Nanotechnologie in de zorg: kansen en risico`s

Nanotechnologie in
de zorg:
kansen en risico’s
Robert Geertsma
RIVM
[email protected]
Nanomedicine
Opportunities
Nanotechnologies
Biological
sciences
Cognitive
sciences
Tissue Engineered Products
Gene Therapy
Drug/device combinations
Smart materials
Minimally invasive surgery
Computer-assisted surgery systems
Active medical devices
Artificial organs
Telemedicine
Medical Imaging
Diagnostics (lab on a chip)
Materials science
Information technology
Converging technologies
2
Geertsma - Nanotechnologie in de zorg: kansen en risico's | KIVI NIRIA, 11 oktober 2012
Surgery - examples
●Conventional surgical tools
– Suture needle with stainless steel nanocrystals (1-10 nm) – on the market
›Sandvik Bioline 1RK91™ needles (AB Sandvik, Sweden)
– Diamond-coated surgical blade (surface roughness 20-40 nm) – on the market
›Diamaze PSD (GFD Gesellschaft für Diamantprodukte mbH, Germany)
●Future directions
– Nanosurgery
Optical tweezers for manipulation & immobilisation of cells, organelles and biomolecules
Femtosecond laser systems in neurosurgery, ophthalmology and dermatology
– Minimally invasive surgery
Carbon nanotube-reinforced catheters
– Lab-in-a-cell
3
Geertsma - Nanotechnologie in de zorg: kansen en risico's | KIVI NIRIA, 11 oktober 2012
Cancer therapy
(examples)
●Thermotherapy
– Photothermal ablation using gold-coated silica nanoshells
›Technology licensed to Nanospectra Biosciences Inc, USA
›Clinical investigation http://www.nanospectra.com/
– Magnetic field-induced thermotherapy using superparamagnetic iron oxide NPs
›MagForce®, MagForce Nanotechnologies AG, Germany
›CE Mark June 2010, available in Germany
4
Geertsma - Nanotechnologie in de zorg: kansen en risico's | KIVI NIRIA, 11 oktober 2012
Implantable
materials/devices
orthopaedics
●Bone replacement materials
– Hydroxyapatite (HA) and tricalcium phosphate (TCP) NPs – on the market
›
Ostim®, Osartis GmbH, Germany (HA)
›
NanOss™, Angstrom Medica Inc, USA (HA)
VITOSS®, Orthovita Inc, USA (TCP)
OsSatura™, IsoTis International, Switzerland (HA + TCP)
›
›
●Implant coatings
– Nano-structured HA for hip, knee and dental prostheses
›Inframat Inc, USA - in vitro studies
›Spire Biomedical Inc, USA
– Nanocrystalline metalloceramic coatings
– Nanocrystalline silver antimicrobial coatings
– Nanoporous alumina on titania alloys
●Surface modifications
– Nano-structured surface using nanofibres
– Surface roughness modification
5
Geertsma - Nanotechnologie in de zorg: kansen en risico's | KIVI NIRIA, 11 oktober 2012
Textiles / wound
care products
●Textiles
–Antimicrobial Nanocrystalline silver particle-incorporated yarns – on the market
›
Nano-silver polymers and cotton yarns, JR Nanotech plc, UK
› BIOSILVER/Mipan Nano-Magic Silver®, Hyosung, South Korea
●Wound care products
– Nanocrystalline silver particle-based wound dressing – on the market
Acticoat* SYLCRYST™, Smith & Nephew plc, UK
– Biodegradable polymer nanofibres
Alltracel Pharmaceuticals plc, Ireland
– Wound dressings with polyurethane & silk nanofibres
6
Geertsma - Nanotechnologie in de zorg: kansen en risico's | KIVI NIRIA, 11 oktober 2012
Active implantable
devices
●Retinal implants
– Neuroprostheses for vision rehabilitation – clinical investigation
Optobionics Corp, USA
Retina Implant AG, Germany
IIP Technologies, Germany
●Pacemakers
– High-speed communication using spintronics – on the market
St. Jude Medical Inc, USA
●Hearing aids
– Spintronic-based sensors to accommodate source of sounds – on the market
Starkey Laboratories Inc, USA
7
Geertsma - Nanotechnologie in de zorg: kansen en risico's | KIVI NIRIA, 11 oktober 2012
in vivo molecular
diagnostics
●Magnetic resonance imaging
–
Superparamagnetic nanocrystalls (images with dark contrast)
›
Superparamagnetic iron oxide (SPIO) nanoparticles (50-500 nm) – on the market
›
Lumirem®, Advanced Magnetics Inc, USA
Ultrasmall superparamagnetic iron oxide (USPIO) nanopart. (<50 nm) – clin. invest.
