“Smart Nanoparticles” · Laser heating of gold nanoparticles provides route to photoswitching...
Transcript of “Smart Nanoparticles” · Laser heating of gold nanoparticles provides route to photoswitching...
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“Smart Nanoparticles”Stimuli Sensitive Hydrogel Particles
L. Andrew Lyon, Associate ProfessorL. Andrew Lyon, Associate ProfessorSchool of Chemistry and BiochemistrySchool of Chemistry and Biochemistry
Georgia Institute of TechnologyGeorgia Institute of Technology
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Hydrogels
Crosslinked water soluble polymers – a physically restricted, dimensionally-stable, polymer solution
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Responsive HydrogelsPolymeric gels can be designed to undergo environmentally-initiated phase separation events (volume phase transition).
Change in local environment
Swollen stateSolvent-chain interactions
dominate
Collapsed stateChain-chain interactions
dominate
pH, Photons,Temperature, Ionic Strength, Electric Fields, Pressure, [Analyte]
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Typical Responsive Gelpoly(N-isopropylacrylamide) (pNIPAm) – Thermoresponsive Gel
31 °C
ONH
ONH
( )
( )
HO
H
HO
H
HO
HH
OH
HO
HHO
H
HO
H H OH
HO
H
H OH
HO H
HO
H
H OH
HOH
H OHH
O H
HO
HH
OH
HO
H
HO
H
HO
HH
OH
HO
H H OH
HO
H
H OH H
O H
HO
H
H OH
HOH
H OHH
O H
ONH
( )
ONH
( )
Swollen/Hydrophilic Collapsed/Hydrophobic
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Polymer Phase SeparationPhase separation of poly-N-isopropylacrylamide occurs via an entropically-driven coil to globule transition.
Xiaohui Wang; Xingping Qiu; Chi Wu Macromolecules, 1998, 31 (9), 2972 –2976.
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Responsive HydrogelsVolume phase transitions in simple gels can be modeled as a crosslinked polymer in a vdW fluid.
A change in osmotic pressure on either side of the interface induces a solvation/desolvationresponse
0.8
0.4
0.0
-0.4
Osm
oti
c P
ress
ure
0.12 4 6 8
12 4
log [Gel Volume]
1
0.5
Decrease Solvent Quality/Increase χ
( )[ ]2231
00
0 1ln121 vnnvnv
vnn
nn
Nn
TkTk xB
Mel
B
χπππ++−−
⎥⎥⎥
⎦
⎤
⎢⎢⎢
⎣
⎡
⎟⎟⎠
⎞⎜⎜⎝
⎛−⎟⎟⎠
⎞⎜⎜⎝
⎛=
+=
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“Smart” Polymers
web.mit.edu/physics/tanaka/background/patterns.html
Chen, Park, and Park J. Biomed. Mat. Res. 1999, 44(1), 53-62.
Asher, Sharma, Goponenko, and Ward Anal. Chem. 2003, 75(7), 1676-1683.
Shimoboji, Larenas, Fowler, Hoffman, and Stayton Bioconj. Chem. 2003, 14(3), 517-525.
endoglucanase 12A
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pNIPAm Microgel/Nanogel Synthesis
Controllable Parameters:particle porosity/solvent content (crosslinker identity/conc.)
size – 50 nm to 5 μm (initiator, surfactant conc.)phase transition magnitude
volume phase transition shape
Oligoradical Precursor Particle
Growing Particle Microgel
Precipitation Polymerization
NHO NH
NH
O
OX
O+ +SDS
APS
70 oC
>4 hrs.
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Hydrogel DesignParticle design via copolymerization
thermosensitivepH sensitive/polyelectrolytes
Crosslinker length
OHO
O OO
OO
O
NONH
ONHO
NH2
NONH
O
SO
OOH
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Hydrogel Design: Responsivity/Sensitivity
Electric Field Light Metal Ions
NH O
NN
OO
O
OO
O
NH O
OHO
NHO
NH2
NHO
SO
OOH
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Hydrogel Particle Characteristics
Infinite SphericalNetwork
High water content (90-99% v/v)a microgel is effectively all surface area
Highly MonodisperseHighly Monodisperse
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Volume Phase Transitions
Dynamic Light Scattering (Photon Correlation Spectroscopy)
2 mol% crosslinked pNIPAm in
water
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Multiresponsive Hydrogels
pNIPAm-co-Acrylic Acid – pH and temperature dependent
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Core/Shell Synthesis
Collapsed core particles act as preexisting hydrophobic nuclei onto which growing polymer (the shell) adds.
Must control hetero-nucleation vs. homonucleation to achieve monodisperse populations.
70 °C 25 °C+ Shell
SwollenCore
CollapsedCore
CollapsedCore/Shell
SwollenCore/Shell
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p-NIPAm-co-AAc1 μm
p-NIPAm
Core/Shell Particle Characterization
Light scattering data typically show an increase in particle size between core and
core/shell with invariant polydispersity.
0
20
40
60
80
100
0 50 100 250 300Radius (nm)
% In
tens
ity
CoreCore-Shell
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Multiresponsive Core-Shells
160
140
120
100
80
Rad
ius,
nm
504030Temperature,
oC
p-NIPAm Core
p-NIPAm -co-AAc Shell
pH 6.5
Jones, C. D., Lyon, L. A. Macromolecules, 2000, 33, 8301-8306.
1
1
2
2
3 4
3
4
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Phase Transition Tuning
Phase transition temperature determined by hydrophilic/hydrophobic balance.
Ratio of N-isopropyl to N-tert-butyl determines transition point.
NHO NH
NH
O
OX
O+ +SDS
APS
70 oC
>4 hrs.
X=N-tert-butyl
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Phase Transition Tuning
(○) 1 mol-%, ( ) 5 mol-%, (□) 10 mol-%, ( ) 20 mol-% and ( ) 40 mol-% TBAm
Debord, J. D.; Lyon, L. A. Langmuir, 2003, 19, 7662-7664.
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Phase Transition Tuning – pH and Hydrophobicity
Poly(N-isopropyl acrylamide-co-N-tert-butyl acrylamide-co-acrylic acid) microgels– electrostatic repulsion mediates hydrophobic collapse. pH 3.5
pH 8.0
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Multi-Functional Nanogels
PEG-grafted “core” and core/shell particles
How does PEG-grafting impact protein adsorption?
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Multi-Functional Nanogels
“Bare” pNIPAmmicrogels (no PEG) display strong T-dependent protein adsorption. Below phase transition = hydrophilic; above phase transition = hydrophobic.
25 °C
40 °C
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Multi-Functional NanogelsPEG-Modification renders collapsed particles hydrophilic.
Gan, D.; Lyon, L. A. Macromolecules, 2002, 35, 9634-9639.
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Multi-Functional NanogelsNMR Analysis indicates a relative change in polymer hydration – PEG “core” phase separates to shell surface.
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Polyelectrolyte/Microgel Multilayers
=Anionic Microgel
=Polycation (PAH)
NH2
( )
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Microgel Film Formation
pNIPAm-AAc = polyanionpoly(allylamine)•HCl (PAH) = polycation
Passive Adsorption Spin Coating
1 layer
3 layer
1 layer
3 layer
Serpe, M. J.; Jones, C. D.; Lyon, L. A. Langmuir, 2003, 19, 8759-8764.
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Co-Deposition of MacromoleculesInsulin-impregnated films obtained via
incubation of particle solution with peptide.
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Labeled Insulin Incorporation
Linear increase in insulin content with
particle layer number.
Nolan, C. M.; Serpe, M. J.; Lyon, L. A. Biomacromolecules 2004, in press.
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Pulsatile Insulin Release
Fast, pulsatile insulin release during film deswelling.
9-layer film in0.02M PBS
pH=7.4
Medium Replacement
Heat to 40 C
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Bio-Functional Nanogels with Designed Topology
Biotinylated core beneath a shell with tunable pore size.
Cleavable diol crosslinks (DHEA)
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Bio-Functional Nanogels with Designed Topology
HABA assay for biotin-avidin binding
“Bare” Cores
Biotin CoresAvidin binding(~60 kDa)
Avidin-HRP binding(~150 kDa)
Partially degraded shell MW dependent binding.
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Towards a Smarter Nanogel
Drug/Gene/RNA delivery Goals:
1. Long Circulation Time2. Cell-Specific Targeting3. Receptor Mediated
Endocytosis4. Endosomal Escape5. Cytosolic or Nucleus-
Localized Release
These steps comprise a state-dependent “program”
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Cancer Targeting with NanogelsFolic acid - an effective ligand for targeting solid tumors.
Folate(-) Nanogels Folate(+) Nanogels
Fluorescent Hydrogel Core
Folate Labeled Shell
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Cancer Targeting with NanogelsDual staining (particle+lysotracker) illustrates
endosomal escape.
Nayak, S.; Lee, H.; Chmielewski, J.; Lyon, L. A., submitted.
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Cancer Targeting with NanogelsThermal trigger induces cytotoxicity
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Other Stimuli: PhotonsPhotosensitive microgels via T-jump dyes
ε = 150,000; φ = 0
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Photosensitive Microgels
Increasing dye concentration = greater photoheating.
Increasing T(bath)
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Hydrogel Micro-OpticsSubstrate-supported microgels behave as microlenses.
SEM DIC
LENS LENS
Serpe, M. J.; Kim, J.; Lyon, L. A. Advanced Materials, 2004, 16, 184-187.
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Tunable Aqueous Microlenses
pNIPAm-co-AAc –temperature and pH tunable lensing.
pH 3.0
pH 6.5
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Photoswitchable MicrolensesLaser heating of gold nanoparticles provides route to
photoswitching
ONOFF
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AcknowledgementsThe Group
Justin Debord (g) – BioconjugatesClint Jones (g) – Core-Shell/Crystals (now at PSU)
Christine Nolan (g) – Thin Films/Insulin DeliverySatish Nayak (g) – Bioconjugates
SaetByul (Stella) Debord (g) – Colloidal CrystalsMike Serpe (g) –Thin Films/Lenses/Drug Delivery
Jonathan McGrath (g) – Templated MicrogelsJongseong Kim (g) – Films/Polyelectrolytes/Lenses
Ashlee St.John (g) – Colloidal CrystalsBart Blackburn (g) – Cell TargetingNeetu Singh (g) – Bioconjugates
Ryan Mulkeen (ug) – Colloidal Crystals
CollaboratorsVictor Breedveld (GT-ChE)
Mohan Srinivasarao (GT-PTFE)Jean Chmielewski (Purdue-Chem)
Mike Ogawa (BGSU-Chem)Joe LeDoux (GT-BME)
SupportNSF-CAREER
NSF-DMRNSF-STC (MDITR)
Office of Naval ResearchDARPA (BOSS)
Beckman Foundation Sloan Foundation
Dreyfus FoundationGT Blanchard Fellowship