Songtao Li1, Hongling Zhao2, Xiaoxia Mao2, Yanfang Fan3, Xiujun Liang3, Ruxing Wang2, Lijun Xiao4, Jianping Wang4, Qi Liu2, Guiqin Zhao5. 1. Hebei Province Key Laboratory of Research and Development of Traditional Chinese Medicine, Institute of Chinese Mateia Medica, Chengde Medical University, Chengde, 067000, China. songtao-li@hotmail.com. 2. Hebei Province Key Laboratory of Research and Development of Traditional Chinese Medicine, Institute of Chinese Mateia Medica, Chengde Medical University, Chengde, 067000, China. 3. Institute of Basic Medicine, Chengde Medical University, Chengde, 067000, China. 4. Department of Immunology, Chengde Medical University, Chengde, 067000, China. 5. Hebei Province Key Laboratory of Research and Development of Traditional Chinese Medicine, Institute of Chinese Mateia Medica, Chengde Medical University, Chengde, 067000, China. zgq164190162@163.com.
Abstract
PURPOSE: Transferrin receptors (TfRs) are overexpressed in tumor cells but are scarce in normal tissues, which makes TfR an attractive target for drug treatment of cancer. The objective of this study was to evaluate the potential of BP9a (CAHLHNRS) as a peptide vector for constructing TfR targeted peptide-drug conjugates and selective drug delivery. METHODS: Doxorubicin (DOX) was connected to BP9a via a disulfide-intercalating linker to afford a reduction-responsive BP9a-SS-DOX conjugate. By using HepG2 human liver cancer cells and L-O2 normal hepatic cells as TfR over-expressing and low-expressing in vitro models, respectively, TfR mediated cellular uptake of this conjugate was studied by using flow cytometry and confocal laser scanning microscopy. The in vitro cytotoxicities of the conjugate against HepG2 and L-O2 cells were examined by cell counting kit-8 (CCK-8) assay to evaluate its tumorous specificity. RESULTS: Cellular uptake and TfR blockage test results showed that the BP9a-SS-DOX conjugate gained entry into HepG2 cells via endocytosis mediated by TfR and mainly accumulated in cytoplasm. The in vitro antiproliferative activity of this conjugate against HepG2 cells (IC50 6.21 ± 1.12 μM) was approximately one-sixth of that of free DOX (IC50 1.03 ± 0.13 μM). However, its cytotoxic effect on L-O2 cells was obviously reduced compared with that of free DOX. CONCLUSIONS: The BP9a-SS-DOX conjugate showed specific antiproliferative activity against HepG2 liver cancer cells. Our study suggests that BP9a has the potential to target chemotherapeutic agents to tumor cells over-expressing TfR and facilitate selective drug delivery.
PURPOSE:Transferrin receptors (TfRs) are overexpressed in tumor cells but are scarce in normal tissues, which makes TfR an attractive target for drug treatment of cancer. The objective of this study was to evaluate the potential of BP9a (CAHLHNRS) as a peptide vector for constructing TfR targeted peptide-drug conjugates and selective drug delivery. METHODS:Doxorubicin (DOX) was connected to BP9a via a disulfide-intercalating linker to afford a reduction-responsive BP9a-SS-DOX conjugate. By using HepG2humanliver cancer cells and L-O2 normal hepatic cells as TfR over-expressing and low-expressing in vitro models, respectively, TfR mediated cellular uptake of this conjugate was studied by using flow cytometry and confocal laser scanning microscopy. The in vitro cytotoxicities of the conjugate against HepG2 and L-O2 cells were examined by cell counting kit-8 (CCK-8) assay to evaluate its tumorous specificity. RESULTS: Cellular uptake and TfR blockage test results showed that the BP9a-SS-DOX conjugate gained entry into HepG2 cells via endocytosis mediated by TfR and mainly accumulated in cytoplasm. The in vitro antiproliferative activity of this conjugate against HepG2 cells (IC50 6.21 ± 1.12 μM) was approximately one-sixth of that of free DOX (IC50 1.03 ± 0.13 μM). However, its cytotoxic effect on L-O2 cells was obviously reduced compared with that of free DOX. CONCLUSIONS: The BP9a-SS-DOX conjugate showed specific antiproliferative activity against HepG2liver cancer cells. Our study suggests that BP9a has the potential to target chemotherapeutic agents to tumor cells over-expressing TfR and facilitate selective drug delivery.
Authors: Periannan Kuppusamy; Haiquan Li; Govindasamy Ilangovan; Arturo J Cardounel; Jay L Zweier; Kenichi Yamada; Murali C Krishna; James B Mitchell Journal: Cancer Res Date: 2002-01-01 Impact factor: 12.701
Authors: Tracy R Daniels; Ezequiel Bernabeu; José A Rodríguez; Shabnum Patel; Maggie Kozman; Diego A Chiappetta; Eggehard Holler; Julia Y Ljubimova; Gustavo Helguera; Manuel L Penichet Journal: Biochim Biophys Acta Date: 2011-08-05