INTERACTION OF PEG-PHOSPHOLIPID CONJUGATES WITH PHOSPHOLIPID - IMPLICATIONS IN LIPOSOMAL DRUG-DELIVERY

Mixtures of PEG-phospholipid conjugates and phosphatidylcholine show mainly three different physical states: lamellar phase with components exhibiting some miscibility, lamellar phase with components phase separated and mixed micelles. Relative proportions of the three states in a given mixture depend on PEG chain length, acyl chain length and the degree of unsaturation (cis double bond) of the PEG-phospholipid conjugate, and the acyl chain composition of the phosphatidylcholine. Long chain (MW greater than or equal to 5000) PEG-phospholipid conjugates tend to form phase separated lamellae with phosphatidylcholine, which might explain the reason why these conjugates are not suitable for the preparation of long circulating liposomes. Short chain (MW = 1000-3000) PEG-phospholipid conjugates show a strong tendency to form mixed micelles with phosphatidylcholine. However, in the presence of cholesterol, stable lamellar phases with components showing miscibility are obtained. This could be the reason why both short chain PEG-phospholipid conjugates and cholesterol are found in the long circulating liposome formulations. The physical basis for these observed phenomena is discussed in terms of PEG chain-chain interaction and the role of cholesterol in modifying the interactions.