Encapsulation of gadobutrol in AVE-based liposomal carriers for MR detectability

Artificial virus-like envelopes (AVEs) are liposomal carriers that may be useful for target-site-specific delivery of contrast agents. We speculated that T1 relaxation times of a suspension of Gadolinium-filled AVEs might be shortened after internalization and lysosomal breakdown. To test this hypothesis we evaluated the T1 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. T1-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 putatitive increase of the T1-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 × 103 showed a significant T1-shortening effect. The degradation of the liposomes with Triton X-100 resulted in a further reduction down to concentrations of 1:10 × 103. In addition, cellular uptakes of Gd-chelate-RGD-AVEs also lead to a significant T1-shortening. Our study shows that Gadolinium can be efficiently encapsulated into AVEs and that Gd-chelate-AVEs can be detected by MRI T1-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 αvβ3 receptor.