Nano Notes

Prefixes for each scale up to -24

If the earth was one meter than a nanometer would be the size of a marble or an egg?
Free electrons moving between surfaces – surface plasma
Intrinsic frequency of oscilation – no of oscilation between tow surfaces – or resonace frequency

1/17/16

Metallic nanoparticles: 10-100 nm

If the electromagnetic wave matches the oscialtion frequency – resonance

• Resonace surface plasma

o Nanoparticles will absorb and emit light
o Inelastic scattering
o Elastic scattering or rayliegh scattering
• Enhanced Spectrum vs convential spectrum
o The Ehanced Factor is e8 compared to the convential
o Enhancement factor in the hotspots there is an Ehanced Factor of e14
• If a metallic particle was elongated there would be two axis for electron to go around
• In the graph of the I vs lambda there are two peaks correlated to the size of the axis
o The second packet is 650-950 nm for wave to complete
• The broad spectrum in the second package can be used as a heater (nano heater).
• A shell around the particle will change the distance that the electron travels and therefore
changes the light emitted. Changing the shell’s diameter and thickness can be used to control the
output.
• Another method that can be used is a cage. The electrons are likely to concentrated around the
edges.
• Nano Gap junction – the surface plasma resonance couples cuasing plasmatic coupiling.
• PEG layer.
o Is resistant to protein absorption as it is similar to water in that it is fluid and always
moving
• SERS

1/19/17

• At what size can a particle no longer be modeled by classical methods

o For silver and gold the diameter length is 2nm
• Bohr radius is radius with the highest probability that electrons will be traveling
• Quantum leap – energy is added until a threshold is reached allowing the electron to travel to
another orbital.
• Particle in a box –
• Not a complete sphere but a crystal
• Quantum yield
• Today it is closer to 98%. This is the chance a photon will exit if a molecule is bombared
with energy
• 1998 a coating was found that could make the semiconductor coating soluble in water.
o The first material was SiO
o The second material discovered was a sulfer particle with acetic acid.
 • Key concepts:
o Bohr radius
o Particle in the box
o Quantum size Confinement effect
o Quantum dots – looks like a dot that has quantum size confinement properties
o Quantum Yield
o Nanocrystals
o Louis Brus
o Mark Reed

1/24/17

Collidal Gold
Color from particles comes from scattered light – This is seen using a dark field microscope.
Reporter molecule
PEG-SH is resistant to non specific binding. Wraps around the molecule
EPR effect
Enhanced Raman fingerprint to identify particles
Light attninuation – light scattering explains while more can be seen in the tumor instead of the liver.
Difference in energy is the Stokes Raman Scattering
Anti Stokes Raman Scattering if falls an additional leval
Stokes shifter raman wavelength
Surface charge and double layer
Solvation layer – compact layer or zeta potential

1/26/17

Quantum size confinement – Semiconductor Quantum Dots

0 dimensional – energy is formed is due to boundary conditions

Band Gap – energy required for an electron to jump – therefore there is no band gap in conductors
Exciton – an electron – hole pair
Bohn Exciton diameter is 10 nm
The band gap will go up
Size Tunable QDs
Composition Tunable QDs
Strain-Tunable QDs
Biconjugated Quantum Dot
With acetic acid
Engineering Size and Stability
The coating may add too much size to a particle
Multiplexing
1/31/17

Size dependant magnetic properties

Magnetic moment

Electron Spinning

Energy was coordinate is not clearly defined

At room temperature the activation energy (Ea) is less than KT (K is Bozeman constant))
Randomize spin orientation
Nanoparticle/nanocluster (multiple particles with various spins) – spin can be coupled
Domains
If all the spins are in the same direction than it is a single domain
There ca

Nanocluster below
There may be multiple domains in a nanocluster. However they may all cancel out so that the overall
cluster is non magnetic.

Magnetic alignment may occur if a nanocluster is placed near another magnetic particle. The domains
within the nanocluster will all orient in one direction. Removing the magnetic field will re randomize the
domains.

Magnetic effects

Diamagnetic- can be used to propel

The induced magnetic moment is the opposite direction of the external field
Paramagnetic M inside> M outside

Ferromagnetic field
After the magnetic field the direction of the spins are generally the same
Example is Fe3O4 – mixed valence

Hydradynamic size – size in solution can be determined using a zeta sizer/ based on the dynamic light
scattering
When the magnetic field changes the magnetic dipole reverses direction.

