Liposomal drug delivery system

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LIPOSOMES

What are liposomes?

Liposomes are simple microscopic vesicles in which an aqueous volume is entirely enclosed by a membrane composed of lipid molecule.

Structurally, liposomes are concentric bilayered vesicles in which an aqueous volume is entirely enclosed by a membraneous lipid bilayer mainly composed of natural or synthetic phospholipids

Liposomes

ADVANTAGES OF LIPOSOMES:

Some advantages of liposomes are:

§ Provides selective passive targeting to tumour tissues (liposomal doxorubicin) (in short tissue targeting)

§ Increase efficacy and therapeutic index

§ Increased stability of encapsulated drug

§ Reduction in toxicity of the encapsulated agent

§ Site avoidance effect (avoids non-target tissues)

§ Improved pharmacokinetic effects (reduced elimination, increased circulation life times)

§ Flexibility to couple with site-specific ligands to achieve active targeting

STRUCTURAL COMPONENTS OF LIPOSOMES:

§ The main component of liposomes are:

o Phospholipids

o Cholesterol

PHOSPHOLIPIDS:

§

PHOSPHOGLYCERIDSPhospholipids are the major structural components of biological membranes such as the cell membrane

TWO TYPES OF PHOSPHOLIPIDS (ALONG WITH THEIR HYDROLYSIS PRODUCTS)

SPHINGOLIPIDS

§ The most common phospholipid used is phosphatidylcholine (PC).

§ Phosphatidylcholine is an amphipatic molecule in which exists

o A hydrophilic polar head group, phosphocholine.

o A glycerol bridge

o A pair of hydrophobic acyl hydrocarbon chains

§ Molecules of PC are not soluble in water

§ In aqueous media they align themselves closely in planar bilayer sheets in order to minimize the unfavourable action between the bulk aqueous phase and the long hydrocarbon fatty chain. (i.e. they orient themselves so that the fatty acid chains face each other, and the polar heads face the aqueous phase- this reduces the instability which exists when the molecules exist alone)

§ Such unfavourable interactions are completely eliminated when the sheets fold on themselves to form closed sealed vesicles.

§ In short this is what happens :

§ PC molecules contrast markedly with other amphipathic molecules such as detergents and lysolecithin- in that they form

Bilayer sheets

Not molecular structure

§ This is thought to be because the double fatty acid chain gives the molecule an overall tubular shape, more suitable for aggregation in planar sheets compared with detergents with a polar head and single chain whose conical shape fits nicely into spherical micellar structure.

§ The effect of molecular geometry on the structure of amphiphilic aggregates.

· Con like molecules tend to pack into structures with high radii of curvature and inverse con like molecules from structure with large negative curvatures.

· Cylindrical molecules such as phosphatidycholine organize into flat lamellar bilayered structures, which can further form bilayered spheres.

o Phosphatidylcholine (or lecithin) can be derived from natural and synthetic sources.

o At various temperatures, lecithin membranes can exist in different phases (phases are states such as solid gel state or fluid liquid state).

o The transition from one phase to another can be detected by physical techniques as the temperature is increased.

o The most widely used method for determining the phase transition temperature (Tc) is micro-calorimetry.

o In general,

§ Increase the chain length

§ Increasing the saturation of the chains

o Increase the phase transition temperature and also the stability of the molecule.

What exactly happens during phase transition?

§ At elevated temperature lipid membrane passes from tightly ordered gel state (stable) to a liquid crystal phase (metastable or unstable) where freedom of movement of the individual molecule is higher

§ This is due to the fatty acid chain adopting a new conformation other than the all Trans straight chain configuration, such as a gauche conformation state (a phenomenon known as chain tilt)

Some other commonly used phospholipids:

§ Naturally occurring phospholipids:

o PC: phosphatidylcholine (one chain is oleoyl and the other is palmitoyl)

o PE: phosphatidylethanolamine

o PS: phosphatidylserine

§ Synthetic phospholipids:

o DOPC: dioleoylphosphatidylcholine

o DSPC: distearoylphosphatidylcholin

o DOPE: dioleoylphosphatidylethanolamine

o DSPE: distearoylphosphatidylethanolamine

Cholesterol:

§ Incorporation of sterols in liposome bilayer brings about major changes in the preparation of these membranes.

§ Cholesterol by itself does not form a bilayer structure.

§ However, cholesterol act as a fluidity buffer, i.e. below the phase transition temperature, it makes the membrane less ordered and slightly more permeable; while above the phase transition temperature it makes the membrane more ordered and stable.

§ It can be incorporated into phospholipid membranes in very high concentration upto 1:1 or even 2:1 molar ratios of cholesterol to PC.

§ Cholesterol inserts into the membrane with its hydroxyl groups oriented towards the aqueous surface and aliphatic chain aligned parallel to the acyl chains in the centre of the bilayer.

Mechanism of cholesterol acting as a fluidity buffer.

§ Cholesterol incorporation increases the separation between the cholin headgroups and hydrogen bonding interactions-thus pushing the phospholipids apart making the layer less ordered at lower temperatures.

§ However the higher concentrations that cholesterol is used, the membrane area occupied by the combination of acyl chains and cholesterol is greater than (or equal to) that taken by phosphocoline head group. This difference in the area retards chain tilt (the phenomenon responsible for phase trranisation – i.e. Trans to gauche conformation change). Above the transition temperature, the reduction in the freedom of the acyl chains causes the membrane to remain condensed and rigidized, with a reduction in area through closer packing and resultant decreases in fluidity.