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 overexpressed 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.

Improved therapeutic responses for liposomal doxorubicin targeted via thrombospondin peptidomimetics versus untargeted doxorubicin

“…The amount of peptide linked to the surface of liposomes represented a 60% of the available reactive NGPE terminal carboxyl ends. These results were in agreement to a previous systematic study carried out with the same type of liposomes16. Besides, physicochemical interactions between peptides and lipids were performed, and the results indicate that these peptides have low affinity for lipids.…”

“…Liposomal composition was selected according to previous studies16. PC and NGPE were saturated, and PG was from natural sources.…”

“…# NGPE is a PE derivative with a carboxy terminal group used for binding peptides or proteins to the lipid bilayer surface. PG was included to provide a negative charge to the vesicles that would improve entrapment of cationic DOX16.…”

A simple HPLC method for doxorubicin in plasma and tissues of nude mice

“…DOX has been a center of research interest in the development of drug delivery system (DDS) for systemic and local administration (Veronese et al, 2005;Alminana et al, 2004;Weinberg et al, 2007). Pharmacokinetic (PK) characterization of these DDS requires a robust, sensitive, yet simple HPLC method for DOX in biological matrices (Loadman and Calabrese, 2001).…”

A novel small peptide as an epidermal growth factor receptor targeting ligand for nanodelivery in vitro

“…21 The mixture included glyceryl monostearate, lecithin, soybean oil, DSPE-PEG 2000 -COOH, and polyoxyethylene (40) stearate. AEYLR and RALEL were conjugated with NLCs using the method of Almiñana et al 22 During preparation of the FITC-NLC, the DSPE-PEG 2000 -Biotin was added as a lipid and the NLCs were prepared as previously described. The FITC was coupled with the NLCs through the biotin-avidin system.…”