Hysterieses
Higher magnetic moment per atoms
Decanting Effect

Magnetic nanoparticles – Applications

Cells will be stuck together if ferromagnetic
MRI

2/2/17

Self assembled nanostructures: liposomes, micelles and monolayers

Hydrophobic and hydrophilic structure
Hydrophobic structure latches onto oils
AMphphilic polymer
Block polymer

PEG – poly ethyionol glycol

Stealth technology - PEG

Self Assembled Monolayers – R-CH2-CH2-CH2-CH2-S

Sulfer binds to gold very tightly

A space can be used to measure how electrons trafer to the gold from the R group – Allows measure of
energy transfer

Carbon Nanostrctures
Carbon allotropes-a (diamond)
Congetated electrons – provide color
Zig zag vs armchair confinguration

2/7/17

Kinetic and thermodynamic control

Starting Point:/Ending Points (1 and 2)

Activation energy: energy to reach ending point .
There may be multiple paths. One to Ending point 1 or to path 2.
Thermodynamic favored process vs Kinetically favored process
Nano micells will go back to monomers (dissociation) if dilution occurs (and vice versa)
Theroetically it should dissociate in blood, however it does not dissociate because
The dissociation is thermodynamic favored but it is not kinetically favored and will therefore take
a long time of the particle to fall apart.
The reason why that it is kinetically unfavorable is because for one piece of the micelle to fall apart all of
the parts have to fall apart.
Triplet state: when the spin of the electrons are is the same direction
Singlet state: when the spins are in different directions.
Nanoscale interactions

Covalent Bonding
Hydrogen Bonding
Inter/Intra Molecular Hydrogen Bonding
Electrostatic interactions (ionic bonding)
Vaner Waals interactions
Hydrophobic effect
Enthalpy
Entropy
Pi effect – pi electron circle

2/9/17
Kinetic and thermodynamic control (stability)
Hydrogen bonding with DNA (guadine and cytosine)
Pi-Pi stacking
Displaced
Edge to face
Sandwhich
Cation Pi Stacking
Hydrophobic reactions can be attributed to entropy

2/14/17

Photolithography
Theroethical smallest wavelength for focus is half the wavelength (diffraction limit)
Electron Beam – lithography
Spatial Resolution
Super Resolution imaging
Dip Pen – nanolithography
Alkane Thiol (ink)
Sulfur group binds to the pens surface
Atomic Force Microscope (AFM)
Scanning Tunneling Microscope (STM)
Tip Enhanced Ramaa Scatering (TERS)
Near Field Scanning Optical Microcopy (NSOM)
Shrink an optical fiber to less than the diffraction limit
This will prevent the optical beam from propogating
This causes exponential decay at the tip
Tip enhanced Raman Scatering (TERS)
Transmission Electron Microscopy (TEM)
More expensive and higher resolution ( sample can’t be too thick)
Dynamic Light Scattering (DLS)
2/16/17

Nanomedicine

IV injectioin
Protein Binding
Otherwise knows cell binding membrane
Intenesgation/endocytosis
Intracellular transport
Bonding to cytoplasmic targets
Transport into nucleus -> nuclear target
Method to excrete or clear out nano particles
Can lead to toxicity

Non specific binding with liporprotiens and albumims

Small proteins and loose proteins will still bind to the nanoparticle
Small proteins bind faster
Early on binding is with small proteins
After more time both small and large proteins bind
Larger protein bind at later time

Nanoparticle Cell Interaction

Ligand receptor binding
Internalization – receptor mediated endocytosis
Endsome – whatever is inside the cell
Nanoparticle is Dead on Arrival due to being immediately degraded by the cell
Typical cell -10 to 20 micormeter
Typical nucleus – 1to2 micrometer
Mass Transport - diffusion (random walk)

Molecular Motors
Kinesin Myosin
Nanoparticle transport inside cells
Intra cellular transport
Nucleus contains nuclear pores – each abiut 2-4 nano meters
Opsin gateion

2/21/17

In Vivo

Issues
Organ Uptake – via liver and spleen
RES: Reticulo enothelio system
Phago cytic system
Liver
Fenstration
Each window is fenestra
Nanoparticle leaves the fenestra
Cooper Cell (macrophage) internalize the nanoparticle
Macrophages in blood

EPR-Enhanced Permeability and Retention

Blood Vessels Capilary
Leaky blood vessels
Tumor Interstituial Spaee
Within the Tumor Microenviroment
The tumor makes the environment more acidic
Fibroblast cells - everything contained within the stroma
Lymphatic vessels drain fluids
Pressure is higher in intra tumeral
Permeability refers to the leaky vascule
Collapse lymphatic
80% have the EPR effect

