title: Liposomes as carriers of amphiphilic gadolinium chelates: the effect of membrane composition on incorporation efficacy and in vitro relaxivity.
abstract: 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 (T1) relaxivity) were investigated using a fractional factorial design. A highly lipophilic Gd-chelate was required to ensure complete liposome incorporation. High T1-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 T1-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 T1-relaxivity.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, University of Oslo, PO Box 1155 Blindern, N-0317 Oslo, Norway. christian.glogard@farmasi.uio.no
authors.forename: Christian
authors.initials: C
authors.lastname: Gløgård
authors.forename: Gry
authors.initials: G
authors.lastname: Stensrud
authors.forename: Ragnar
authors.initials: R
authors.lastname: Hovland
authors.forename: Sigrid L
authors.initials: SL
authors.lastname: Fossheim
authors.forename: Jo
authors.initials: J
authors.lastname: Klaveness
mesh_terms: D002614:Chelating Agents / Q000737:chemistry* / Q000493:pharmacokinetics; D004337:Drug Carriers / Q000737:chemistry / Q000493:pharmacokinetics; D005682:Gadolinium / Q000737:chemistry* / Q000493:pharmacokinetics; D008081:Liposomes / Q000737:chemistry* / Q000493:pharmacokinetics; D008567:Membranes, Artificial; D011092:Polyethylene Glycols / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D002614:Chelating Agents; D004337:Drug Carriers; D008081:Liposomes; D008567:Membranes, Artificial; D011092:Polyethylene Glycols; D005682:Gadolinium