ABSTRACT
Effective delivery of radiosensitizer to target tumor cells, causing preferentially increased tumor cytotoxicity, while simultaneously minimizing damage to healthy cells around the tumor, is an ideal strategy for the improvement of radiotherapeutic efficacy against human cancer. We aimed to enhance radiotherapeutic efficacy by using biocompatible gold nanoparticles (AuNP) as a vehicle for systemic delivery of ss-lapachone (lap). Lap is a novel anticancer agent displaying potent cytotoxicity against cancer cells expressing NAD(P)H:quinone oxidoreductase-1 enzyme (NQO1). Although lap is expected to be a very promising radiosensitizer, its poor solubility and non-specific distribution obstruct preclinical evaluation and clinical application. In this study, the property of AuNPs carrying lap (AuNPs/lap) for active-targeting tumor cells and improving in vivo radiotherapeutic efficacy was evaluated. Murine monoclonal anti-EGFR antibody was conjugated to the AuNPs/lap as a ligand for active targeting. The active tumor-targeting property of AuNPs/lap conjugating anti-EGFR antibody was validated in vitro experiments using cell lines expressing EGFR at different levels. In mice bearing xenograft human tumors, the intravenous injection of AuNPs/lap exhibited highly enhanced radiotherapeutic efficacy. AuNPs/lap offers a new modality for improvement of radiotherapeutic efficacy and feasibility of further clinical application for human cancer treatment.
Subject(s)
Drug Carriers , Gold/chemistry , Lung Neoplasms/radiotherapy , Metal Nanoparticles , Naphthoquinones/administration & dosage , Radiation-Sensitizing Agents/administration & dosage , Animals , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/metabolism , Biological Transport , Cell Line, Tumor , Cell Survival , Chemistry, Pharmaceutical , Drug Compounding , Drug Evaluation, Preclinical , ErbB Receptors/metabolism , Humans , Injections, Intravenous , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Mice , Mice, Inbred BALB C , Mice, Nude , Naphthoquinones/chemistry , Radiation-Sensitizing Agents/chemistry , Reproducibility of Results , Time Factors , Xenograft Model Antitumor AssaysABSTRACT
Most of methylxanthine derivatives including caffeine have been known to radiosensitize cancer cells, but the obstacles such as toxicity, request of high dose and poor solubility hinder their preclinical evaluations and clinical applications. In this study, we evaluated the efficacy of 1-methylxanthine (1-MTX), a caffeine metabolite as a radiosensitizer and the in vivo effectiveness of the temperature-sensitive liposomal 1-methylxanthine (tsl-MTX) in combination with ionizing radiation and regional hyperthermia. In human colorectal and lung cancer cells, treatment of 1-MTX sensitized cells to ionizing radiation. To evaluate the in vivo capability of 1-MTX to radiosensitize tumors, we developed temperature-sensitive liposomal 1-MTX using DPPC:DMPC:DSPC (4:1:1 molar ratio) with intention of overcoming lethal toxicity of 1-MTX and controlling drug-release. The particle size of the liposomes was approximately 200 nm in diameter. The release of 1-MTX from the liposomes was responding to increase of temperature. In xenograft tumor-bearing mice, the tsl-MTX administered using the i.p. route showed delay of tumor growth. Importantly, tsl-MTX in combination with radiation and regional hyperthermia exhibited marked delay of tumor growth, suggesting that 1-MTX effectively enhanced radiation-induced suppression of tumor growth. In conclusion, tsl-MTX has highly efficacious anticancer competence in vivo, enhancing radiotherapeutic effectiveness, and feasibility for further clinical applications.
Subject(s)
Radiation-Sensitizing Agents/chemistry , Radiation-Sensitizing Agents/pharmacology , Temperature , Xanthines/chemistry , Xanthines/pharmacology , Animals , Cell Line, Tumor , Cell Survival/drug effects , Cell Survival/physiology , Humans , Liposomes , Mice , Mice, Inbred BALB C , Mice, Nude , Radiation-Sensitizing Agents/therapeutic use , Xanthines/therapeutic use , Xenograft Model Antitumor Assays/methodsABSTRACT
The Ku protein is essential for the repair of a majority of DNA double-strand breaks in mammalian cells. The purpose of this study was to investigate the relationship between the expression of Ku70/80 and sensitivity to radiation in cancer cell lines of the head and neck. The sensitivity to radiation in various head and neck cancer cell lines (AMC-HN-1 to -9) was analyzed by colony forming assay. Of the nine cell lines examined, the most radiosensitive cell line (AMC-HN-3) and the most radioresistant cell line (AMC-HN-9) were selected for this experiments. The expression of Ku70/80 was examined after irradiation using real time PCR, Western blotting and immunofluorescence in two different cell lines. Cell cycle distribution after irradiation were analysed. A differential radioresponse was demonstrated by expression of Ku70/80 in AMC-HN-3 and AMC-HN-9 cells. While the expression of Ku70 was slightly increased in the radioresistant AMC-HN-9 cell line, the expression of Ku80 was remarkably increased, suggesting a correlation between Ku80 expression and radiation resistance. Overexpression of Ku80 plays an important role in the repair of DNA damage induced by radiation. Ku80 expression may provide an effective predictive assay of radiosensitivity in head and neck cancers.
