Nanoparticles for Drug Delivery

EBME 316

Molecular Dispersions - definition & particle size

Homogeneous solutions of solutes (e.g. aqueous solution of NaCl and glucose).

Particle size: < 1nm

What are 4 ways nanoparticles can be useful in drug delivery?

1. Can prolong systemic circulation of a drug.

2. Can be biologically active

3. Can increase the solubility of a drug

4. Can alter the therapeutic efficacy of a drug

colloidal dispersion - definition & size

A heterogeneous system containing even distribution of particulate matter in other substance, e.g. milk. The system is also called a sol. The phases cannot be separated by gravity.

Particle size: 1-1000 nm

coarse dispersion - definition & particle size

A heterogeneous system containing a dispersed phase of large particles that can be readily separated by gravity.

Particle size: > 1 micrometer

Colloids

A system of a dispersed phase of heterogeneous particles in the size range of 1-1000 nm evenly dispersed in a continuous dispersion phase (medium).

lyophilic colloids

colloid particles have lyophilic (solvent-loving) property and can interact with the dispersion medium.

dispersed phase generally consists of large organic molecules within colloidal size range, e.g. proteins

Molecules of the dispersed phase are solvated.

Viscosity of the dispersion medium is increased greatly by the presence of dispersed phase. At sufficiently high concentrations, the sol may become a gel.

Dispersions are stable generally in the presence of electrolytes. They may be salted out by high concentrations of soluble electrolytes due to desolvation of the dispersed phase.

What does the dispersed phase of a lyophilic colloid usually consist of?

large organic molecules within colloidal size range (e.g. proteins)

dispersions of lyophilic colloids are generally (stable/unstable) in the presence of electrolytes.

stable; but may be salted our by high concentrations of soluble electrolytes due to desolvation of the dispersed phase.

lyophilic means:

solvent-loving

Lyophobic colloids

The colloidal particles are lyophobic (solvent-hating) to the dispersion medium and has little interaction with the molecules of the dispersion medium.

Lyophobic colloids are generally comprised of inorganic particles dispersed in water, e.g., gold colloid, silver colloid in water.

Materials do not disperse spontaneously and special procedures are required to make colloidal dispersion

Viscosity of the dispersion medium is not greatly increased by the presence of lyophobic colloidal particles.

Lyophobic dispersions can be stabilized by a small amount of electrolytes, but become unstable in the presence of higher concentrations of electrolytes due to the neutralization of the charge on the particles.

Lyophilic or amphiphilic colloids may improve the stability of the lyophobic colloids.

What do lyophobic colloids generally composed of?

inorganic particles dispersed in water

Lyophobic colloids (do/do not) disperse spontaneously.

Do not; special procedures are required to make colloidal dispersion.

Viscosity of the dispersion medium (is/is not) increased by the presence of lyophobic colloidal particles.

Is not

What are some uses of and examples of lyophobic colloids?

Can be used as therapeutics or imaging agents

Gold nanoparticles, cancer therapy, iron oxide nanoparticles, MRI contrast agents

Association (Amphiphilic) Colloids

A colloidal system formed by the aggregates (micelles) of amphiphiles in water.

Hydrophilic or lipophilic portion of the amphiphile is solvated, depending on the aqueous or nonaqueous nature of the dispersion medium.

Colloidal aggregates are formed spontaneously when the concentration of amphiphile exceeds the critical micelle concentration.

Viscosity of the dispersion medium is increased as the concentration of the amphiphile increases.

In aqueous solutions, the critical micelle concentration is reduced in the presence of electrolytes. Salting out may occur at high salt concentrations.

Amphiphilic colloids - what do electrolytes do to the critical micelle concentration?

lower it

Formation of amphiphilic colloids:

Amphiphiles are the molecules having a hydrophilic fraction and a lipophilic fraction. They can be low molecular weight molecules and polymers.

What is the critical micelle concentration (CMC)?

CMC is the concentration of amphiphiles above which micelles form.

How can you measure CMC?

pyrene fluorescence assay

Which category of colloid does Doxil belong to?

Amphiphilic (association) colloid

What is the Faraday-Tyndall Effect?

When a strong beam of light is passed through a colloidal sol, a visible cone is formed due to the scattering of light by the colloidal particles.

Brownian motion

The erratic motion of a particle is caused by bombardment of the particles by the molecules in the dispersion medium.

The velocity of the particles increases with decreasing particle size.

