1. Nanoparticles for Biomedical Applications Part I: Preparation & Stabilization
Jingwu Zhang
5/3/06

2. Nanoparticles for biomedical applications
Imaging agents
Gold, Silver, Quantum Dots, Magnetic Nanoparticles
Chemical sensors
DNA Modified Au particles
Drug delivery devices
Nanocapsules
Therapeutic agents (?)
Conjugated Au particles stick to cancer cells
A cluster of gold nanoparticles 50 nanometers in diameter created a much larger crater in ice
Nano-sized delivery systems based on lipids and amphiphilic block copolymers

3. 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

4. Preparation of Monodisperse Nanoparticles

5. Possible Applications of Colloidal Gold (C. W
Possible Applications of Colloidal Gold (C.W.Corti et al, Gold Bulletin 2002, 35/ ) (B.Chaudhuri and S. Raychaudhuri, IVD Technology 2001 March)
                                             
Microwire
Nanoswitch

6. 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 , [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 , No )
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

7. Colloidal Gold Synthesis (Turkevich, et. al. Discussions Faraday Soc
Colloidal Gold Synthesis (Turkevich, et. al. Discussions Faraday Soc , No )
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
Cit-
H2AuCl4
H2O, 100OC

8. 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%)

9. TEM images gold nanoparticles Produced by citrate reduction

10. Homegeneous Nucleation
Interface Energy r2
Volume Free Energy r3 r* DG
DGr r
DGr*
Free energy change for formation of bulk
Saturation Ratio:
S=C/Cs
C=concentration; Cs=solubility
Free energy change for generating the surface:
ΔGs=4πr2σ=4π(r/a)2γ
γ=surface energy per atomic site
Maximum Gibbs free energy for nucleation

11. Homogeneous Nucleation
Size Critical Nucleus
Nucleation Rate
Activation Energy Sm

12. Preparation of Uniform Particles Strategy 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.

13. Steps for making Au nanocrystals
1: HAuCl4 + 3e- = Au
2: Supersaturation build-up
3: Homogeneous Nucleation
4: Growth of Nuclei
5: Stabilization by Dispersants
[Au]
Metastable Zone: S=1 to Sm

14. Preparation of Uniform Particles Strategy 2: Seeded Growth
Preparation of seed crystals
Growth on seeds in meta-stable zone
Growth
2:1
3:2
Diameter ratio
growth
4:3
The particle size distribution becomes narrower with time.
This strategy was first used by Zsigmondy to produce monodisperse gold sols

15. Preparation of Uniform Particles Strategy 3: Aggregation of Nanosized Precursors
This strategy has been employed by Matijevic and co-workers to make a variety of
transition metal oxide by controlled hydrolysis techniques

16. Hematite (α-Fe2O3) Prepared by Forced Hydrolysis (Matijević and Schneider, 1978)
pHiep=9.2
50nm
J. Zhang & J. Buffle, J. Coll Int. Sci 174 (1995)

17. Preparation of silver particles
Stabilizing agent
AgNO3 + NaBH4
Na3Citrate
NaOH Ag
Reducing agent
pH Control

18. Colloidal Stability in Electrolyte Solutions

19. Mechanism of surface Charge GenerationOH O-
COO-
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) X- X- X-
Si(IV)
Al(III)-
Al(III)

20. Electrical double layer
Helmholtz Model
Guouy-Chapman Model
Stern Model

21. Colloidal Stability: DLVO Theory Derjaguin-Landau (1941) & Verwey-Overbeek(1948)
Van der Waals Attraction R s
Electrostatic Repulsion
Energy Maximum
Sm = 3 nm for hematite

22. Total interaction free energy
VT=VA+VR+VS
VS = steric repulsion

23. 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

24. Size Evolution vs. Ionic Strength Fe2O3: 10mg/L (2. 4x1013/L), pH=3
Size Evolution vs. Ionic Strength Fe2O3: 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

25. CCC for selected sols

26. Schulze-Hardy rule (recognized at end of 19th century)
The CCC for similar electrolyte solutions is similar but not identical.
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

27. Stabilization of Nanoparticles by Polymers

28. Colloidal stabilization by polymers

29. Examples of polymers Synthetic polymers
Biopolymers: protein, DNA, Polysaccharide

30. Isotherm of polymer adsorption
Configuration of polymer chain on surface
(a) A typical high-affinity polymer adsorption isotherm
(b) Langmuir adsorption isotherm, usually followed by small molecules

31. 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

32. Destabilization of Colloids by Polymers
Polymer bridging
Charge Neutralization
Electrostatic Patch Model

33. Double roles of polymers Flocculation and Stabilization
Steric stabilization
Charge reversal
Electrostatic & steric
Increasing polymer concentration

34. Aggregation of Hematite by PAA (Mw=1.36x106)
Polymer Concentration (ppm)
Collision efficiency factor
Zeta-potential
DLA
Pre-DLA
Post-DLA

35. Effect of Molecular Weight
Collision efficiency factor
Zeta-potential

36. Q&A

37. Methods for determining particle size

38. Dynamic Light Scattering (PCS)
                       PM
With this method each size measurement takes less than a minute. Thus it is especially useful for aggregation kinetics studies.

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