Tumor regression following intravenous administration of a tumor-targeted p73 gene delivery system.
The potential of gene therapy to treat cancer is hampered by the lack of safe and efficacious gene delivery systems able to selectively deliver therapeutic genes to tumors by intravenous administration. With the long-term aim of developing an efficacious cancer-targeted gene medicine, we demonstrated that transferrin-bearing polypropylenimine dendrimer complexed to a plasmid DNA encoding p73 led to an enhanced anti-proliferative activity in vitro, by up to 120-fold in A431 compared to the unmodified dendriplex. In vivo, the intravenous administration of this p73-encoding dendriplex resulted in a rapid and sustained inhibition of tumor growth over one month, with complete tumor suppression for 10% of A431 and B16-F10 tumors and long-term survival of the animals. The treatment was well tolerated by the animals, with no apparent signs of toxicity. These results suggest that the p73-encoding tumor-targeted polypropylenimine dendrimer should be further explored as a therapeutic strategy for cancer therapy.
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, United Kingdom.
Fanny
F
Lemarié
Daniel R
DR
Croft
Rothwelle J
RJ
Tate
Kevin M
KM
Ryan
Christine
C
Dufès
D000613:Aminobutyrates / Q000737:chemistry; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000627:therapeutic use*; D050091:Dendrimers / Q000008:administration & dosage / Q000737:chemistry; D003952:Diagnostic Imaging; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007275:Injections, Intravenous; D008163:Luminescent Measurements; D008546:Melanoma, Experimental / Q000473:pathology* / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D009687:Nuclear Proteins / Q000235:genetics* / Q000627:therapeutic use*; D012074:Remission Induction; D014162:Transfection; D014168:Transferrin / Q000378:metabolism; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
D000613:Aminobutyrates; D004268:DNA-Binding Proteins; D050091:Dendrimers; D009687:Nuclear Proteins; C000606460:TP73 protein, human; D014168:Transferrin; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D004247:DNA