Polymer Nanotechnology: Synthesis and Novel Applications Instructors Professor Yvon G. Durant

Copyrighted - University of New Hampshire

Oct 31 2005

1

Pathways to Polymer Nanoparticles • Nanofabrication

Reactive molding in nano-templates Application of shear forces to spherical particles • Dispersion Polymerization Suspensions, Latices, Mini and Microemulsions • Assembly •Self and Directed Copyrighted - University of New Hampshire • Application of surface and interfacial forces

Oct 31 2005

2

1

Particle surface are (sq m/gram)

The Effect of Subdividing Material 10000 1000 100 10 1 1

10

100

1000

Particle radius (nm)

Oct 31 2005

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3

Utility of Polymer Nanoparticles Based on Size, Geometry and Chemistry • Coatings, adhesives, impact modifiers • Medical diagnostics • Drug delivery • Magnetic particles • Conductive particles • Stimuli responsive particles Oct 31 2005

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4

2

Multiple Component Polymer Microparticles

Hemisphere morphology

Core shell morphology

Unsuccessful encapsulation

Successful encapsulation

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Oct 31 2005

5

Characterization of Multiple Phase Particles • Internal structure (morphology) Microscopy, thermal analysis 0.04

0.035

TEM d(Cp)/dT (J/g/C/C)

0.03

0.025 Final 25% conv 50% conv 67% conv 83% conv seed 2nd Stage

0.02

0.015

0.01

TEM

0.005

0 0

20

40

60

80

100

120

140

Temperature (C)

DSC Oct 31 2005

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6

3

Objectives of This Workshop • Introduce methods by which polymer nanoparticles are made •Introduce methods by which these nanomaterials are characterized •Discuss applications of polymer nanoparticles

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Oct 31 2005

7

Cationic Polymerization +

+

Mn , X

+

M n+1 , X

M

Bishop Watson "Chemical Essays", 1789, London M. Deville Ann. Chem., 1839, 75,66 M. Berthelot Bull. Soc. Chim. Fr. 1866, 6, 294 acid

Initiation

Propagation

H CF 3 SO 3 H

CF 3 SO 3

+

H CF 3 SO 3

+

+

H n-1

Oct 31 2005

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8

4

Polymer Nanotechnology: Synthesis and Novel Applications Polymer synthesis

Conformation

Fiber Random coil

Oct 31 2005

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10

5

Architecture

a linear polymer

Oct 31 2005

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11

Crosslinking

Entanglement versus crosslink = physics versus chemistry Oct 31 2005

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12

6

Molecular weight - Number Average Molecular Weight - Viscosity Molecular Weight - Weight Average Molecular Weight - Z-average Molecular Weight

Oct 31 2005

a=0.5 to 1 Function of solvent

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13

Representation Gaussian (bell) curve Typically on log scale

Typically linear

Typically a log scale

Oct 31 2005

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7

2 major categories • Chain growth

• Step growth

Oct 31 2005

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15

Chain growth : Active centers • Radical polymerization • Ionic polymerization – Anionic – Cationic

• Coordination polymerization – Involves a catalytic center

• Polycondensation

Oct 31 2005

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16

8

Addition / condensation

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Oct 31 2005

17

Block copolymer architecture diblock-copolymers

Star block copolymer

Tri block-copolymers

gradient-copolymers

Block-gradient -copolymers

Block pendant copolymer

Oct 31 2005

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18

9

Radical polymerization

Initiation Radical generation

Termination Propagation Oct 31 2005

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19

Polycondensation -1

Oct 31 2005

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20

10

Polycondensation - 2

+

Oct 31 2005

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21

Living Polymerizations

Anionic Cationic Ring Opening Ring opening metathesis

11

Anionic Polymerization Mn , Mt

+

+

M n+1 , Mt

M

(poor) electrophile

+

R Li

Initiation

R Li +

Ph

Ph

STYRENE Lewis Base

Lewis Base

R Li

R Ph

Li

Propagation Ph

Ph

Ph

Ph

Counter ion (cation) Usually Li+, Na+, K+ or Cs+ Copyrighted - University of New Hampshire

Oct 31 2005

23

Anionic Polymerization H R CH2

14 OH-

C

35

NH2- / NH3

50

55

styryl anion / ethyl benzene

pKa

/ H2O Bu- Li+ / BuH •carbanions are not short-lived species •carbanions are terminated by oxygen, water and many polar functionalities •carbanions are negatively charged •carbanions can be pyrophoric (beware!) •carbanions are tetrahedral (sp3 hybridized) •carbanions are very basic (conjugated acid : alkane). They can only be formed by reacting with a stronger base. Oct 31 2005

