A new strategy for attachment of antibodies to sterically stabilized liposomes resulting in efficient targeting to cancer cells.
The development of long-circulating formulations of liposomes (S-liposomes), sterically stabilized with lipid derivatives of poly(ethylene glycol) (PEG), has increased the likelihood that these liposomes, coupled to targeting ligands such as antibodies, could be used as drug carriers to deliver therapeutic drugs to specific target cell populations in vivo. We have developed a new methodology for attaching monoclonal antibodies to the terminus of PEG on S-liposomes. A new end-group functionalized PEG-lipid derivative pyridylthiopropionoylamino-PEG- distearoylphosphatidylethanolamine (PDP-PEG-DSPE) was synthesized for this purpose. Incorporation of PDP-PEG-DSPE into S-liposomes followed by mild thiolysis of the PDP groups resulted in formation of reactive thiol groups at the periphery of the lipid vesicles. Efficient attachment of maleimide-derivatized antibodies took place under mild conditions even when the content of the functionalized PEG-lipid in S-liposomes was below 1% of total lipid. The resulting S-immunoliposomes showed efficient drug remote loading, slow drug release rates and increased survival times in circulation compared to liposomes lacking PEG. When antibodies recognizing several different tumor-associated antigens were coupled to the PEG terminus of S-liposomes a significant increase in the in vitro binding of liposomes to the target cells was observed. The binding of S-immunoliposomes containing entrapped doxorubicin to their target cell population resulted in increased cytotoxicity compared to liposomes lacking the targeting antibody.
Allen
T M
TM
Department of Pharmacology, University of Alberta, Edmonton, Canada.
Brandeis
E
E
Hansen
C B
CB
Kao
G Y
GY
Zalipsky
S
S
D000912:Antibodies, Neoplasm / Q000276:immunology; D001666:Binding Sites, Antibody; D004317:Doxorubicin / Q000008:administration & dosage*; D004337:Drug Carriers; D006801:Humans; D008081:Liposomes; D010714:Phosphatidylethanolamines; D011092:Polyethylene Glycols; D011725:Pyridines; D014407:Tumor Cells, Cultured
D000912:Antibodies, Neoplasm; D004337:Drug Carriers; D008081:Liposomes; D010714:Phosphatidylethanolamines; D011725:Pyridines; C095031:pyridyldithiopropionoylamino-poly(ethylene glycol)-distearoylphosphatidylethanolamine; C038089:1,2-distearoylphosphatidylethanolamine; D011092:Polyethylene Glycols; D004317:Doxorubicin