Antitumor activity of an epithelial cell adhesion molecule targeted nanovesicular drug delivery system.
Site-specific delivery of anticancer agents to tumors represents a promising therapeutic strategy because it increases efficacy and reduces toxicity to normal tissues compared with untargeted drugs. Sterically stabilized immunoliposomes (SIL), guided by antibodies that specifically bind to well internalizing antigens on the tumor cell surface, are effective nanoscale delivery systems capable of accumulating large quantities of anticancer agents at the tumor site. The epithelial cell adhesion molecule (EpCAM) holds major promise as a target for antibody-based cancer therapy due to its abundant expression in many solid tumors and its limited distribution in normal tissues. We generated EpCAM-directed immunoliposomes by covalently coupling the humanized single-chain Fv antibody fragment 4D5MOCB to the surface of sterically stabilized liposomes loaded with the anticancer agent doxorubicin. In vitro, the doxorubicin-loaded immunoliposomes (SIL-Dox) showed efficient cell binding and internalization and were significantly more cytotoxic against EpCAM-positive tumor cells than nontargeted liposomes (SL-Dox). In athymic mice bearing established human tumor xenografts, pharmacokinetic and biodistribution analysis of SIL-Dox revealed long circulation times in the blood with a half-life of 11 h and effective time-dependent tumor localization, resulting in up to 15% injected dose per gram tissue. These favorable pharmacokinetic properties translated into potent antitumor activity, which resulted in significant growth inhibition (compared with control mice), and was more pronounced than that of doxorubicin alone and nontargeted SL-Dox at low, nontoxic doses. Our data show the promise of EpCAM-directed nanovesicular drug delivery for targeted therapy of solid tumors.
Hussain
Sajid
S
Department of Biochemistry, University of Zürich, Zürich, Switzerland.
Plückthun
Andreas
A
Allen
Theresa M
TM
Zangemeister-Wittke
Uwe
U
D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism; D001682:Biological Availability; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000031:analogs & derivatives / Q000378:metabolism; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D016503:Drug Delivery Systems; D004705:Endocytosis / Q000187:drug effects; D000071858:Epithelial Cell Adhesion Molecule; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D006801:Humans; D008081:Liposomes; D051379:Mice; D036103:Nanotechnology / Q000379:methods*; D023041:Xenograft Model Antitumor Assays
D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; D000071858:Epithelial Cell Adhesion Molecule; D008081:Liposomes; C035237:3-O-(1-hexadecyl)cholesterol; D004317:Doxorubicin; D002784:Cholesterol