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24

12

Cationic Polymerization +

+

Mn , X

+

M n+1 , X

M

Bishop Watson "Chemical Essays", 1789, London M. Deville Ann. Chem., 1839, 75,66 M. Berthelot Bull. Soc. Chim. Fr. 1866, 6, 294 acid

Initiation

Propagation

H CF 3 SO 3 H

CF 3 SO 3

+

H CF 3 SO 3

+

+

H n-1

Oct 31 2005

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25

Ring Opening polymerization

Oct 31 2005

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26

13

Ring Opening Metathesis Polymerization

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Oct 31 2005

27

Ring-Opening Polymerization O Na+OH-

+

HO CH2 CH2

O-

Na+

O

etc... CH2 CH2

O

HO CH2 CH2

n

O

CH2 CH2

O-

Na+ Wurtz 1879

- Ring Strain Controls the Polymerization (C2O best)

Oct 31 2005

n

ΔH(kJ/mol)

ΔS (J/K/mol)

3 4 5 6 7 8

-113 -105 -21 2 -22 -34

-69 -55 -43 -10 -16 -3

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ΔG (kJ/mol) -92.5 -90 -9 +6 -16 -34 28

14

led l o Living ntr Radical Polymerization o C

SFRP ATRP RAFT

Pseudo living SFRP

N O

C

^

130°C

+ N ^ O

n+...

n

+...

Oct 31 2005

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30

15

Atom Transfer Radical Polymerization

+ MeX

IMn°

IMnX + Me X = Br, Cl N

PPh3 Cl Ru PPh 3 Cl PPh3

N Cl Cu N N N

Ni Br N

Sawamoto, 1995 MMA

O

Br C

Matyjaszewski, 1995 MMA, S CATALYSTS

Teyssie, 1997 MMA

C

H

Br

Me

CCl4

O

CBr4

INITIATORS

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Oct 31 2005

31

The Preparation of Well-Defined Water Soluble/Swellable (Co)Polymers by ATRP - K. Matyjaszewski •

Atom Transfer Radical Polymerization is one form of Controlled Radical Polymerization (CRP)

O

O

O

O I

I

O

O

n

Br

O

O

O

O C^

n... O

O

O

O

Br

Cu N

• •

N

Cu N

N

N

N

N

N

With ATRP one can control the architecture (blocks, stars, gradients, graft, dendrimers….) Fundamental mechanism : depletes termination

Oct 31 2005

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16

ATRP - Recent improvements

• Mw/Mn=1.1 • styrene, acrylates, methacrylates, acrylonitrile • 2-HEA, 2-HEMA, 2-(dimethylamino) ethyl methacrylate, N-(2hydroxypropyl)methacrylamide, methacrylic acid (from tBMA). • • •

Works in water Works at 60 to 80°C Suspension and emulsion (use PEO/PE-PEO as stabilizers)

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Oct 31 2005

33

Reversible Addition Fragmentation Chain Transfer (RAFT) I

0.01 eq R° + M

1000 eq

S

4

Ph

C

R

S

Ph

R°

1

kp

S

MnR

+ RMm°

3

RMn° S

ktr Ph

1 eq

S C

+ RMn°

ki

C

2 S

MnR

+ R°

5

S

ktr Ph

C

S

MmR

+

RMn°

Ctr = ktr/kp ~ 500

Rizzardo, 1998 Not based on a persistent radical effect Oct 31 2005

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34

17

0.012 0.01 0.008 0.006 0.004 0.002 0

2.5

60000

2 1

50000

0.5 0

50 Time (hours)

0 100

The number of dead chains = I The number of dormant chains = CS2 Initial MW = MW0 Ctr -1 [MON]

Mn (g/mol)

1.5

PDI

[C S 2 ] (m o l/l)

Reversible Addition Fragmentation Chain Transfer (RAFT)

40000 30000 20000 10000

Ctr = 300 Ctr = 30 Ctr = 3

[CTA]

Kinetics = Kinetics of conventionnal radical polymerization

0 0

0.2 Conversion

Styrene/CS2 = 1000 CS2/AIBN = 20

Copyrighted - University of New Hampshire

Oct 31 2005

0.4

35

Classes of biopolymers • Nucleic acids – DNA/RNA

• Proteins – Fibrous • Major structural material for animals

– Globular

• Polysaccharides – Unbranched • Major structural material for plants, insects and others

