Abstract
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.
Highlights
Lung cancer is one of the most commonly diagnosed malignancies in developed countries and is a growing problem in developing countries [1]
Isolation of phages binding to non-small cell lung cancer (NSCLC) cells We used a phage-displayed random peptide library to isolate phages that were able to bind to NSCLC CL1-5 cells
Using the Genetics Computer Group (GCG) software analysis, we found that these selected phages (PC3-1, PC4-1, PC4-5, PC5-2 and PC5-4) displayed the consensus motif, tryptophan (W)-threonine (T)/tyrosine (Y)-tyrosine (Y) (Table 1)
Summary
Lung cancer is one of the most commonly diagnosed malignancies in developed countries and is a growing problem in developing countries [1]. NSCLC makes up approximately 80% of all lung cancer cases [2] and has a limited response rate to current chemotherapeutic agents, with tumor shrinkage in only 20% of patients and a two-year survival rate between 10% and 16% [3]. One major reason for this unsatisfactory outcome of chemotherapy is compromised drug delivery to the lung cancer tissues due to high interstitial fluid pressures (IFP) within the tumor [4]. Administered chemotherapy cannot be adequately delivered into solid tumors because of the immature vasculature with abnormal architecture [5] and leaky, heterogeneous vessel walls [6] as well as the high IFP within tumor tissues [7,8]. Cancer cells are exposed to a lower concentration of the drug than normal cells [9], resulting in decreased effectiveness and increased toxicity. It is important to develop a strategy to enhance the amount of drugs delivered to tumor tissues in a targeted way while sparing normal tissues
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