Lecture 41 - Liposomes and Microparticulate Systems

Liposomes?

A spherical vesicle containing one or more lipid bilayers enclosing liquid filled compartments

What is the difference between micelles and liposomes?

The principles of formation are exactly the same

The only difference is liposomes form when the surfactant has two HC chains, while micelles form when the surfactant has one HC chain

What is DPPC?

An example of a two tailed HC surfactant phospholipid used to make liposomes

How does a single chain surfactant affect the shape?

The polar head group is equal or larger than the HC chain

This allows it to pack efficiently and form stable micelles

Why do liposomes form?

Because the double HC chains cannot form a micelle → if they did it would allow too much water access

Instead create the lipid bilayers with aqueous core

How are liposomes formed in the lab?

Dissolve lipids in a solvent

Remove solvent to form a thin, dry lipid film.

Hydrate the lipid film with aqueous solution to form lipid cake

Size and homogenize vesicles using sonication or extrusion

Sonication/extrusion turns the large multilamellar vesicles into small unilamellar vesicles

How can drug be incorporated into a liposome?

One the surface

In the aqueous core

Solubilized in the lipid bilayer

In the phospholipid

What is the size of multilamellar vesicle?

MLV

1-5 um

Aqueous fluid volume → 0.5ul/mg of lipid

What is the size of small unilamellar vesicle?

SUV

20-100 nm

Aqueous fluid volume → 4 ul/mg of lipid

What is the size of large unilamellar vesicle?

LUV

100-250 nm

Aqueous fluid volume → 11 ul/mg of lipid

Smallest to larges size liposomes?

MLV < SUV < LUV

What is passive targeting in liposomes?

The liposomes get into the blood stream via IV

Once there they interact and get coated by blood opsonins, marking them for removal by mononuclear phagocytic system

These opsonin coated liposomes accumulate in the MPS and in the liver/spleen

once in the MPS/liver/spleen they get degraded thus releasing drug

What does uptake by MPS allow?

It allows the oponsin coated liposomes to be used for passive targeting of drugs to organs like the liver/spleen

• transport of the administered drug to a specific site of action via normal distribution patterns in the body

How is passive targeting used in IM or SQ injections?

The liposomes end up in the lymphatic system/local lymph nodes

Allowing the opportunity for liposomes to be used in delivery of vaccines

can improve antigen specific immune response

What is liposomes surface engineering?

They avoid uptake by MPS by being coated by hydrophilic polymers, like PEG

The PEG increases liposome circulation times and promotes opportunities for the liposomes to interact with target cells rather than those of the MPS

Where can PEGylated surface engineered liposomes accumulate?

In sites with leaky vasculature, like tumor sites or sites of inflammation

Once in those sites the liposomes slowly release the drug resulting in high local concentrations at the site of action

Example of stealth liposomes

Doxil

Uses surface modified PEGylated

90% of the drug is encapsulated in the liposomes

What are the advantages of liposomes?

Biodegradable/inert

Can carry hydrophobic/hydrophilic drug

Reduced drug toxicity

Passive or active targeting

Drugs are more stabilized and less susceptible to degradation

What is particulate delivery of drugs?

Is the delivery of drugs which relies on presenting either the drug, or a formulated composition containing the drug as particles in micrometer/nanometer size range

What are the main ways drug particulates can be used in the body?

Injected directly at site, depot systems for slow release, or systemically injected

How can systemic particulates be targeted to specific sites?

Through active or passive targeting to deliver drug specifically

Microparticles size?

Between 0.1u and 100u

or

100nm-100,000 nm in size

Nanoparticles size?

1-100 nm in size

What happens to microparticles and nanoparticles after being injected into tissues/cavities?

Microparticles remain at the site of injection, while nanoparticles can be transported and cleared from the site of injection

What happens if microparticles are delivered intravenously (IV)?

Can embolize/lodge/obstruct blood vessels with the same diameter

Causes infraction in an organ

What happens if nanoparticles are delivered intravenously (IV)?

Too small to cause embolisms/lodging and are thought to circulate freely throughout vasculature

Similar to liposomes, if they have hydrophobic exteriors will be cleared rapidly by reticuloendothelial system (RES)

Can microparticles cross biological barriers?

Unlikely to cross most biological barrier

Typically must be injected into desired site of action

Can nanoparticles cross biological barriers?

Yes

Tumor blood vessels are leaky, allowing nanoparticles to accumulate passively more in tumors than in normal tissue

Which particles are taken up by which mechanisms?

Microparticles (~10 μm): taken up by specialized phagocytic cells (macrophages, dendritic cells, neutrophils) via phagocytosis

Nanoparticles: taken up by all cells via pinocytosis

What is Abraxane?

An IV nanosuspension

Accumulation of nanoparticles in the tumor tissue via passive targeting

Also has active targeting on the surface to be transported across blood vesicle walls

What is Lupron depot?

A microspheres IM administration

Supplied in dual compartment syringe, of solid and suspending vehicle

Drug is embedded in microcapsules in biodegradable polymer, released via diffusion and bioerosion

Where in liposomes does it incorporate hydrophilic drugs, lipophilic drugs, and amphiphilic drugs?

Hydrophilic drugs → aqueous core

Lipophilic drugs → lipid bilayer

Amphiphilic drugs → surface