– Branched

• Lipids

Oct 31 2005

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36

18

Non-covalent forces dictate tertiary structure

Oct 31 2005

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37

Dispersion Polymerization Methods to Create Polymer Nanoparticles

Oct 31 2005

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38

19

Single Component Polymer Particles • Disperse polymer solution in water/surfactant • Shear to create dispersed particles Concern with particle size distribution • Remove solvent while stabilizing particles Concern with very viscous particles • Internal particle uniformity depends on rate of solvent removal Oct 31 2005

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39

Two Component Polymer Particles

Solvent Phase separation during solvent removal

1Φ 2Φ

P1 Oct 31 2005

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P2 40

20

Two Component Polymer Particles Internal particle structure depends upon 1. Interfacial energies (3 interfaces)

2. Rate of solvent removal

Oct 31 2005

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41

Examples of Two Component Polymer Particles via Artificial Latex Process

Artificial latex particles of two immiscible polymers exhibit distinct morphologies and can provide a convenient model system to study some aspects of particle morphology control. Oct 31 2005

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42

21

Reactive Processes General Mechanisms for Particle Formation • Nucleation within pre-formed dispersed phase Suspension and emulsion (micelle) polymerizations • Polymer precipitation from solution Dispersion and emulsion (homogeneous nucleation) polymerizations Copyrighted - University of New Hampshire

Oct 31 2005

43

Particle Size Ranges Achievable via Reactive Processing

1 mm

100μm

10μm

Suspension Polymerization

1μm

100 nm

10 nm

1 nm

Emulsion Polymerization

Dispersion Polymerization

Oct 31 2005

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22

Suspension Polymerization Water Surfactant

Oct 31 2005

Monomer/Polymer Initiator, chain transfer agent, crosslinker

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45

Suspension Polymerization • Stabilizers (surfactants) – often are water soluble polymers, e.g. PVOH, PVP. Added at ~0.1% of aqueous phase. • Initiators (oil soluble), peroxides, azo compounds. • High stirring rates required to create particles and to keep them suspended (Brownian motion insufficient). • All organic phase ingredients must be added to monomer stream as there is no effective transport through aqueous phase. Oct 31 2005

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23

Dispersion/Precipitation Polymerization

Organic Solvent Initiator,Surfactant

Monomer Chain transfer agent

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Oct 31 2005

47

Dispersion/Precipitation Polymerization Mechanism • Early stage polymerization in solution to form low MW polymer

chains • Precipitation of polymer from solution to form particles • Partition of monomer(s), initiator, CTA between solution and particle phases • Adsorption of surfactant on particle surface • Continued polymerization, occurring more and more in the particle phase Oct 31 2005

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24

Dispersion/Precipitation Polymerization • Broad range of copolymers can be produced

• Choice of solvents (often mixtures with alcohols) is critical • Use of continuous phase to transport reactants to particle phase • Can do “second stage” processing to add second type of comonomer to create composite particles • Decent particle size distribution control Copyrighted - University of New Hampshire

Oct 31 2005

49

Emulsion Polymerization

Water Surfactant

Monomer Chain transfer agent, crosslinker

Water Initiator

Oct 31 2005

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25

Emulsion Polymerization • Limited to free radical chemistry, but a wide range of monomers can be used • Water phase provides for low viscosity and very good heat removal – environmentally positive • Latex particles are small enough to be effected by Brownian motion and thus stirring speeds can be low • Mechanical stability is much better than than in other dispersion polymerization methods, but can be an issue • Process is easily adapted to multi-stages to build composite particles with many morphologies • Particle surfaces can be easily modified with reactive end groups Copyrighted - University of New Hampshire

Oct 31 2005

51

Emulsion Polymerization Mechanism • Add water and surfactant to reactor • Add water insoluble monomer, CTA, crosslinker, etc. to form emulsified droplets (10-50 micron) • Add water soluble initiator to start reaction • Micellar or or precipitation (called homogeneous) polymerization to nucleate particles • Particles grow by continued adsorption of monomers and conversion into polymer Oct 31 2005

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26

Second Stage Emulsion Polymerization seed latex particle

Initiator addition

monomer feed

surfactant molecule

M

I→2R•

I M

M

M

RMn• M

M

M+R•→RM1•

M

M

RMn•

M M RMn•

M

I

I I M M

M RMn• M

M

RMZ•

entry

RMn•

M

M

RM•+RM•→RMMR M M

Oct 31 2005

M

RM1•+M→RM2•

M RMn•

M M M

M M

I

RMn•

I

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53

Emulsion Polymerization Characteristic features of latex particles • Single component particles are spherical when made in a one step process • Small enough to generally avoid settling/creaming because of Brownian motion • Small size leads to potentially high latex viscosity at solids contents exceeding 40-50% • Functional polymers can be located at particle surface