Increasing viscosity of the medium decreases and finally stops Brownian motion.

*Note: don’t forget the optical properties equations

Stability of Colloid Systems:

A lyophobic sol is thermodynamically stable. The particles in such a sol are stabilized by the repulsion of like charges present on the particle surface. Presence of a small amount of electrolytes to a lyophobic sol tends to improve its solubility.

The stability of a lyophobic sol can be improved by surface modification of the particles with amphiphiles and polymers.

Lyophilic and association sols are thermodynamically stable and constitutes a single phase. Their stability is not affected by a moderate amount of electrolyte. However, salting out can occur when a sufficient amount of salt is added.

Organic solvents can decrease the stability of hydrophilic colloids.

Mixing 2 hydrophilic colloids with opposite surface charges may cause phase separation, or coacervation.

How can you improve the stability of a lyophobic sol?

The presence of a small amount of electrolytes. Or, surface modification of the particles with amphiphiles and polymers.

Organic solvents can (increase/decrease) the stability of hydrophilic colloids.

Decrease

What happens when you mix 2 hydrophilic colloids with opposite surface charges?

It can cause phase separation (aka coacervation)

Association colloid impact on solubility

Association colloids (micelles) have the ability to increase the solubility of substances that are normally insoluble or only slightly soluble in the dispersion medium used, especially in water.

What is turbidity?

The measurement of light scattering

Factors affecting solubilization:

The solubility capacity of amphiphilic micelles depends greatly on the chemistry of the surfactants and the location of the drug in the micelle.

• For a hydrophobic drug solubilized in a micelle core, an increase in
  the lipophilic alkyl chain length of the surfactant enhances solubility.

• For ionic amphiphilic micelles, an increase in the radius of the
  hydrocarbon core can greatly enhance solubilization of a hydrophobic
  drug.

• pH alters the ionization equilibrium of a polar drug compound and,
  therefore, modify the partition of the drug in between the micelles and
  water.

• Diblock copolymers with a hydrophilic block and a hydrophobic block
  have high solubilization capacity of hydrophobic drugs.

How to enhance solubility of a hydrophobic drug solubilized in a micelle core?

Increase the lipophilic alkyl chain length of the surfactant

How to enhance solubilization of a hydrophobic drug in ionic amphiphilic micelles?

Increase the radius of the hydrocarbon core.

Diblock copolymers with a hydrophilic block and a hydrophobic block have (low/high) solubilization capacity of hydrophobic drugs.

high

Drug Delivery with Colloids and Nanoparticles:

1. Hydrogels

2. Liposomes

3. Micelles

4. Proteins

5. Polymer conjugates

6. DNA and RNA

7. Nanoparticles

8. Virus Particles

Liposomes for Drug Delivery

• Liposomes can encapsulate any drug with high loading and no structural
  limitations.

• Liposomes increase the stability of encapsulated drugs.

• Liposomes reduce the toxicity of encapsulated drugs.

• Liposomes improve the pharmacokinetic property of encapsulated drugs.

• Liposomes provide passive targeted delivery of the encapsulated drugs
  into solid tumor.

• Liposomes can also provide active targeted delivery of the encapsulated
  drugs into solid tumor by incorporating targeting agents on the surface.

• Liposomes improve the therapeutic index of encapsulated drugs.

Structural components & structure of liposomes:

phospholipids, cholesterol

1. unilamellar liposomes are formed by a single phospholipid layer. ca. 200 nm

2. Multilamellar liposomes are formed by several phospholipid layers. > 500 nm

Phospholipids (definition, solubility, formation)

1. Oil-like materials with 2 closely located lipid tails

2. soluble in most organic solvents, not in water

3. Form planar bilayers in water

Cholesterol (structure, function)

1. Rigid lipophilic structure

2. By itself, does not form a bilayer structure

3. Acts as a fluidity buffer to make the membrane less ordered, more flexible, stable and permeable, especially below Tc.

4. Makes membrane more ordered and stable above the phase transition temperature.

5. Can be incorporated into the lipid membrane in high concentration, up to 1:1 or even 2:1 molar ratio of cholesterol and lipid.

Surface modification of liposomes

stealth liposomes (PEG-coated liposomes)

• Extends blood-circulation time

• Reduces mononuclear phagocyte system uptake

• Increases stability

• Reduces uptake in the liver and spleen

Components of targeted liposomes

1. targeting ligand

2. surface modifier

3. therapeutic payload

4. permeability barrier