Surface ligands on nanoparticles control their properties and interactions, which can be harnessed for biomedical imaging, cell targeting, and therapeutic applications.
4. Phase Transfer of Nanoparticles
(1) Ligand exchange (2) Additional ligand layer (3) Amphiphilic polymer
4
5. PEG-Modified Nanoparticles
Solubility in organic solvents and
water where PEG is heavily hydrated,
forming random coils
Less non-specific binding in cells by
PEG-modified nanoparticles
Introduction of new functional
groups on nanoparticles by bifunctional
PEG
Separation by gel electrophoresis of Nanoparticles modified with NH2-PEG-
nanoparticles with a defined number of NH2 yield nanoparticles with exactly one or
chemical groups with PEG with two amino groups, separated by gel
molecular weight above 5000 g/mol, electrophoresis (Sperling et al. 2006).
which forms discrete bands
5
7. Quantum Dot Properties
High quantum yield compared to common fluorescent dyes
Broadband absorption: light that has a shorter wavelength than
the emission maximum wavelength can be absorbed, peak
emission wavelength is independent of excitation source
Tunable and narrow emission, dependent on composition and
size
High resistance to photo bleaching: inorganic particles are more
photostable than organic molecules and can survive longer
irradiation times
Long fluorescence lifetime: fluorescent of quantum dots are 15
to 20 ns, which is higher than typical organic dye lifetimes.
Improved detection sensitivity: inorganic semiconductor
nanoparticles can be characterized with electron microscopes
7
8. Quantum dots conjugated with folate–PEG–
PMAM for targeting tumor cells
Folate–poly(ethylene glycol)–polyamidoamine ligands encapsulate and solubilize
CdSe/ZnS quantum dots and target folate receptors in tumor cells.
Dendrimer ligands with multivalent amino groups can react with Zn2+ on the surface
of CdSe/ZnS QDs based on direct ligand-exchange reactions with ODA ligands
Y. Zhao et al. Journal of Colloid and Interface Science 350 (2010) 44–50. 8
9. Poly(amidoamine) (PAMAM) Dendrimer
Ligands
More dense than linear ligands, which improves stability
More anchoring groups, which generate strong interactions between QDs and PAMAM
Terminal groups (amine, carboxyl, and hydroxyl) of polyamidoamine (PAMAM)
dendrimers can be modified with different functionalities to link with various biomolecules
9
Y. Zhao et al. Journal of Colloid and Interface Science 350 (2010) 44–50
10. Quantum Dots for Imaging of Tumor Cells
Figure 2. Phase contrast images (top row) and
fluorescence image NIH-3T3 cells incubated with QDs2;
(c) SKOV3 cells were incubated with QDs2
FPP-QDs specifically bind to tumor cells via the
membrane expression of FA receptors on cell surface
Y. Zhao et al. Journal of Colloid and Interface Science 350 (2010) 44–50.10
12. Monofunctionalized Nanoparticles
by a Solid Phase Exchange Reaction
Bifunctional alkanethiol ligands with a carboxylic acid group are immobilized
on a solid support such as polymeric Wang resin at a low density.
Exchange reaction of resin-bound thiol ligands with gold nanoparticles results
in one resin-bound thiol ligand on each nanoparticle.
Cleavage from the resin yields nanoparticles with a single carboxylic acid
functional group. 12
Schaffer, et al. Langmuir, Vol. 20, No. 19, 2004.
13. Monofunctionalized Gold Nanoparticles
For solid phase exchange product there is Figure 1. TEM image of gold nanoparticle
minimal hydrogen bonding since C=O dimers formed by coupling reaction of
stretching vibration band appears at higher carboxylic group modified gold
wavenumbers. nanoparticles with bifunctional 1,2-
ethylenediamine.
13
Schaffer, et al. Langmuir, Vol. 20, No. 19, 2004.
