title: pH-sensitive paramagnetic liposomes for MRI: assessment of stability in blood.
abstract: The pH-dependent stability of dipalmitoyl phosphatidyl ethanolamine/palmitic acid (DPPE/PA) liposomal GdDTPA-BMA was investigated in human blood and after exposure to selected blood components. Relaxometry, visual observations and cryo-transmission electron microscopy (cryo-TEM) were employed for the assessment of stability. The liposomes were stable in buffer at physiological pH and the T(1)-relaxivity (r(1)) of the system was significantly lowered compared to that of non-liposomal GdDTPA-BMA, which could be explained by an exchange limited relaxation process. Lowering the pH, however, gave a marked increase in r(1), due to liposome aggregation and subsequent leakage of GdDTPA-BMA. After a few minutes incubation in human blood the liposomes were destabilised and leaky at both high and low pH, and blood components likely to cause the instability were studied. Physiological level of Na(+) (150 mM) did not affect the relaxometric behavior of the liposomes at pH 7.4, but shifted the pH-r(1) profile laterally to higher pH-values compared to a level of 50 mM Na(+). Increased screening of the surface charges and, concomitantly, a lowering of the energy-barrier against aggregation is a plausible explanation for this phenomenon. In contrast, both Ca(2+) and Mg(2+) (physiological level, both 2 mM) caused massive aggregation of the liposomes and leakage of contents, and were therefore much more detrimental to the stability of the liposomes than a physiological level of Na(+). This could be due to the higher screening ability of divalent cations, but aggregation could also be induced through an inter-liposomal "bridging" effect. Physiological level of both Na(+) and Ca(2+) caused less leakage than for lower Na(+) concentration (50 mM Na(+) and 2 mM Ca(2+)), probably due to competition for the negative surface charges. Albumin also destabilised the liposomes, and it was shown to be due to an interaction between albumin and PA in the liposomal membrane.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, University of Oslo, Norway. knut-egil.lokling@amersham.com
authors.forename: Knut-Egil
authors.initials: KE
authors.lastname: Løkling
authors.forename: Roald
authors.initials: R
authors.lastname: Skurtveit
authors.forename: Sigrid L
authors.initials: SL
authors.lastname: Fossheim
authors.forename: Gro
authors.initials: G
authors.lastname: Smistad
authors.forename: Ingrid
authors.initials: I
authors.lastname: Henriksen
authors.forename: Jo
authors.initials: J
authors.lastname: Klaveness
mesh_terms: D003287:Contrast Media; D019786:Gadolinium DTPA / Q000097:blood; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008081:Liposomes / Q000097:blood*; D008279:Magnetic Resonance Imaging / Q000379:methods*
chemical_list: D003287:Contrast Media; D008081:Liposomes; C064925:gadodiamide; D019786:Gadolinium DTPA