Sunday, March 13, 2011

What is the effect of the phase transition temperature of the lipid on the liposome formulation?

Physicochemical properties of liposomes depend on many factors such as ionic strength, pH and temperature. Usually liposomes have low permeability to the encapsulated molecules (unless the molecule is membrane permeable). The permeability of the membrane changes with temperature. One of the most important properties of the lipid bilayer is the relative fluidity and mobility of each individual lipid molecule in the bilayer. The mobility of the lipids change with the temperature. At a given temperature a lipid bilayer can exist in a solid (gel) or liquid phase. In both phases the lipid molecules are constrained to the two dimensional plane of the membrane but in liquid phase the lipid molecules can diffuse much more freely within the plane. At a given temperature a lipid molecule will exchange location with its neighboring lipid molecules millions of times a second and go through the process of random walk.

Phase transition temperature of phospholipids and lipid bilayers depends on the following:

1) The length of the acyl chain in the lipid
2) The degree of saturation of the hydrocarbon chains in lipid
3) The ionic strength of the suspension medium
4) The type of the polar head group

The phase behavior of the lipid bilayer is determined by the Van der Waals interactions between adjacent lipid molecules. The interaction is mainly governed by two factors:

1) The length of the acyl chain in the lipid
2) The packing of the lipids in the bilayer

Longer tail lipids have more area to interact. This will increase the strength of the interaction and consequently decrease the mobility of the lipid. Therefore at a given temperature a short tailed lipid will be more fluid than an otherwise identical long-tailed lipid.

The degree of unsaturation of the lipid tails can effect the packing of the lipids in the bilayer. An unsaturated double bond can produce a kink in the alkane chain. This kink will create extra free space within the bilayer which allows additional flexibility in the adjacent chains. Unsaturated lipids have a significantly lower transition temperature compare to saturated lipids.

Liposome made from pure phospholipids (in the absence of cholesterol) will not form at temperatures below the phase transition temperature of phospholipid. If the encapsulated molecule is temperature sensitive (e.g. a protein) then pure long chain saturated lipids can not be used in the liposomes because the lipids have to be heated up and the protein can not tolerate high temperatures.

Most lipid bilayers are not composed of a single type of lipid. In nature lipid membranes are usually a complex mixture of various lipid molecules. If some of the lipids in the mixture are liquid at a given temperature while other lipids are in gel phase, then the two phases will exist in spatially separated populations. This phenomenon is called "phase separation".

"Trigger release liposomes" such as temperature sensitive liposomes or radiation sensitive liposomes should be engineered in a way to have phase separated domains. The existence of the phase separated domains make the liposomes unstable upon trigger and therefore the liposomes release their content upon trigger.

The presence of cholesterol exerts a profound influence on the property of the lipid bilayers. It has been known for the past four decades that the addition of cholesterol to a fluid phase bilayer decreases its permeability to water. Cholesterol molecules fill in the free space that was formed due to the kink in the chain of the unsaturated lipid and this will decrease the flexibility of the surrounding lipid chains. This interaction also increases the mechanical rigidity of fluid bilayers and decreases their lateral diffusion. In contrast, the addition of cholesterol to gel phase bilayers disrupts local packing orders and increases the diffusion coefficient and decreases the elastic modulus.

See the original Q&A on Quara: