Biodistribution Study of Doxorubicin Encapsulated in Liposomes: Influence of Peptide Coating and Lipid Composition

Abstract

In this paper we describe the biodistribution of doxorubicin (DXR) encapsulated in three different types of liposomes. Common composition was hydrogenated phosphatidylcholine (HPC)/phosphatidylglycerol (PG) cholesterol (Chol)/X, X being either 10% N‐glutaryl phosphatidylethanolamine (NGPE), 10% NGPE + 6% distearoyl‐phosphatidylethanolamine‐polyethyleneglycol 2000 (DSPE‐PEG), or 10% NGPE + 6% DSPE‐PEG‐COOH. These series of vesicles were coated with an active or an inactive sequence of laminin (laminin receptors, integrins, are over‐expressed in tumor cells). Single doses of these preparations were injected, i.v., into healthy mice. For biodistribution experiments, mice were sacrificed at three different time‐points post‐treatment. Doxorubicin and doxorubicinol (DXOH) levels were determined in plasma, heart, lung, kidney, spleen, and liver using HPLC with daunorubicin (DNR) as internal standard. The results obtained indicate that compositions containing DSPE‐PEG have the longest half‐lives in plasma, as was to be expected according to the data in the literature. However, the presence of the peptides on the surface of liposomes reduces concentration values in this tissue. Distribution in other organs reveals high differences, among the liposomal samples studied, depending mainly on the presence of active or inactive peptide on the surface of vesicles. Liposomes coated with the laminin active sequence show lower accumulation in studied tissues than free DXR. This indicates that heart toxicity, associated to DXR treatments, could be diminished, and open promising perspectives for its future study in tumor‐bearing animals.

Keywords:

• Doxorubicin
• Liposomes
• Pharmacokinetics
• Laminin
• Integrins
• Targeting

Acknowledgments

This work was supported by a grant from the CICYT‐SAF97‐0129. Núria Almiñana and Dolores Polo were recipients of grants from the Science and Technology Ministry of the Spanish Government. The authors would like to thank J. A. Uroz, J. Minguillón, and L. Gómez for their technical assistance.