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Nanomedicine
First, a short video
https://www.youtube.com/watch?v=2VcNpl8-PRI&feature=youtu.be
From the European Nanomedicine Nanotechnology Platformhttp://www.etp-nanomedicine.eu/public
Introduction – Goals of Nanomedicine
• End goal of nanomedicine is improved diagnostics, treatment and prevention of disease
For a great review see: http://www.wtec.org/nano2/Nanotechnology_Research_Directions_to_2020/
See also https://commonfund.nih.gov/nanomedicine/index (US National Institutes of Health)
Introduction
• Nanotechnology holds key to a number of recent and future breakthroughs in medicine
Nanoparticles for Pathogen Detection
• Gold nanoparticles can be functionalized with thiolated oligonucleatides.
• Bound to the oligonucleatides are fluorophores which are quenched by their proximity to the nanoparticle.
• When the targeted RNA (H2N2, HIV or a cancer) bindes to the oligonucleatide, the fluorophore is released and becomes fluorescence.
• The fluorescence can be detected in a BioMEMS device.
• Challenge is developing oligonucleatides with high selectivity for the target RNA.
Nanoparticle Probe Targeted RNAFluorophore Release
Nanoparticles for Targeted Detection of Cancer
• As an example, nanoparticle probes were developed by Chad Mirkin at Northwestern Univ. that target the survivin RNA sequence known to exist in a certain breast cancers.
• Experiments are done ex-vivo.
• On the left, cancer cells fluoresce.
• On the right, healthy cells show minimal fluorescence.
Breast Cancer Cells Healthy Cells
Nanoparticles for In-vivo Detection of Pathogens
• Fluorescence is not a viable option in-vivo, but magnetic tagging works very well.
• Harmless virus can used as a building block to produce contrast agents that can be used in Magnetic Resonance Imaging (MRI).
• Here, magnetic metal ions are bonded to the virus as are molecules that bind to cancer cells.
• A full body MRI scan detects these contrast agents and even very small tumors throughout the body
Targeted Delivery to Tumors
• Goal is to inject treatment far from tumor and have large accumulation in tumor and minimal accumulation in normal cells/organs.
Cancer Treatments
• Tumor penetration is a key issue for successful chemotherapy
Nanoparticle use in Cancer Treatments
• Because of their small size, nanoparticles can pass through interstitial spaces between necrotic and quiescent cells.
• Tumor cells typically have larger interstitial spaces than healthy cells
• Particles collect in center bringing therapeutics to kill the tumor from inside out.
Nanoparticle Targeting and Accumulation
• To maximize their effectiveness, the microenvironment of the tumor must be quantified and vectors developed to specifically target the tumor.
• These treatment approaches have shown great promise in mice.
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First Successful Nanomedicine - Abraxane
Making Gold Nanoparticles
• AuCl4- salts are reduced using NaBH4 in the presence of thiol capping ligands
• The core size of the particles formed can be varied from <1 nm to ~ 8 nm
• The surface functionality can be controlled through the choice of thiols
• Diffusion speed can be controlled by length of thiols
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Nanoparticles as Sensors and Therapeutics
• Glutathione (GSH) provides a selective and tunable release mechanism
• Once inside cells, fluorophores and drugs selectively dissociate
Nanoparticle Success
• Both cationic and anionic particles penetrate and accumulate in tumors.
• However, only cationic particles diffuse fully throughout the tumor.
• Work of Neil Forbes and Vince Rotello at UMASS
Alternatives to Nanoparticles - Surfactants
• Surfactants are composed of a hydrophilic head and a long hydrophobic tail
• When dissolved in water above the critical micellar concentration (CMC) surfactants can self-assemble into large aggregate
• Spherical micelles are around 10nm in size
• Hydrophobic drugs can be encapsulated and in their core and delivered throughout the body or to a specific target.
Nanotechnology in Tissue Engineering – Cartilage Replacement
• Samuel Stupp at Northwestern has shown that nanotechnology can be use to regenerate severed spinal cords.
• Two polypeptides amphiphiles are used that when mixed in an aqueous solution self assemble into a nanotube
• As seen on right, these nanotubes display peptide growth factors.
• In mice, these systems have been shown to promote axonal outgrowth and bridging of injured areas (bottom right).
Nanotechnology in Tissue Engineering – Cartilage Replacement
• Because cartilage doesn’t have vasculature and cannot repair itself, accepted treatments have been mostly mechanical in their approach.
• Joint lubricants: • Simple and effective at short-term pain relief but do not address cause of the
problem or repair any damage.
• Debridement/lavage/microfracture:• Small lesions are repaired by shaving or shaping contour of cartilage.• Microfracture penetrates subchondral plate (bone) and actually causes growth of
fibrocartilage – a lesser form, not desirable.