Oct 31 2005

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27

Emulsion Polymerization Micellar Mechanism • Surfactant in excess of CMC forms aggregates of molecules with oily ends in center and hydrophilic ends towards water • Monomer diffuses to micelles to concentrate in the center • Free radicals diffuse through the water and penetrate the micelles to create a latex particle • These new particles grow in size by absorbing monomer transported through the water. Surfactant adsorbs on growing surfaces to stabilize the particles • Particle size and number dependent on surfactant level, initiator level and temperature Oct 31 2005

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55

Emulsion Polymerization Homogeneous Nucleation Mechanism • Oligomeric radicals form in the aqueous phase and grow until they precipitate to form a new particle • New particles absorb monomers, adsorb surfactant, and are penetrated by initiator radicals • New oligomer radicals produced in water phase either adsorb onto existing particles or precipitate to form new particles • New particle formation continues until all new oligomer radicals adsorb onto existing particles

Oct 31 2005

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28

Multiple Stage Processing via Polymerization • Build upon the structure of the precursor particle by adding another polymer to it • Polymerize the two (or more) polymers in separate processes and locations. Blend the two, effecting particle interactions leading to a single, more complicated particle. Particle “engulfment” technology has been demonstrated • Alternatively, can add the “second stage” as a monomer and create the composite particle by in-situ polymerization • Second stage polymerization is commonly practiced and requires phase separation to occur within the primary (seed) particles Copyrighted - University of New Hampshire

Oct 31 2005

57

Second Stage Emulsion Polymerization seed latex particle

monomer feed

surfactant molecule

M

M

M

M M

M

M

M

M

M M

M

M

M

M M M

M M M

M

M M

M

M M

M

M

M M M

M

Oct 31 2005

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29

Second Stage Emulsion Polymerization seed latex particle

Initiator addition

monomer feed

surfactant molecule

M

I→2R•

I M

M

M

RMn• M

M

M+R•→RM1•

M

M

RMn•

M M RMn•

M

I

I I M M

M RMn• M

RMZ•

M

entry

RMn•

M

M

RM•+RM•→RMMR M M

M

RM1•+M→RM2•

M RMn•

M M M

M M

I

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Oct 31 2005

I

RMn•

59

Batch Reaction Seed Latex

Condenser

Surfactant Water Monomer Initiator

Oct 31 2005

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30

Semi-Batch Reaction Condenser

Monomer Surfactant

Initiator

Water

Water

Seed Some Surfactant Some Water Some Monomer Copyrighted - University of New Hampshire

Oct 31 2005

Phase Diagram

61

M2 1Φ 2Φ

tch ba

Polymerization Pathways

Semi-batch

P1 Oct 31 2005

P2 Copyrighted - University of New Hampshire

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31

Multiple Component Polymer Nanoparticles Two Component Particles – Morphological Options THERMODYNAMIC CONTROL

Oct 31 2005

KINETIC CONTROL

Inverted Core-Shell

CoreShell

Octopus - like

Core-Shell

Moon - like 3rd quarter

Moon - like 1st quarter

Raspberry - like

Occlusion or Salami - like

Eye-Ball - like

Acorn - like

Sandwich - like

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63

Sensitivity of Particle Morphology Control

Batch reaction

Semibatch reaction

System: P(MA-co-MMA) seed, PS second stage. All conditions are identical except mode of addition of monomer, batch vs. semibatch. Oct 31 2005

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32

Latex Particle Morphologies: Fully Consolidated Particles

Oct 31 2005

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Latex Particle Morphologies: Partially consolidated

Oct 31 2005

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33

Latex Particle Morphologies: Occluded morphologies (not consolidated)

Oct 31 2005

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67

Latex Particle Morphologies: No apparent morphology??

This represents a composite particle in which contrast between the phases should be apparent in TEM (by selectively staining one phase with Ruthenium). No obvious morphology is observed!? Oct 31 2005

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34

Polymer Nanotechnology: Synthesis and Novel Applications Polymer Synthesis III

Miniemulsion Polymerization

http://www.mpikg-golm.mpg.de/kc/landfester/

Oct 31 2005

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35

Miniemulsion Polymerization • Create a meta-stable emulsion of the monomer(s). • Use 2 key elements : – High shear source to break large droplets • Sonicator • Microfluidizer • Homogeneizer

– Use a water insoluble molecule to stabilize the particle • Sometimes called cosurfactant (missleading) • Hexadecane, Eicosane, polymer, macromonomer, macroinitiator, CTA, ...

