Nanoparticles for Biomedical Applications

Part I: Preparation & Stabilization

Jingwu Zhang

5/3/06

Nanoparticles for biomedical applications

Imaging agents Gold, Silver, Quantum

Dots, Magnetic Nanoparticles

Chemical sensors DNA Modified Au

particles Drug delivery devices

Nanocapsules Therapeutic agents (?)

Nano-sized delivery systems based on lipids and amphiphilic block copolymers

Conjugated Au particles stick to cancer cells

A cluster of gold nanoparticles 50 nanometers in diameter created a much larger crater in ice

Outline

Preparation of monodisperse nanoparticles Gold nanoparticles Methods for achieving uniform particle size

Colloidal Stability in electrolyte solutions Surface charge DLVO theory Schulze-Hardy rule

Stabilization of Nanoparticles by polymers Polymer adsorption Stabilization mechanisms

Preparation of Preparation of Monodisperse Monodisperse NanoparticlesNanoparticles

Possible Applications of Colloidal Gold (C.W.Corti et al, Gold Bulletin 2002, 35/4 11-118)(B.Chaudhuri and S. Raychaudhuri, IVD Technology 2001 March)

          

                                   

Nanoswitch

Microwire

Making Colloidal Gold: 1857 Faraday prepared gold colloids by reduction of gold chloride

with phosphorus. "Experimental relations of gold (and other metals) to light." In: Philosophical Transactions, 147, Part I, pp. 145-181, [1]. London Taylor & Francis 1857.

1861 Thomas Graham coined the word “colloid” to describe systems which exhibited slow rates of diffusion through a porous membrane.

Zsigmody (Nobel Prize, 1925) developed “seed” method to produce uniform and stable gold sols.

1908 Mie interpreted the vivid color of colloidal gold (Verification of Mie theory for light scattering).

1951 Turkevich, et. al. studied nucleation and growth of gold particles in sodium citrate (Discussions Faraday Soc. 1951, No. 11 55-75)

1973 Frens developed a simple sodium citrate reduction method to produce colloidal gold of uniform and controlled size.

Ref: M.A. Hayat “ Colloidal Gold” Vol 1, 1989

Colloidal Gold Synthesis(Turkevich, et. al. Discussions Faraday Soc. 1951, No. 11 55-75)

Solution color varies extensively with particle size Usually a deep red, but also dark brown/purple

to light orange/yellow Colloid size can be controlled by Au:Citrate ratios

Anywhere between 1nm - 100nm Extremely stable

OH

HO

O

OH

O

O

HO

H2O, 100OCH2AuCl4

Cit-

Cit-

Cit-

Cit-

Reduction by Citrate (Frens,1973)

Boil 50mL 0.01% HAuCl4 (0.29mM)

Add 1.75mL 1% Na3Citrate

Keep boiling for a few minutes

Mean particle size is 12nm (CV 20%)

TEM images gold nanoparticles Produced by citrate reduction

Homegeneous Nucleation

SgkTGV ln

Interface Energy r2

Volume Free Energy r3

r*

G

Gr

r

Gr*Free energy change for formation of bulk

Saturation Ratio:

S=C/Cs

C=concentration; Cs=solubility

Free energy change for generating the surface:

2

3

)ln(3

16

SkTGC

ΔGs=4πr2σ=4π(r/a)2γMaximum Gibbs free energy for nucleation

γ=surface energy per atomic site

Homogeneous Nucleation Size Critical

Nucleus

Nucleation Rate

Activation Energy

SkT

arC ln

2 3

)/exp( kTGkJ Cnn

2

3

)ln(3

16

SkTGC

Sm

Preparation of Uniform ParticlesStrategy 1: Control of nucleation

Monodisperse nanoparticles can be produced by confining the formation of nuclei to a very short period, so that the particle number remains constant and all grow together to the same size.

This strategy was first used by La Mer to produce highly monodisperse sulfer sols.

1: HAuCl4 + 3e- = Au

2: Supersaturation build-up

3: Homogeneous Nucleation4: Growth of Nuclei 5: Stabilization by Dispersants

Steps for making Au nanocrystals

SAu

AuS

][

][

LmolAu S /102Solubility][ -12

[Au]

Metastable Zone: S=1 to Sm

Preparation of Uniform ParticlesStrategy 2: Seeded Growth

Preparation of seed crystals Growth on seeds in meta-stable

zoneGrowth

2:1

3:2Diameter ratio

growth

4:3

The particle size distribution becomes narrower with time.