Supravist™, Schering AG, Germany
–
Markers in or on implants/instruments to enable (real-time) imaging
›
MagnaFy-MRI , MRWire, Nano4Imaging, DE
10
-1
1
10
1
10
2
Nanometres
10
3
10
4
10
5
10
6
10
7
10
8
wit
water X@C60 dendrimer SPIO
molecule
8
Geertsma - Nanotechnologie in de zorg: kansen en risico's | KIVI NIRIA, 11 oktober 2012
in vitro molecular
diagnostics
●DNA microarrays
–Optical detection of DNA sequences – on the market
›e.g. GeneChip®, Affymetrix Inc, USA
–Electronic detection of DNA sequences – on the market
›Nanochip® Molecular Biology Workstation, Nanogen Inc, USA
›Tag-It™ Cystic Fibrosis Kit, Tm Bioscience Corporation, Canada
●Lab-on-a-chip (LOC)
–Microtechnology-based LOCs for enzyme detection – on the market
›LabChip®, Caliper Life Sciences, USA
›LabCD ®, Tecan Group Ltd, Switzerland
–LOC equipped with nanopores for DNA sequencing
›Ultra-rapid sequencers: 1000 base per second
–Point of care measurement of lithium blood levels
›Medimate BV, Netherlands
9
Geertsma - Nanotechnologie in de zorg: kansen en risico's | KIVI NIRIA, 11 oktober 2012
Drug delivery
Nanomaterials used in nanodrugs
●Nanocrystals
●Liposomes
●Micelles
●Polymers
●Proteins
●Cyclic peptides
●Dendrimers
●Carbon nanomaterials
●Nanoshells
●Quantum dots
10
Geertsma - Nanotechnologie in de zorg: kansen en risico's | KIVI NIRIA, 11 oktober 2012
Summary
Opportunities
● Nanotechnology is expected to have great impact on
many areas in medical technology, especially:
–Surgery
- Implant technology
–Cancer diagnosis
- Tissue Engineering
–Cancer therapy
- Drug delivery
–Biosensors
- Gene delivery
–Molecular imaging
● Nanotechnology is foreseen to change health care in a
fundamental way:
–Novel methods for disease diagnosis and therapy
–New and effective tools for disease prevention
–Point-of-care, fast testing → daily screening of health
–Therapeutic selection tailored to the patient’s profile
11
Geertsma - Nanotechnologie in de zorg: kansen en risico's | KIVI NIRIA, 11 oktober 2012
Nanomedicine: new opportunities – also new risks?
Nature
water
molecule
10
-1
DNA
1
virus
10
1
10
2
erythrocyte
10
3
10
4
apple
10
5
10
6
10
7
10
Nanometres
Nanotechnology
nanopore, dendrimer,
nanoshell, fullerene,
nanotube, nanowire,
nanocrystalls
cantilevers,
microneedles
lab-on-a-chip
Nanomaterials (nanoparticles) can have sizes similar to structures at subcellular level
and (theoretically) can reach and interact with such structures.
12
Geertsma - Nanotechnologie in de zorg: kansen en risico's | KIVI NIRIA, 11 oktober 2012
8
?
Nanotechnologies ≠ Nanomaterials
Risks related to nanomaterials are generally
not applicable to nanotechnology products
like nanoelectronics !!