Oct 31 2005

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71

Miniemulsion stability

Water Surfactant(s) Monomer(s) Stabilizer No stabilizer

With stabilizer Oct 31 2005

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36

Particle size control

K. Landfester, N. Bechthold, F. Tiarks, and M. Antonietti, Miniemulsion Polymerization with Cationic and Nonionic Surfactants: A Very Efficient Use of Surfactants for Heterophase Polymerization. Macromolecules Copyrighted - University of New Hampshire1999, 32, 2679.

Oct 31 2005

73

Mini to micro emulsion

K. Landfester, Recent Developments in Miniemulsions - Formation and Stability Mechanisms. Macromol. Symp. 2000, 150, 171.

Oct 31 2005

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37

Microemulsion Recipe MJB-10: microemulsion (seed) Water 82.84% NaHCO3 0.043% Na2O5S2 0.011% SDS 8.27% KPS 0.17% Styrene 8.67% Water, Salts, SDS, stirred, degassed. Add 20% of styrene. Heat. When at 80C, add KPS. Let react for 20 minutes. Start feeding with styrene, over 2 hours. 30 minutes of Post polymerization. SCexp = 15.1% Conversion = 77.47% Size = CHDF: Dv = 35.5 nm, Dn = 33.2 nm Nanotrac: Dv = 36.8 nm, Dn = 25.13 nm

Oct 31 2005

MJB10

MJB21

33nm

108nm

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Encapsulation of magnetite in polymer particles by miniemulsion

Oct 31 2005

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38

Block copolymer direct from miniemulsion 140 130

TRM-031b TRM-031c 21312 34987 32815 56720 1.54 1.62 0.845 0.71 33540 52227.6 7:26 6:52 132 129 3 3 208 423 287 526 none high 31 22.2 26.4 19.4 43.7 43.7 49-51 1.84

Tem perature (°C)

Mn (g/mole) Mw (g/mole) Mw/Mn Conversion Mn (g/mole) (theoretical f=1.3) Polymerization time (h:min) Polymerization Temperature (°C) Polymerization Pressure (Atm) PD (nm) before polymerization PD (nm) after polymerization Coagulum Initial monomer content (%) Final Solid Content (%) Tg (°C) (DSC) Tg (°C) (calculated for blend) Sty/BA Block ratio (block/precursor)

2 2 3 1.30

120 110 100

TRM031b

90 80 0

60 120 180 240 300 360 420 480 540 600 Tim e (m in.)

140 130 Tem perature (°C)

Comp. Potassium Myricyl Sulfate (pphm di-octyl sulfosuccinate (pphm) Eciosane (pphm) OH-TEMPO/tBHP (mole/mole)

120 110 100

TRM031c

90 80 0

60 120 180 240 300 360 420 480 540 600 Tim e (m in.)

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Oct 31 2005

Block copolymer

77

PS-b-P(S-BA) Mn=34987 Mw/Mn=1.62 PS block Mn=21312 Mw/Mn=1.54 PS-b-P(S-BA) cum. PS block cum.

100

cumulative (%)

80

1.4

70

1.2

60

1

50

0.8

40

0.6

30

0.4

20

0.2

10 0 1000000

dwt/dLogM

1.6

90

100000

10000

0 1000

Molecular weight (g/mole)

TRM031 Oct 31 2005

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39

AFM Block copolymer spin cast from THF, 8000rpm, 20 sec

Oct 31 2005

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79

Self Assembly

• Lipids • PGlu – PLeu • UNH tri-block

Oct 31 2005

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80

40

Liposomes

Liposome

Lipid bilayer

http://www.avantilipids.com/PreparationOfLiposomes.html

Oct 31 2005

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81

Self assembly of Liposome Multi Lamellar Vesicles

Small Unilamellar Vesicles Photo courtesy of FEI Company Japan Ltd.)

