targeted Carriers

• Activated carbon for reversible adsorption of drugs• Iron particles for magnetic targeting • Extravasation from blood vessels under local magnetic field

Targeted Drug Delivery with Nanoparticles

•Chemotherapeutic agents delivered directly to the tumour via liposomes.  •Liposomes carry the agent and a contrast agent.  •Liposome cell wall bursts when it is heated (at the tumour site), releasing the drug & activating contrast agent•Optimal, localized intervention

Primate:Coronal MR images of Corona Radiata (CR) target

“Diapeutic” Intervention-Image Guided Convection Enhanced Delivery

Courtesy of Krys Bankiewicz, John Park and Tracy McKnight, UCSF

minutes

10 32 52 72 97

Therapeutic Gene in a Delivery System• Packaged in a virus (intravenous)

• Liposome delivery system (intravenous)

• DNA-protein complex (intravenous)

• ABCD Nanoparticles

• Aerosol

• Nasal spray

• Nano Rods

• Ultrasound activated microbubbles

Removeand

culture cells

Transfer therapeutic gene to cells

Return cells with therapeutic gene to patient

Gene Therapy

ABCD Nanoparticle Concept for Nucleic Acid Delivery

Synthetic, self assembly nanoparticles constructedfrom tool-kits of synthetic chemical components

A; nucleic acids (siRNA, mRNA, pDNA)B; lipid envelope layerC; stealth/biocompatibility polymer layerD; biological recognition ligand layer

K. Kostarelos & A. D. Miller, Chem. Soc. Reviews, 2005, 34, 970-994.

Microfluidics for Healthcare

Applications Include

• Drug Discovery• Proteomics & Genomics• Radio-Pharmacy• In Vitro Diagnostics

Benefits• High Speed and reduced system complexity• Small sample volume (nanolitre to microlitre)• High Content Analysis and multiplexing• Low cost disposable modules

Nano-droplet reactors

10µ

Courtesy of Abe Lee, UC - Irvine

High-content Integrated Quantitative Molecular Diagnostics: High IQ-MD

Lab Automation: Sample Prep, SMM, & SMD

1mm

Microfluidic Pumps

Cell trapping

In-vivo IR Spectroscopy

Cell sorting by adhesion protein

Cell lysing nSERS

Microfluidic interface

Confocal microscopy

Confocal nSERS

In-vivo detectionwindow

Nanogap Junction

µCIAs

Cellular Analysis

Prof. Luke P. Lee, Berkely

Microfluidics Enabled Surface Plasmon Resonance for Protein Studies

• Label-free analysis of interactions between proteins and other molecules, including small molecules such as drug candidates

• Applications include:• Antibody characterization• Proteomics• Immunogenicity• Lead Characterization• Biotherapy Biacore

Flexchip

GE Healthcare Biacore Instruments

Microfluidics for PET Tracer Synthesis

Benefits to the user• Enables dose on demand

• Self shielded, no hot-cell

• Rapid synthesis

• Simple operation

• Integrated QC analysis

• GMP multi-tracer synthesis

Raw radio-nuclide supply

Patient dose

Microfluidic synthesizer

Reagent chip

Cyclotron

Nanotechnology and Biosensors

Nanotechnology will contribute to a wide range of diagnostic applications through the development of:

• Implantable Diagnostic Devices• Internal Diagnostics• Intracellular Diagnostics• Pathogen Detection• Contaminant Detection • Enabling Technologies

• Nanotubes & nanowires• Quantum dots• Hybrid organics/inorganics

Nano BioSensors in the ER

• Benefits• Real time, in situ reading ofbiochemical activity• Cellular level optical imaging• Sensor guided precision

surgical tools

NanowiresGE Global Research (2002)

Nano BioSensors in the Doctor`s Office

• Benefits• Total blood analysis in minutes• Rapid, accurate disease

diagnosis• Patient specific disease

treatment

Self Assembled Block Copolymer Thin Films (GE Global Research, 2002)

• Enabling Technologies• Molecular recognition• High density nano-arrays

• Enabling Technologies• Wireless communications• Self powered devices• High resolution displays

Nano BioSensors at Home

Organic Light Emitting Diode (GE Global Research, 2002)

• Benefits• Simple patient administered diagnostic tests• Automatic transmission ofoutpatient data from home tothe doctor

Integrated Hall Effect Sensor (GE Global Research, 1998)

Electrochemical

pH

Thermometric

Optical

Piezoelectric

Magnetic

Pathogen Biosensor

Signal

Physiochemical Transducer

Change

•Binding (affinity)•Chemical reaction•Release of a detectable species

Biomolecular recognition event

Enzyme

Antibody

Micro-organism

Cell

Aptamer

Nucleic Acid

Multiple binding sites

Raman Tag

YY

Y

Y

Y

YYY

50 nm Au

SiO2 Shell

Antibodies

• Nanoparticles engineered to provide Raman signal• Antibody-coated for specificity for pathogens• Multiple tags and multiplexed assays• Microfluidics provide simple new methods

1 particle gives Raman signal ~ 5 billion moleculesRaman signal of 1 mM Analyte from 2 µg Au/L particles

PathogenYY

Y

Y

YY

YY

YY

Y

Y

YY

YY

YY

Y

Y

YY

YY

YY

Y

Y

YY

YYYY

Y

Y

YY

Y

Y

YY

Y

Y

YY

YY

Pathogen Detection with Surface Enhanced Raman Spectroscopy(SERS)

SERS system for detection of drugs, chemicals,explosives and biotoxins

Portable, user-friendly, handheld device that reliably identifies a broad range of substances in liquid, powder & solid formsRemote operation and wireless modem

Systems Integration is Key to Success

• In Vitro Analysis• Protein targeting fluorescent

nanoparticles, Microfluidics Lab on a Chip,Nanowire & Nanocantilever sensors

• Medical Imaging• MEMS, Nano Systems

• Communication Satellites• 3D, Thin, Low Power Packaging

• Mobile Communications• Miniature, High Performance

Systems

Point of Decision Application

MEMS based pocket ultrasound system replacing stethoscope

Conclusions•Nanotechnology will enable new applications:

– Combined therapeutics, diagnostics & monitoring– Real time remote physiological monitoring– Remote therapy follow up– Targeted drug delivery, activation & imaging– Biomarker discovery– Point of care medicine– Tissue engineering– Surgical and interventional procedures

• Academia and SME’s will make initial discovery• Major industries will lead system integration• Education will be key for nanotechnology implementation