Antibody targeting of doxorubicin-loaded liposomes suppresses the growth and metastatic spread of established human lung tumor xenografts in severe combined immunodeficient mice.
Beta1 integrins, expressed on the cell surface of human non-small cell lung carcinomas, are used here as a target for the selective delivery of anti-cancer drug-loaded liposomes. Fab' fragments of a monoclonal antibody specific for human beta1 integrins were conjugated to sterically stabilized liposomes. Confocal microscopy of beta1 integrin-positive lung tumor cells incubated with fluorescently labeled anti-beta1 Fab immunoliposomes revealed a tumor-specific binding and efficient internalization of the liposomes into the tumor cells. The ability of these liposomes to deliver cytotoxic drugs to the tumor and kill these cells was demonstrated in vitro by incubating tumor cells with doxorubicin-loaded anti-beta1 Fab' immunoliposomes. The drug-loaded immunoliposomes were >30-fold more cytotoxic to the tumor cells than drug-loaded liposomes without antibody, nonspecific Fab' control immunoliposomes with drug or immunoliposomes without drug. The therapeutic efficacy of doxorubicin-loaded immunoliposomes was also evaluated in a metastatic human lung tumor xenograft/severe combined immunodeficient (SCID) mouse model. SCID mice that received i.v. injections of human lung tumor cells developed primary tumor nodules in the lung that subsequently metastasized to the liver and adrenal gland. Treatment of SCID mice bearing established lung tumor xenografts with doxorubicin-loaded anti-beta1 Fab immunoliposomes resulted in a significant suppression of tumor growth (monitored periodically by quantifying serum levels of a tumor marker), whereas tumors grew progressively in mice treated with control formulations. In addition to suppressing the growth of the primary lung tumor nodules, the immunoliposomes prevented the metastatic spread of the tumor to the liver and adrenal glands and increased the median survival time of the tumor-bearing mice. We conclude that Fab' immunoliposomes directed to tumor-associated integrins represent a potentially viable approach clinically for the selective delivery of drugs to solid tumors and may be useful in preventing the metastatic spread of lung cancer.
Sugano
M
M
Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Egilmez
N K
NK
Yokota
S J
SJ
Chen
F A
FA
Harding
J
J
Huang
S K
SK
Bankert
R B
RB
D000310:Adrenal Gland Neoplasms / Q000556:secondary; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D016023:Integrins / Q000276:immunology; D008081:Liposomes / Q000276:immunology* / Q000378:metabolism* / Q000627:therapeutic use; D008113:Liver Neoplasms / Q000556:secondary; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000276:immunology*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D018613:Microscopy, Confocal; D009368:Neoplasm Transplantation; D011485:Protein Binding; D013997:Time Factors; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D016023:Integrins; D008081:Liposomes; D004317:Doxorubicin