Effects of polyethyleneglycol chain length and phospholipid acyl chain composition on the interaction of polyethyleneglycol-phospholipid conjugates with phospholipid: implications in liposomal drug delivery

Abstract

Purpose: The purpose of this study was to investigate polyethyleneglycol(PEG)-phosphatidylethanolamine(PE) conjugate interaction with phospholipid bilayers, in an attempt to explain the dependence of liposome circulation time on formulation.

Methods: Differential scanning calorimetry, electron microscopy, dynamic light scattering and NMR were the major methods used in the study.

Results: Mixtures of PEG-phospholipid conjugates and phosphatidylcholine existed in three different physical states: a lamellar phase with components exhibiting some miscibility, a lamellar phase with components phase separated, and mixed micelles. Beyond 7 mol-percent of PEG(1,000-3,000)-dipalmitoyl phosphatidylethanolamine (DPPE), and 11 mol% PEG(5,000)-DPPE in dipalmitoyl phosphatidylcholine (DPPC), a strong tendency towards mixed micelle formation was observed. All concentrations of PEG(12,000)-DPPE and PEG(5,000)-DPPE beyond 8 mol% formed phase separated lamellae with phosphatidylcholine. Decreasing the acyl chain length from C(16:0) to C(14:0) caused a decrease in tendency towards micelle formation and phase separation. These tendencies increased upon increasing acyl chain length to C(18:0). Phase separation was at least partly due to PEG chain-chain interaction. This was supported by an increased fraction of PEG chains exhibiting a fast NMR transverse relaxation in DPPC/PEG(5,000)-DPPE mixtures as compared to that in distearoyl phosphatidylcholine (DSPC)/PEG(5,000)-dioleoyl-PE (DOPE).

Conclusions: These phenomena are discussed in relation to both bilayer and steric stabilization of liposomes, and the lack of prolonged circulation with certain formulations is discussed.