3. Active vs Passive Transport for any agent

When the nano particle goes through the fenestration
PASSIVE: Particle will diffuse through the environment and eventually be internalized by the cancer cell
ACTIVE: Change in Hydraulic Pressure causes convection – much more efficient
However a higher pressure within the tumor environment can cause the particle to leave (rather than
enter)
Extravagate: when the particle leaves the extracelluar space and enters the tumor

4. active vs passive tumor targeting

(see notes in noteb

2/23/17

OPsonization – nonspecific proteins absorbed in blood

Dead on arrival agents – particles which get degraded quickly
Multivalency/mono valent bonding
Multivalent Bonding – more stable – has a lower Kd
Ka=[R-l]/[R][L]

Extravasation: The nanoparticle leave the membrane/before it enters the tumor cell

Normal and Tumor vasculature

Intravital Microscopy of Tumor Cells

3/2/17
Nanotoxicology

1. Roots of exposure and intake

a. Lung and nose
i. Aveloar cells on the lung surface can take up nanoparticles deposited
b. Derma Skin Exposure
i. Epidermal Cells
 ii. Lympathic Nodes
c. Oral
i. Goes through GI Tract
d. IV Injection
2.
Molecular and Cellular Mechanisms of Nano Toxicity
Interaction with protein and cell membrane
Example: a nanoparticle can cover the receptors on a cell impairing the function of the
receptor
Interactions with DNA and RNA can cause gene mutation and expression changes as well as the
chemical bonding linkages
Inert nanoparticles in the organ can be a potential threat.

2. Degradation and clearance

a. Heptobilliary GI Tract

Animal Models
Small – Mice
Xenograph vs natural occurring tumors
Clinical Studies
Human Clinical Studies have three phases
Phase 1 – 10,30 patients/ Toxicity safety and Dosing/ organ distribution + clearance to try to
identify how safe the drug is.
Phase 2 – Simmilliar with more patient. Still not focused on identifying the efficacy of the
nanoparticles
Phase 3 – Key study that examines the efficacy of the nanoparticle and comparison with the state
of the art. Must be a blinded randomized and powered studies.

Lighter effect ( correlation vs causation ) – people with a lighter in their pocket have a higher risk of
gaining cancer
Beta Amaloid Hypothesis

Aducanumab – antibody created by biogen for alzheimers. It reduces the amaloyd in the brain . It also
improves memory and cognition.

3/7/17

Engineering Nanoparticles for molecular Imaging and Therapeutic Applications

1. Semiconductor QD
2. Metallic Nanoparticles (SERS,SRP, Thermo)
3. Organic/Poly Nanoparticles => therapy diagnostic
4. Plasmonics

Image guided Surgery in pancreatic cancer- Simply identifying the edge of the cut out tumor can be used
to identify whether the tumor was fully cut or not.

Brain Tumor
Microscopic deposits exist outside the solid brain tumor. The individual parts are more difficult to
remove.
Use a handheld spectrometer to identify the tumor area. The skull needs to be opened. The patients drinks
Amino Levelinic acid which stimulates the synthasis of porphryn.
Spectropen – allows for microscopic incions

Theranostics nanoparticle for interated imaging and therapy

Nanoparticles for SERS need to be attached with a molecule. The molecule is the enhancer/enhanced. The
particle then needs to covered in PEG and a targeting ligand

Image guided surgery: Naturally occurring Lung Tumor in Large Animals

ICG-Albumin Complex
Endoscopic and Robotic Surgery and Image guidance
Miniaturizing devices for minimall invasive surgery
MOthership nanoparticles and vascular unpacking
Circulation halftime (10-20 hrs)
Small tumors seem to be promising for active targeting at some point

3/28/17

Large surface to volume ratio means that many affinity particles can be added to the particle
Main issue with the nanoparticles was aqueous issues
Ligand exchange and polymer coating can be used to make the particle compatible with water
Bioconjugation – covalent coupling/electrostatic attraction/ receptor ligand
Modern Bioaffinity Probes Streptavidin Conjugate/ antibody conjugate/ligand Conjugate
NP are brighter and more stable but are larger and interact differently
Spectral Library=> Compare sample data to a known data
Optically Encoded Microbeads
650nm is an optical window
Silicon + copper indium are new inert materials being used in vitro

4/6/17