Large Unilamellar Vesicles : LUV Oct 31 2005

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41

Self Assembly

• PGlu - PLeu

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Oct 31 2005

83

Synthetic Scheme O

MeO2C CO2Me

O

HN NH3 +

HN

O O

H2N CO2

O

N H

H n

CO2Me

O O

O H2N

N H

O

CO2

H N

n

H2O

H m

H+

CO2H O H2N O

Oct 31 2005

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N H

n

H N

H m

84

42

Self-assembly in water

water soluble PGlu

water insoluble PLeu micelles lamellar structures

rods Copyrighted - University of New Hampshire

Oct 31 2005

85

Self Assembly Process (L = 12, G = 35) transfer to water

diafiltration

crystallization

20 oC

NMP Dh (nm)

28

18

18

2*Rg (nm)

-

9

9

Mw (g/mol)

620 000

320 000

320 000

900 883 617 >900 >900 >900 >765 >900 >900

PCC >900 >900 >900 >900 >900 >900 >900 >900 >900 >900 >900 >900 >900 >900 >900 >900

Florida DGAFC >900 >900 >900 368 >900 >900 >900 >900 >900 >900 >900 >900 >900 >803 >900 >900

OGAFC 101 173 255 83 >900 >900 436 400 577 607 824 420 377 625 >900 >836

Pennsylvania DGAFC PCC 341 390 258 284 444 470 389 470 505 823 474 684 >1100 >1100 >1100 >1100 630 >1100 578 >1100 >1100 413* >1100 354* 386 >1100 298 365 NA NA NA NA

25% increase

NA - Not Available, OGAFC - Open-graded asphaltic concrete, * - Data may not be reliable due to snowplow damage, DGAFC - Dense-graded asphaltic concrete, PCC - Portland cement concrete Copyrighted - University of New Hampshire

Oct 31 2005

155

Wear resistance improvement • Hybrid technology • Combine properties of PU and water base acrylics – Wear resistance properties of urethanes – Cost of acrylics Polyacrylate

Conventional polymer binder

PolyUrethane shell

Polyacrylate core advanced polymer binder

• Binder can be prepared by miniemulsion polymerization

Oct 31 2005

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156

78

Application

Oct 31 2005

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Oct 31 2005

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158

79

Drug release

Release Concept “In Vivo” Vs. “In Vitro” In-vitro

In-vivo Nature membrane

Liposome

Peptide flux Peptide Permeation enhancer

Oct 31 2005

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160

80

Trigger strategy (in vitro)

PEPTIDE

PEPTIDE

TRIGGER

PEPTIDE

PEPTIDE

RELEASE STUDY Copyrighted - University of New Hampshire

Oct 31 2005

161

Release study strategy 37 oC

1. Take 0.5 ml sample out periodically

buffer

2. Centrifugal extraction

FLD

3. filtration (MWCO 10 K/50K) "blank' release

160 140

Adjusted Fluorescence

120 100 80 60 40

37C

20 0 0

5

10

15

20

25

30

35

40

Tim e (hr)

Oct 31 2005

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81

Transmembrane transport mechanism of insulin with excipient triggering Phase I Phase II

Phase III

Release at 37C with cholesterol

Concentration(mg/ml)

0.006 0.005 0.004 0.003 0.002 Blank

0.001

1XCPE&CSO 1XCPE&CSO+B-

0 0

5

10

15

20

flux

25

30

35

40

45

50

55

Time (hour)

Defect CPE-215 molecules

Liposome

Oct 31 2005

Low insulin leak rate

High insulin leak rate

T=0

Phase I

Medium insulin leak rate

Phase II

Low insulin leak rate

Phase III

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163

Drug delivery

82

Oral Delivery of Proteins Numerous barriers - Stomach (pH ~ 3) => Use of an enteric coating - Intestine (pH ~ 6.8 -7.4)

Oct 31 2005

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165

Oral Delivery of Proteins

Oct 31 2005

Enzyme : trypsin, chymotrypsin, pepsin, carboxypeptidase, lipase, amylase,sucrase, maltase, lactase Copyrighted - University of New Hampshire

166

83

Oral Delivery of Proteins Intracellular transport

Paracellular transport through tight junctions (< 1 nm)

80 nm

700 nm

Mucus Size issues : Hydrophobic, viscous, pH ~ 5 Oct 31 2005

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167

Oral Delivery of Proteins

Large series of digestive proteins :

Oct 31 2005

- Efflux proteins - Cytochroms - Proteases

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84

Oral Delivery of Insulin Encapsulation of insulin in a vesicle (= nanobag)

What are the properties of these vesicles ?

