Chemosensitization of carcinoma cells using epithelial cell adhesion molecule-targeted liposomal antisense against bcl-2/bcl-xL.
Nanoscale drug delivery systems, such as sterically stabilized immunoliposomes binding to internalizing tumor-associated antigens, can increase therapeutic efficacy and reduce toxicity to normal tissues compared with nontargeted liposomes. The epithelial cell adhesion molecule (EpCAM) is of interest as a ligand for targeted drug delivery because it is abundantly expressed in solid tumors but shows limited distribution in normal tissues. To generate EpCAM-specific immunoliposomes for targeted cancer therapy, the humanized single-chain Fv antibody fragment 4D5MOCB was covalently linked to the exterior of coated cationic liposomes. As anticancer agent, we encapsulated the previously described antisense oligonucleotide 4625 specific for both bcl-2 and bcl-xL. The EpCAM-targeted immunoliposomes (SIL25) showed specific binding to EpCAM-overexpressing tumor cells, with a 10- to 20-fold increase in binding compared with nontargeted control liposomes. No enhanced binding was observed on EpCAM-negative control cells. On cell binding, SIL25 was efficiently internalized by receptor-mediated endocytosis, ultimately leading to down-regulation of both bcl-2 and bcl-xL expression on both the mRNA and protein level, which resulted in enhanced tumor cell apoptosis. In combination experiments, the use of SIL25 led to a 2- to 5-fold sensitization of EpCAM-positive tumor cells of diverse origin to death induction by doxorubicin. Our data show the promise of EpCAM-specific drug delivery systems, such as antisense-loaded immunoliposomes, for targeted cancer therapy.
Hussain
Sajid
S
Department of Pharmacology, University of Bern, Friedbühlstrasse 49, CH-3010 Bern, Switzerland.
Plückthun
Andreas
A
Allen
Theresa M
TM
Zangemeister-Wittke
Uwe
U
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology*; D016503:Drug Delivery Systems; D004705:Endocytosis / Q000502:physiology; D000071858:Epithelial Cell Adhesion Molecule; D005260:Female; D006801:Humans; D008081:Liposomes / Q000008:administration & dosage / Q000378:metabolism; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage* / Q000235:genetics; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D051020:bcl-X Protein / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*
D000903:Antibiotics, Antineoplastic; D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; D000071858:Epithelial Cell Adhesion Molecule; D008081:Liposomes; D016376:Oligonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D004317:Doxorubicin