Nanotechnology in medical applications - State-of-the-art / Risks
RIVM reports 265001 001 / 002 , 2005 - www.rivm.nl
601785 003 , 2009
EU ObservatoryNANO - www.observatorynano.eu/project/
EC N&ET WG http://ec.europa.eu/enterprise/medical_devices/net/net_en.htm
13
Geertsma - Nanotechnologie in de zorg: kansen en risico's | KIVI NIRIA, 11 oktober 2012
Effect of size
Example of tissue distribution of spherical gold nanoparticles
ICP-MS measurements
4000
10 nm
50 nm
3500
100 nm
250 nm
concentration gold
(ng/gram organ)
3000
2500
• Most in liver, spleen
• 10 nm particles more
widespread
2000
1500
1000
500
0
Blood
Liver
Spleen
Lungs
Kidneys
Repr.
Organs
Thymus
Heart
Brain
De Jong et al., Biomaterials, 2008
14
Geertsma - Nanotechnologie in de zorg: kansen en risico's | KIVI NIRIA, 11 oktober 2012
Effect of shape
Issue of nanofibres/nanotubes - CNT versus asbestos
Donaldson et al., Particle and Fibre Toxicology, 2010
15
Geertsma - Nanotechnologie in de zorg: kansen en risico's | KIVI NIRIA, 11 oktober 2012
Effect of coating
Blood clearance of PEG-AuNR and CTAB-AuNR
Blood clearance of PEGylated and non PEGylated Au
nanorods
2500
Control
Au blood level (ng/g)
PEG-AuNR
2000
CTAB-AuNR
1500
1000
500
0
-96
0,25
0,5
1
2
4
8
24
48
96
144
192
Time after injection (hour)
Lankveld et al., Nanomedicine, 2011
16
Geertsma - Nanotechnologie in de zorg: kansen en risico's | KIVI NIRIA, 11 oktober 2012
Effect of adsorption
Nanoparticles do not exist as single particle entity, they
adsorbe things, e.g. proteins
What do we know
– Protein corona is important for
biological interactions
– Corona is not static, proteins get
on and off
What do we not know
– Dependence on nanomaterial?
– Dependence on size?
– Dependence on …?
Implications for interpretation of
testing
17
EU FP6 project NanoInteract,
courtesy of Prof Kenneth Dawson, UCD, Dublin, Ireland
Geertsma - Nanotechnologie in de zorg: kansen en risico's | KIVI NIRIA, 11 oktober 2012
Nanotechnology- emerging risk?
● Is it an emerging risk?
– Some nanomaterials already for decades in use (silica, titanium
dioxide, zinc oxide, silver, iron oxide)
– Current research on a plethora of new materials and variations of
existing materials
● Liposomes considered nanomedicines by EMA
– About 15 products on market
– Example cytostatic doxorubicin
– Not recent, developed last century
Wikipedia
18
Geertsma - Nanotechnologie in de zorg: kansen en risico's | KIVI NIRIA, 11 oktober 2012
De “nanosimilars” discussie
● Several recent scientific papers, EMA Reflection Papers
● Examples: liposomes, nano-iron products: >20 years, patents expired
● Iron sucrose: after substitution of originator by “generic”, patients unstable,
need to increase dose 35%, adverse effects ⇒ efficacy and safety
● Special testing requirements necessary, like for biosimilars?
19
Geertsma - Nanotechnologie in de zorg: kansen en risico's | KIVI NIRIA, 11 oktober 2012
Summary
toxicological risk
assessment
● Exposure assessment – dose, route
– NOTE: not all nanotechnology means exposure to nanomaterials
● Toxicokinetics – absorption, distribution, metabolism, excretion
– Dependent on size, shape, material, etc…
● Physico-chemical and toxicological properties of nanomaterials (and
surfaces) different from bulk material – parameters?
– What value is border/turning point for toxic behaviour?
● Not all nanomaterial formulations are toxic
● Many factors with varying effects
Evaluation of products: case by case in their
final composition/nanoformulation !
20
Geertsma - Nanotechnologie in de zorg: kansen en risico's | KIVI NIRIA, 11 oktober 2012
Nanotechnologies – risks
●Balance patient safety - availability of innovation
21
Geertsma - Nanotechnologie in de zorg: kansen en risico's | KIVI NIRIA, 11 oktober 2012