title: Encapsulation of gadobutrol in AVE-based liposomal carriers for MR detectability.
abstract: Artificial virus-like envelopes (AVEs) are liposomal carriers that may be useful for target-site-specific delivery of contrast agents. We speculated that T(1) relaxation times of a suspension of Gadolinium-filled AVEs might be shortened after internalization and lysosomal breakdown. To test this hypothesis we evaluated the T(1) relaxation times of Gadobutrol-containing AVEs before and after degradation in vitro and after receptor-mediated cellular uptake. AVEs were filled with 1 M Gadobutrol (Gadovist; Schering AG, Berlin, Germany) yielding Gd-chelate-AVEs. T(1)-relaxation times were calculated using an inversion recovery technique for different concentrations of the liposomal suspension. AVEs were degraded in vitro to mimic the release of the encapsulated Gadolinium in cells and to determine a putative increase of the T(1)-effect. Finally, Gd-chelate-AVEs where equipped with integrin-binding RGD ligands and the T1 relaxation times of these Gd-chelate-RDG-AVEs were determined after cellular uptake into endothelial or melanoma cells. Gadobutrol could be encapsulated into AVEs at a high concentration of 1 M (Gd-chelate-AVEs). The Gd-chelate-AVEs could be visualized by MRI. Concentrations down to 1:4 x 10(3) showed a significant T(1)-shortening effect. The degradation of the liposomes with Triton X-100 resulted in a further reduction down to concentrations of 1:10 x 10(3). In addition, cellular uptakes of Gd-chelate-RGD-AVEs also lead to a significant T(1)-shortening. Our study shows that Gadolinium can be efficiently encapsulated into AVEs and that Gd-chelate-AVEs can be detected by MRI T(1)-weighted measurements. The MRI detectability is enhanced by degradation. Gd-chelate-RGD-AVEs can be used to enhance the Gd uptake in cells expressing the alpha(v)beta(3) receptor.
authors.affiliation: Department of Diagnostic Radiology, School of Medicine, Philipps University, Marburg, Germany. heverhagen@gmx.net
authors.forename: Johannes T
authors.initials: JT
authors.lastname: Heverhagen
authors.forename: Andreas
authors.initials: A
authors.lastname: Graser
authors.forename: Alfred
authors.initials: A
authors.lastname: Fahr
authors.forename: Rolf
authors.initials: R
authors.lastname: Müller
authors.forename: Heiko
authors.initials: H
authors.lastname: Alfke
mesh_terms: D001692:Biological Transport; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008081:Liposomes; D008279:Magnetic Resonance Imaging / Q000379:methods; D009942:Organometallic Compounds / Q000493:pharmacokinetics*; D011859:Radiography; D014018:Tissue Distribution; D014471:Umbilical Veins / Q000166:cytology / Q000000981:diagnostic imaging; D014759:Viral Envelope Proteins
chemical_list: D008081:Liposomes; D009942:Organometallic Compounds; D014759:Viral Envelope Proteins; C090600:gadobutrol