This strategy was first used by Zsigmondy to produce monodisperse gold sols

Preparation of Uniform ParticlesStrategy 3: Aggregation of Nanosized Precursors

This strategy has been employed by Matijevic and co-workers to make a variety oftransition metal oxide by controlled hydrolysis techniques

Hematite (α-Fe2O3) Prepared by Forced Hydrolysis (Matijević and Schneider, 1978)

2 4 6 8 10 12

-40

-20

0

20

40

/mV

pH

J. Zhang & J. Buffle, J. Coll Int. Sci 174 (1995) 500-509

50nm

pHiep=9.2

Preparation of silver particles

AgNO3 + NaBH4

Na3Citrate

NaOH

Ag

Reducing agent

Stabilizing agent

pH Control

Colloidal Stability in Colloidal Stability in Electrolyte SolutionsElectrolyte Solutions

Mechanism of surface Charge Generation

Ionization of functional groups at surface

Ion adsorption from solution

Crystal lattice defects (clay mineral system, due to isomorphous replacement of one ionic species by another of lower charge)

OH

O-

COO-

X-

X-

X-

Si(IV)

Si(IV)

Al(III) Al(III)-

Al(III)-

Electrical double layer

Helmholtz Model

Guouy-Chapman Model

Stern Model

Colloidal Stability: DLVO TheoryDerjaguin-Landau (1941) & Verwey-Overbeek(1948)

22

2

22

2

2

2

44

4ln

44

2

4

2

6 RRss

Rss

RRss

R

Rss

RAA

)exp(64

2

200 s

kTRCR

Van der Waals Attraction

Electrostatic Repulsion

1

1

12 mmm ss

AR

Energy Maximum

2/12000

I

kT

eN A

sR

Sm = 3 nm for hematite

Total interaction free energy

VT=VA+VR+VS

VS = steric repulsion

Influence of electrolyte concentration on particle-particle interaction energy

Debye Parameter

К ~ I1/2 ~ electrolyte concentration

Double layer thickness (unit: Å):

К-1 = 3.04/I1/2

Size Evolution vs. Ionic StrengthFe2O3: 10mg/L (2.4x1013/L), pH=3.0, 25.0±0.3°C

Critical coagulation concentration (CCC): The concentration of an electrolyte about which aggregation occurs rapidly

CCC for selected sols

Schulze-Hardy rule (recognized at end of 19th century)

(a) The CCC for similar electrolyte solutions is similar but not identical.

(b) It is the valency of the counter ion that is of paramount importance in determining the coagulation concentration.

According to DLVO theory:

CCC~1/z6

Stabilization of Nanoparticles Stabilization of Nanoparticles by Polymersby Polymers

Colloidal stabilization by polymers

Examples of polymersSynthetic polymers

Biopolymers: protein, DNA, Polysaccharide

Isotherm of polymer adsorption

(a) A typical high-affinity polymer adsorption isotherm

(b) Langmuir adsorption isotherm, usually followed by small molecules

Configuration of polymer chain on surface

Mechanisms of Colloid stabilization by polymers

Increase in electrostatic repulsion

Decrease in attraction energy

Decrease in Hamaker

Constant Steric repulsion

Volume restriction Osmotic effect

H2O

H2O

Destabilization of Colloids by Polymers

Polymer bridging Charge Neutralization Electrostatic Patch Model

Double roles of polymers Flocculation and Stabilization

Steric stabilization

Charge reversal

Electrostatic & steric

Increasing polymer concentration

Aggregation of Hematite by PAA (Mw=1.36x106)

0.0 0.2 0.4 0.6 0.8 1.0

-20

-10

0

10

20

30

40

/mV

Cp /mg l-1

0.0 0.2 0.4 0.610-4

10-3

10-2

10-1

100

Cp /mg L-1

Polymer Concentration (ppm)

Collision efficiency factor Zeta-potential

DLAPre-DLA

Post-DLA

Effect of Molecular Weight

0 .0 0 0 .0 2 0 .0 4 0 .0 61 0-4

1 0-3

1 0-2

1 0-1

1 00 a

PA A / H e m a tite0 .0 0 0 .0 2 0 .0 4 0 .0 6 0 .0 8

-1

0

1

2

3

b

PA A / H e m a tite

u /

m c

m V

sE

-1

-1

Collision efficiency factor Zeta-potential

60.1

1069.3 4

nw

w

MM

M

53.1

1036.1 6

nw

w

MM

M

Q&AQ&A

Methods for determining particle size

Dynamic Light Scattering (PCS)

                      

PM

0

0

Time

Sca

tter

ing

In

ten

sity

Instructor: Dr. Zhen GuoMatE 297, Spring 2006

Bonding Type IV – Van De Walls Force Bonding Type IV – Van De Walls Force from permanent and induced Dipolefrom permanent and induced Dipole

A B

A B

From Principles of Electronic Materials and Devices, Second Edition, S.O. Kasap (© McGraw-Hill, 2002)http://Materials.Usask.Ca

HC l

(a)(b)

(c)

Fig. 1.11: (a) A permanently polarized molecule is called a anelectric dipole moment. (b) Dipoles can attract or repel eachother depending on their relative orientations. c Suitably orienteddipoles attract each other to form van der Waals bonds.

T im e a ve ra ge d e le c tro n (n e g a tive c h a rg e )d is tr ib u tio n

C lo se d L S h e ll

Io n ic c o re(N u c le u s + K -sh e ll)

N e

From Principles of Electronic Materials and Devices, Second Edition, S.O. Kasap (© McGraw-Hill, 2002)http://Materials.Usask.Ca

A B

S y n c h ro n iz e d f lu c tu a t io n so f th e e le c t ro n s

v a n d er W a a ls fo rce

Instantaneo u s e lec tro n (nega tive charge)d istrib u tio n flu c tu a tes ab o u t the nu cleu s.

Fig. 1.13: Induced dipole-induced dipole interaction and the resultingvan der Waals force.