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 (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.

[1]  Kazuo Maruyama,et al.  Amphipathic polyethyleneglycols effectively prolong the circulation time of liposomes , 1990, FEBS letters.

[2]  R. Muller,et al.  Paramagnetic liposomes as magnetic resonance imaging contrast agents. Assessment of contrast efficacy in various liver models. , 1998, Investigative radiology.

[3]  R. Lauffer,et al.  Gadolinium(III) Chelates as MRI Contrast Agents: Structure, Dynamics, and Applications. , 1999, Chemical reviews.

[4]  Tilcock.  Delivery of contrast agents for magnetic resonance imaging, computed tomography, nuclear medicine and ultrasound. , 1999, Advanced drug delivery reviews.

[5]  K. Hubner,et al.  Gadolinium‐labeled liposomes containing various amphiphilic Gd‐DTPA derivatives: Targeted MRI contrast enhancement agents for the liver , 1991, Magnetic resonance in medicine.

[6]  S. H. Koenig,et al.  The design of liposomal paramagnetic mr agents: effect of vesicle size upon the relaxivity of surface‐incorporated lipophilic chelates , 1992, Magnetic resonance in medicine.

[7]  Babich,et al.  Long-circulating gadolinium-loaded liposomes: potential use for magnetic resonance imaging of the blood pool. , 2000, Colloids and surfaces. B, Biointerfaces.

[8]  J. Klaveness,et al.  Synthesis and physicochemical characterisation of new amphiphilic gadolinium DO3A complexes as contrast agents for MRI , 2000 .

[9]  M. Botta.  Second Coordination Sphere Water Molecules and Relaxivity of Gadolinium(III) Complexes: Implications for MRI Contrast Agents , 2000 .

[10]  J. M. Garrison,et al.  pH dependence of relaxivities and hydration numbers of gadolinium(III) complexes of macrocyclic amino carboxylates , 1990 .

[11]  V. Torchilin,et al.  Controlled delivery of Gd-containing liposomes to lymph nodes: surface modification may enhance MRI contrast properties. , 1995, Magnetic resonance imaging.

[12]  R. Schwendener.  Liposomes as carriers for paramagnetic gadolinium chelates as organ specific contrast agents for magnetic resonance imaging (mri) , 1994 .

[13]  A. Seelig,et al.  High Relaxivity for Monomeric Gd(DOTA)‐Based MRI Contrast Agents, Thanks to Micellar Self‐Organization , 1999 .

[14]  E. Terreno,et al.  NMR relaxometric investigations of solid lipid nanoparticles (SLN) containing gadolinium(III) complexes. , 1998, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[15]  R. Gatenby,et al.  Hepatic metastases: liposomal Gd-DTPA-enhanced MR imaging. , 1989, Radiology.

[16]  J. Teissié,et al.  Ionization of phospholipids and phospholipid-supported interfacial lateral diffusion of protons in membrane model systems. , 1990, Biochimica et biophysica acta.

[17]  Palmisano,et al.  NOVEL PARAMAGNETIC MACROMOLECULAR COMPLEXES DERIVED FROM THE LINKAGE OF A MACROCYCLIC Gd(III) COMPLEX TO POLYAMINO ACIDS THROUGH A SQUARIC ACID MOIETY , 1999, Bioconjugate chemistry.

[18]  Okuhata,et al.  Delivery of diagnostic agents for magnetic resonance imaging. , 1999, Advanced drug delivery reviews.

[19]  S. Marčelja,et al.  Physical principles of membrane organization , 1980, Quarterly Reviews of Biophysics.