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

Abstract

Dioleoylphosphatidylethanolamine (DOPE)-containing liposomes that demonstrated pH-dependent release of their contents were stabilized in the bilayer form through the addition of a cleavable lipid derivative of polyethylene glycol (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 PEG (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 cleavage of the PEG chains and concomitant destabilization of the DOPE liposomes. While formulations loaded with doxorubicin (DXR) were stable in culture media, DXR was rapidly released in human plasma. pH-Sensitive liposomes, targeted 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 lymphoma, the therapeutic efficacy of an anti-CD19-targeted pH-sensitive formulation was superior to that of a stable long-circulating formulation of targeted liposomes despite the more rapid drug release and clearance of the pH-sensitive formulation. These results suggest that targeted pH-sensitive formulations of drugs may be able to increase the therapeutic efficacy of entrapped drugs.

Preparation, Physicochemical Properties, and Transfection Activities of Tartaric Acid-Based Cationic Lipids as Effective Nonviral Gene Delivery Vectors

“…The appropriate addition of DOPE has been reported to increase the gene delivery efficiency of cationic liposomes. [49][50][51] In an effort to research the influence of cationic lipid/DOPE ratios on the capacity of gene delivery efficiency, we prepared a series of cationic liposomes with different cationic lipid/DOPE molar ratios of 1 : 0.5, 1 : 1, 1 : 2, and 1 : 3 at equal lipid/DNA molar ratio of 3 : 1. The transfection activity was evaluated through the percent of positive transfected cells and MFI by flow cytometry in 293T cells as shown in Fig.…”

On the formulation of pH-sensitive liposomes with long circulation times

“…In another approach, DOPE-containing liposomes were stabilized in the bilayer form through the addition of a cleavable lipid derivative of PEG in which the polymer was attached to a lipid anchor via a disulfide linkage (PEGUSUSUDSPE) [56,57]. Liposomes stabilized with either a non-cleavable PEG (PEGUDSPE) or PEGUSUSUDSPE retained an encapsulated dye at pH 5.5.…”

“…Pharmacokinetic studies suggested that PEGUSU SUDSPE was rapidly cleaved in circulation. In addition, therapeutic studies performed in a murine model of B-cell lymphoma demonstrated clearly that the developed pH-sensitive formulation targeted to the CD19 receptor was superior to stable, long-circulating, targeted non-pH-sensitive liposomes, despite the more rapid drug release and clearance of the pH-sensitive formulation [57].…”

“…To improve the therapeutic efficacy of drugs entrapped in pH-sensitive liposomes, a large amount [57], CD3 (on T-leukemia cells) [82], P-glycoproteins (on endothelial cells) [83] and BCG antigen [16]. pH-sensitive liposomes targeted to the folate receptor through coupling of folic acid to the distal end of PEG molecules have been used recently to deliver neoplastic drugs [65,66] and plasmid DNA [65,84,85].…”

The use of single chain Fv as targeting agents for immunoliposomes: an update on immunoliposomal drugs for cancer treatment

“…Although DOPE-containing liposomes can enhance drug delivery to cells, in vivo results were less than desired, because these liposomes had very short circulation times despite the addition of PEG onto the surface of liposomes [146]. Recently, DOPE-free liposomes targeted via transferrin and containing a fusogenic peptide (GALA) incorporated on the liposome surface have been shown to fuse efficiently with the endosomal membrane after internalization [147]; because it is known that surface PEG can interfere with liposome fusion [148], these GALA-modified liposomes were classical liposomes that lacked a stabilizing polymer such as PEG on the liposome surface.…”