-

made of biocompatible constituents can be encapsulated in an enteric coating have an hydrophobic external layer (mucus is hydrophobic) have a small size (~ 100 nm) can release the bioactive drug can be used for all kind of biologically active macromolecules

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1. Self Assembly

insulin

water UNH POLYMER

100 nm 10-7 m

50-150 nm

85

2. 1.Microencapsulation Self Assembly

insulin

water UNH POLYMER

2. Microencapsulation

86

2. Microencapsulation

www.unh.edu/pnl

2. 3.3. Microencapsulation Administration Administration Microencapsulation in gastroresistant capsule (Eudragit)

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3. Administration

Dissolution of the gastroresistant coating Release of the nanoparticles

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3. Administration

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3. Administration

Nanoparticles are internalized, degraded and release insulin

insulin insulin insulin

How to make vesicles ? - Use phospholipids to make liposomes - Use block copolymers

pH = 7.4 Spontaneous self association

hydrophobic Forms the wall of the vesicle Degrades naturally Oct 31 2005

Hydrophilic polymers necessary to form the vesicle and prevent insulin denaturation

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Vesicles inside the intestine Small Intestine

Nanoparticle dispersion

protease

Digestion of the PGlu hairy layer

hydrophobic particle is adsorbed

Enteric Coating microvilii

endocytosis Acidic degradation of PLA Endosome (pH = 5) Insulin delivery

Oct 31 2005

epithelial cell

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Getting around the BBB

•The blood-brain barrier (BBB) The BBB is formed by the endothelium lining the cerebral microvessels with tight junctions in order to maintain rigorous control of the microenvironment within the brain. Even the glucose molecules need transporters to go through the BBB.

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Novel pathway for drug delivery

The neural connections between the nasal mucosa and the brain provide a unique pathway for noninvasive delivery of therapeutic agents to the CNS, by bypassing blood-brain barrier. Copyrighted - University of New Hampshire

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Design to degradation

Shell degradation

Shell degradation

OH COO-

OH COO-

Polyasparagine

Oct 31 2005

Semi-crystalline PLA

Amorphous PLGA

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Sensor Technology

•

Polymeric Nanoparticles synthesis processes – – – –

•

Emulsion Polymerization Mini-emulsion Polymerization Self assembly Directed assembly

Application to biotechnologies – biosensors by molecularly imprinted polymers – liposomes for transmembrane delivery – Bypassing the BBB

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Molecularly Imprinted Polymers

1. 2. 3. 4. Oct 31 2005

Selection of template molecule and functional monomers Self-assembly of template molecule and functional monomers Polymerization Analyte Extraction Copyrighted - University of New Hampshire

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Biomimetic electrochemical sensors based on molecular imprinting •

A chemical sensor selectively recognizes a target analyte molecule in a complex matrix and gives an output signal which correlates with the concentration of the analyte.

The transducer: When the analyte interacts with the recognition element of a sensor, there is a change in one or more physicochemical parameters associated with the interaction. Transducer convert these parameters into an electrical output signal than can be amplified, processed and displayed in a suitable form. ⇒ Molecular imprinting use as sensing materials Advantage: cheap, stable and robust under a wide range of conditions including pH, humidity and temperature Problem: Signal transduction is so low that it seem to be environmental artifacts. Due to the insulating nature of the polymer constituting the MIP

Biomimetic electrochemical sensors based on molecular imprinting / Chap.18 MIP – D. Kriz, R. J. Ansell- Vol 23 -Elsevier

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Preparation of a MIP •

Choice of the target molecules Wide variety of analyte molecules have been successfully used for the preparation of selective recognition matrices

Compound Class Example

Compound Class

Example

amino acids

phenylalanine tryptophan tyrosine aspartic acid

carbohydratesa

galactose glucose fucose

drugs

timolol theophylline diazepam morphine ephedrine

hormones

cortisol enkephalin

pesticides

atrazine

co-enzymes

pyridoxal

proteins

RNase A Urease

nucleotide bases

adenine

a

Molecular Imprinting Technology - A Way to Make Artificial Locks for Molecular Keys http://www.smi.tu-berlin.de/story/How.htm

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SINP : Surface Imprinted NanoParticle 1st stage Miniemulsion Polymerization

P(MMA-EGDMA) Core

MAA EGDMA

2nd stage Emulsion Polymerization

P(MMA-EGDMA) Core

Extraction by dialysis

P(MMA-EGDMA) Core

Caffeine Caffeine P(MAA-EGDMA) shell MJB-20: miniemulsion seed Organic phase = 23% : MMA 85.5%, EGDMA 9.5%, Hexadecane 5%, Water phase = 77% : Water 99%, SDS 0.6%, KPS 0.025%, NP-50 0.39% Prepare the two phases, mix them together, magnetically stir them for 15 minutes, then, sonicate the resulting emulsion for 2 minutes (90%, 9) in ice. SCexp = 22.25%, Conversion = 98.96%, Size = Malvern Nanosizer: Dz = 107.1 nm, Dv = 111.9 nm

