Liposomes as carriers of amphiphilic gadolinium chelates:: the effect of membrane composition on incorporation efficacy and in vitro relaxivity

The effects of membrane composition (phospholipid type and amount of cholesterol), liposome size, drug/lipid ratio (loading) and nature of the amphiphilic gadolinium (Gd) chelate on the incorporation efficacy and magnetic resonance (MR) contrast efficacy (longitudinal (T-1) relaxivity) were investigated using a fractional factorial design. A highly lipophilic Gd-chelate was required to ensure complete liposome incorporation. High T-1-relaxivity was obtained by using liposomes composed of cholesterol and phospholipids with short acyl chain lengths (dimyristoyl phosphatidyl choline (DMPC) and dimyristoyl phosphatidyl glycerol (DMPG). Two key factors, the loading of Gd-chelate and the amount of cholesterol in small-sized DMPC/DMPG liposomes, were studied further in a central composite optimising design. A robust high relaxivity region was identified, comprising high loading of cholesterol and Gd-chelate. However, the highest T-1-relaxivity (52 mM(-1) s(-1)) was found in an area containing no cholesterol and low content of Gd-chelate. Nuclear magnetic resonance dispersion (NMRD) profiles were obtained for five of the liposome compositions from the optimising design, and high relaxivity peaks in the 20 MHz region confirmed the presence of Gd-chelates with a long tau(R). A liposome formulation was selected for surface modification with polyethylene glycol (PEG), without having any effect on the T-1-relaxivity. (C) 2002 Elsevier Science B.V. All rights reserved.