Targeted delivery and triggered release of liposomal doxorubicin enhances cytotoxicity against human B lymphoma cells

Dioleoylphosphatidylethanolamine (DOPE)-containing liposomes that demonstra ted pH-dependent release of their contents were stabilized in the bilayer f orm through the addition of a cleavable lipid derivative of polyethylene gl ycol (PEG) in which the PEG was attached to a lipid anchor via a disulfide linkage (mPEG-S-S-DSPE). Liposomes stabilized with either a non-cleavable P EG (mPEG-DSPE) or mPEG-S-S-DSPE retained an encapsulated dye at pH 5.5, but treatment at pH 5.5 of liposomes stabilized with mPEG-S-S-DSPE with either dithiothreitol or cell-free extracts caused contents release due to cleava ge of the PEG chains and concomitant destabilization of the DOPE liposomes. While formulations loaded with doxorubicin (DXR) were stable in culture me dia, DXR was rapidly released in human plasma. pH-Sensitive liposomes, targ eted to the CD19 epitope on B-lymphoma cells, showed enhanced DXR delivery into the nuclei of the target cells and increased cytotoxicity compared to non-pH-sensitive liposomes. Pharmacokinetic studies suggested that mPEG-S-S -DSPE was rapidly cleaved in circulation. In a murine model of B-cell lymph oma, the therapeutic efficacy of an anti-CD19-targeted pH-sensitive formula tion was superior to that of a stable long-circulating formulation of targe ted liposomes despite the more rapid drug release and clearance of the pH-s ensitive formulation. These results suggest that targeted pH-sensitive form ulations of drugs may be able to increase the therapeutic efficacy of entra pped drugs. (C) 2001 Elsevier Science B.V. All rights reserved.