14. Bioconjugation of Nanoparticles
Covalent Non-Covalent
Binding Interactions
Bifunctional linkers Hydrophobic forces
mercaptoacetic acid used to link modified
is used to link acrylic acid polymer
quantum dots with to TOPO capped
biomolecules quantum dots
Silanization Electrostatic
alkosiloxane interactions
molecules form high affinity of
covalent Si-O-Si cationic
bonds biomolecules for
negatively charged
backbone of DNA 14
15. Gold Nanocages
Precise tuning of LSPR
Potential to trap drug molecules or enzymes in
pores and release them through an externally
controlled mechanism
Photothermal effect for cancer therapeutics
(1) PEG with N-hydroxysuccinimide (NHS) group at one end and an
orthopyridyl disulfide (OPSS) group at the other is attached to the
surface of the nanocages by breaking the disulfide bond of the OPSS
group and forming a gold-thiolate bond
(2) Primary amine on antibody reacts with the NHS group of PEG molecule
15
16. Gold nanocages covered
by smart polymers for
controlled release with
NIR light
Au nanocages are synthesized by
galvanic replacement reaction
between Ag nanocubes and HAuCl4 in
water.
Figure 1. Drug release from gold nanocages
Temperature-sensitive polymer
based on poly(N-isopropylacrylamide)
(pNIPAAm) changes conformation due to
variations in temperature.
Photothermal effect induced by laser
beam with a wavelength matching the
absorption peak of Au nanocage, causes
light to be absorbed and converted into
heat
Drug release due to temperature
increase that causes polymer chains to
Figure 2. TEM images of Au nanocages covered
collapse exposing nanocage pores
by a pNIPAAm-co-pAAm copolymer 16
Yavuz, et al. Nature Materials. Vol 8, December 2009.
17. Polymer Synthesis by ATRP
Atom-transfer radical polymerization of N-isopropylacrylamide (NIPAAm)
and acrylamide (Aam) initiated by a disulphide initiator forming polymer
with tunable low critical solution temperature (LCST) between 32-50 C.
17
18. Controlled Drug Release from Nanocages
Figure 1. Controlled release of alizarin dye Figure 2. Cell viability for samples (C-1) cells
from the Au nanocages covered by a irradiated with a pulsed near-infrared laser for 2 min
copolymer with an LCST at 39 C Absorption without Au nanocages (C-2) cells irradiated with the
spectra of alizarin-PEG released from the laser for 2 min in the presence of Au nanocages; and
copolymer-covered Au nanocages (2/5 min) cells irradiated with the laser for 2 and 5
min in the presence of doxorubicin (Dox)-loaded Au
nanocages.
18
19. Multifunctional Nanoparticles
Nanoparticles for imaging: quantum dots
Targeting agent: antibody or peptide
Cell-penetrating agent: peptide
Stimulus-sensitive element for drug release
19
Stabilising polymer to ensure biocompatibility: polyethylene glycol
20. Multifunctional Magnetic Nanoparticles
• Magnetic nanocrystals as ultrasensitive MR contrast agents: MnFe2O4
• Anticancer drugs as chemotherapeutic agents: doxorubicin, DOX
• Amphiphilic block copolymers as stabilizers: PLGA-PEG
• Antibodies to target cancer cells: anti-HER antibody (HER, herceptin)
conjugated by carboxyl group on the surface of the MMPNs
20
Yang, etal. Angew. Chem. 2007, 119, 8992 –8995.
21. Targeted Drug Delivery and Inhibition of Tumor Growth
Figure 1. Multifunctional magneto-
polymeric nanohybrids (MMPNs)
containing manganese ferrite
(MnFe2O4) nanocrystals prepared by Figure 2. MR signal intensity and colour maps of NIH3T6.7
nanoemulsion with anticancer drug and MDA-MB-231 cells treated with IRR-MMPNs; black,
(doxorubicin, DOX) and PLGA-PEG HER-MMPNs; white.
Human epidermal growth factor receptor (HER2) -- tumor-targeting marker for breast
cancer
Fibroblast NIH3T6.7 cells -- highly express the HER2/neu cancer markers
MDA-MB-231 cells -- express low levels of the cancer markers 21
Yang, etal. Angew. Chem. 2007, 119, 8992 –8995.
22. Inhibition of Tumor Growth by Magnetic Nanoparticles
HER-MMPNs had the greatest
tumor growth inhibition than since
HER-MMPNs were target-
delivered to HER2/neu receptors
of NIH3T6.7 cells and DOX was
released 22
25. Acknowledgements
Professor Eugenia Kumacheva
Siyon (Lucy) Chung
Dr. Jemma Vickery
Dr. Kun Liu
Ariella Lukash
Anna Lee
Dan Voicu
Ethan Tumarkin
Dr. Jesse Greener
Jai Il Park
Dr. Ziliang Wu
Dr. Dinesh Jagadeesan
25