This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Hussain, S. Articles by Zangemeister-Wittke, U. Search for Related Content PubMed PubMed Citation Articles by Hussain, S. Articles by Zangemeister-Wittke, U.

Research Articles: Therapeutics, Targets, and Development

Chemosensitization of carcinoma cells using epithelial cell adhesion molecule–targeted liposomal antisense against bcl-2/bcl-xL

¹ Department of Biochemistry, University of Zürich, Zürich, Switzerland; ² Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada; and ³ Department of Pharmacology, University of Bern, Bern, Switzerland

Requests for reprints: Uwe Zangemeister-Wittke, Department of Pharmacology, University of Bern, Friedbühlstrasse 49, CH-3010 Bern, Switzerland. Phone: 41-31-632-3290; Fax: 41-31-632-4992. E-mail: uwe.zangemeister{at}pki.unibe.ch

Abstract

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. [Mol Cancer Ther 2006;5(12):3170–80]

Grant support: Krebsliga Zürich and the Sassella-Stiftung of the Zürich Kantonalbank.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁴ http://rsb.info.nih.gov.

Received 7/14/06; revised 9/14/06; accepted 10/18/06.