Oct 31 2005

MJB-21: 2nd stage imprinting Water 57.74% MJB20 (wet) 33.44% NaHCO3 0.042% KPS 0.047% Caffeine 5.78% EGDMA 2.63% MAA 0.31% Water, MJB-21, NaHCO3, were mixed and heated at 80C. When at temperature, add caffeine and start degassing. After 15 minutes, add KPS and start feeding with egdma+maa. Dilute with 250g of hot water (336%) while stirring. SCexp = 2.635% (dilution) Conversion = 57.86% Size = Malvern nanosizer Dz= 108.4 nm, Dv = 114.2nm Brookhaven 90+: Dz = 104.9 nm, Effective Dv = 105.2 nm

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Size distribution

MJB21 by Light scattering

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SEM of nanoparticles

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QCM • A QCM consists of a thin quartz disc sandwiched between a pair of electrodes. Due to the piezoelectric properties of quartz, it is possible to excite the crystal to oscillation by applying an AC voltage across its electrodes.

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Q-Sense D300

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Coated QCM sensor Fracture SEM

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Raw data

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QCM results

Adsorption of caffeine at different caffeine solution concentrations 1 caffeine 0.05g/L caffeine 0.0005g/L caffeine 0.005 g/L

0.9 0.8 0.7

150Hz

F1/F1max

0.6 0.5 0.4

1.6Hz

0.3 0.2 0.1

12Hz

0 0

5

10

15

20

25

time in minutes

With the Langmuir equation the quantity adsorbed can be calculated for the caffeine MIP at a concentration of 0.0005g/L. This value is found to be equal to 7.3×10-6g of caffeine per gram of MIP. The mass of MIP on the crystal is equal to 4×105g. With these two values, the minimum amount detected in this experiment was equal to 0.3nanogram.

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Guanosine Recognition •

Perfect complement to imprint guanosine is cytidine

NH 2

Cytidine

O

O

N

N O

O

•

O

Guanosine

O N

HN N

N

H 2N

O O

O

Modified cytidine monomer O OH

+

O

HO HO

O N OH

O

NH2

O

O

O

N H3PO4 1.3eq EDIC 1.5eq DMAP 2.5eq in water RT 12 hrs

HO

N OH

NH2 N

O

EDCI: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride DAMP: 4-dimethylaminopyridine Oct 31 2005

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LC/MS Base peak chromatogram

m/z 112, 266

NH2 N

RT: 0.05 - 29.98 100 HO

O

NL: 1.57E6 Base Peak F: MS marine_sampl e_05042011 4728

13.10

N

O

95

Na+

90 85

OH

HO

80

13.06

266

75 70 65

NH2

Relative Abundance

60 N

55 O

50

N

O O

45

O

Na+

40 35

m/z 226, 174, etc

HO

OH

334.1

30

m/z 334

24.94 25.06

25

24.89

25.13

20

Two different Isomers apparently

15 10 5

1.81 1.93 1.87 2.12

1.65

11.14

12.61

10.64 3.74

5.04 5.51 6.22

7.02

9.66

13.68

15.72

20.64 20.72 20.80 23.13 17.72 19.78 20.43

28.04 28.64

24.53

0 2

4

6

8

10

12

14 16 Time (min)

18

20

22

24

26

28

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SINP : Guanosine detection 1st stage Miniemulsion Polymerization

2nd stage Emulsion Polymerization

Cytidine-MA

P(MMA-EGDMA) Core

EGDMA

P(MMA-EGDMA) Core

Extraction by dialysis

P(MMA-EGDMA) Core

Guanosine P(MAA-EGDMA) shell

Oct 31 2005

Guanosine

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Latex agglutination Medical diagnostics

New developments in particle-based immunoassays: introduction

Pure & Appl. Chem., Vol. 68, No. 10, pp. 1873-1879, 1996.

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100

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BioSensors for Medical Diagnostic

101

SERS-MIP strategy

PDMS Ag

SERS “hot spots”

100nm

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SERS-MIP strategy

Glass Microfluidic channel

PDMS Ag

Oct 31 2005

SERS “hot spots”

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100nm

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SERS-MIP strategy

Analyte

Oct 31 2005

Ag

Analyte receptor site = synthetic antibody Copyrighted - University of New Hampshire

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SERS-MIP strategy

Glass Microfluidic channel

PDMS Analyte

Ag

SERS “hot spots”

100nm

SERS “super hot spots”

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103

SERS-MIP strategy

Glass Microfluidic channel

PDMS Analyte

Ag

SERS “hot spots”

100nm

SERS “super hot spots”

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Future…

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