A novel peptide enhances therapeutic efficacy of liposomal anti-cancer drugs in mice models of human lung cancer.
Lung cancer is the leading cause of cancer-related mortality worldwide. The lack of tumor specificity remains a major drawback for effective chemotherapies and results in dose-limiting toxicities. However, a ligand-mediated drug delivery system should be able to render chemotherapy more specific to tumor cells and less toxic to normal tissues. In this study, we isolated a novel peptide ligand from a phage-displayed peptide library that bound to non-small cell lung cancer (NSCLC) cell lines. The targeting phage bound to several NSCLC cell lines but not to normal cells. Both the targeting phage and the synthetic peptide recognized the surgical specimens of NSCLC with a positive rate of 75% (27 of 36 specimens). In severe combined immunodeficiency (SCID) mice bearing NSCLC xenografts, the targeting phage specifically bound to tumor masses. The tumor homing ability of the targeting phage was inhibited by the cognate synthetic peptide, but not by a control or a WTY-mutated peptide. When the targeting peptide was coupled to liposomes carrying doxorubicin or vinorelbine, the therapeutic index of the chemotherapeutic agents and the survival rates of mice with human lung cancer xenografts markedly increased. Furthermore, the targeting liposomes increased drug accumulation in tumor tissues by 5.7-fold compared with free drugs and enhanced cancer cell apoptosis resulting from a higher concentration of bioavailable doxorubicin. The current study suggests that this tumor-specific peptide may be used to create chemotherapies specifically targeting tumor cells in the treatment of NSCLC and to design targeted gene transfer vectors or it may be used one in the diagnosis of this malignancy.
Chang
De-Kuan
DK
Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.
Lin
Chin-Tarng
CT
Wu
Chien-Hsun
CH
Wu
Han-Chung
HC
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001435:Bacteriophages / Q000276:immunology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D008024:Ligands; D008081:Liposomes; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D016513:Mice, SCID; D019151:Peptide Library; D010455:Peptides / Q000008:administration & dosage*; D014018:Tissue Distribution / Q000187:drug effects; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000077235:Vinorelbine
D000970:Antineoplastic Agents; D008024:Ligands; D008081:Liposomes; D019151:Peptide Library; D010455:Peptides; D014747:Vinblastine; D004317:Doxorubicin; D000077235:Vinorelbine