• Total joint replacement:• Addresses problem and generally allows full repair, but• Very invasive procedure, native tissue removed• Prostheses do not last a lifetime in active patients.
• Nanotechnology approach• Regrow patient’s own cartillage in-vivo to repair damage
www.hughston.com/hha/
ACT Methods
• A popular tissue engineering approach has been to introduce new cells, via autologous chondrocyte transplantation/implantation (ACT/ACI).
• Some of the earliest work by Benya and Shaffer (1982) showed it was possible to isolate and culture chondrocytes.
• More interesting result was that when cultured in vitro, the cells differentiated and changed their phenotype to produce a lesser quality collagen.
• Need better tissue scaffolds – nanotech.
biomed.brown.edu
Important to tissue engineering:Cells will differentiate purely based on mechanical stimulus.
Important to tissue engineering:Cells will differentiate purely based on mechanical stimulus.
Genzyme ACT method: FDA approved 1997
Hydrogels – Self Assembly
• Hydrogels have applications in drug delivery and tissue engineering
• Regenerating cartilage and other tissue requires scaffolds with similar modulus and other mechanical properties → Need to develop stiffer, tunable hydrogels
• We investigated Polylactide-Polyethylene Oxide-Polylactide triblock copolymers.
• Systems are biocompatible with a hydrophobic ends (PLA) and a hydrophilic center (PEO) which self-assembles in water and can form a gel under the right conditions
CMC Gelation
TriblockCopolymer
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Addition of Nanoparticles
Rheology of Hydrogels
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• The hydrogels formed are very stiff with elastic modulus on the order of 1-10 kPa.
• Within range of moduli of several human tissues including cartilage.
• Gels formed from polymers with higher degree of polymerization maintain a high storage modulus even at physiological temperatures (370C).
• In-vivo applications feasible.
• Rheological response of these polymers can be easily tuned by varying the crystallinity or block length of PLA or through addition of nanoparticles.
R-LactideAmorphous Core
L-LactideCrystalline Core
Khaled et al. Biomaterials (2003)
Photocrosslinking Hydrogels for Cartilage Replacement
• An alternate approach is to make the hydrogel from polymers that can be crosslinked after injection.
• From Jennifer Elisseeff’s lab at Johns Hopkins University.
• Photo-polymerizing the hydrogel increases its modulus, allowing the appropriate phenotype of cartilage to be expressed and protecting damaged area from wear.
Keeping Things Clean – Antimicrobial Surfaces
• Silver is an excellent anti-microbial agent
• Silver nanoparticles are now being added to fibers of clothing and bandages as well as being incorporated into surfaces in hospitals to reduce the rate of bacterial infections
• When co-extruded with a polymer like PLLA, the silver is released slowly over time and has been shown to effectively kill bacteria
Introduction – Goals of Nanomedicine
• One goal is to ultimately integrate detection, diagnostics, treatment and prevention of disease into a personalized single platform
• Goal is to develop handheld diagnostic devices for personalized medical testing and treatment
BioMEMS for Screening and Diagnostics
Biomedical Analysis and Communication System
Disposable Diagnostic BioChip
BioMEMS – Micro and Nanofluidics
UMass Institute for Applied Life Sciences (IALS)
http://www.umass.edu/ials/
See also the IALS Center for Personalized Health Care Monitoringhttp://www.umass.edu/cphm/
Extra slides
Nanoparticle Encapsulation for Drug Delivery
• Nanoparticle shells can be formed around spherical droplets• A.D. Dinsmore, et al., Science 298, 1006 (2002), Y. Lin, et al., Science 299, 226 (2003)
• Shells are porous at lengthscales much smaller than size of nanoparticle.
A: Scanning electron microscope of a dried 10-μm-diameter colloidosome composed of 0.9- μm-diameter polystyrene spheres.
P Interfacial Area = A
Energy = AO/W + 4R2P/O
(Oil)
(Water)
Energy = (A-R2)O/W + 2R2P/O + 2R2P/W
II. Particle sitting astride the interface (half-in, half-out):
[Pickering (1907); Pieranski PRL 45, 569 (1980)]
I. Particle (P) away from interface:
• If |P/O – P/W| < O/W/2, then adsorption reduces surface energy.
Why Particles Adsorb to Interfaces
surface tension
Nanoparticles At Interfaces
nm
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oil-nanoparticle suspension,w/ droplets
water droplet:
• Nanoparticles can be functionalized, cross linked or sintered to make shell permanent, strengthen shell or change shell permeability.
Nano-Encapsulation for Drug Delivery
• By making the holes between nanoparticles approximately the same size as the drug you want to administer you can get a constant release rate – avoids spikes in dosage.
• Can also allow encapsulation of hydrophobic drugs which are difficult to get into you mostly water body.
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Nano-Encapsulated Drug Delivery
Standard Diffusion Based Drug Delivery
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