title: Synthetic anticancer gene medicine exploits intrinsic antitumor activity of cationic vector to cure established tumors.
abstract: The systemic delivery of genetic therapies required for the treatment of inaccessible tumors and metastases remains a challenge despite the development of various viral and synthetic vector systems. Here we show that a synthetic vector system based on polypropylenimine dendrimers has the desired properties of a systemic delivery vehicle and mediates efficient transgene expression in tumors after i.v. administration. The systemic tumor necrosis factor alpha (TNFalpha) gene therapy was efficacious in the experimental treatment of established A431 epidermoid carcinoma, C33a cervix carcinoma, and LS174T colorectal adenocarcinoma. Specifically, the systemic injection of dendrimer nanoparticles containing a TNFalpha expression plasmid regulated by telomerase gene promoters (hTR and hTERT) leads to transgene expression, regression of remote xenograft murine tumors, and long-term survival of up to 100% of the animals. Interestingly, these dendrimers and, to a lesser extent, other common polymeric transfection agents also exhibit plasmid-independent antitumor activity, ranging from pronounced growth retardation to complete tumor regression. The genetic therapy as well as treatment with dendrimer alone was well tolerated with no apparent signs of toxicity in the animals. The combination of intrinsic dendrimer activity and transcriptionally targeted TNFalpha when complexed was significantly more potent than either treatment alone or when both were administered in sequence. The combination of pharmacologically active synthetic transfection agent and transcriptionally targeted antitumor gene creates an efficacious gene medicine for the systemic treatment of experimental solid tumors.
authors.affiliation: Cancer Research UK Centre for Oncology and Applied Pharmacology, Beatson Laboratories, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Christine
authors.initials: C
authors.lastname: Dufès
authors.forename: W Nicol
authors.initials: WN
authors.lastname: Keith
authors.forename: Alan
authors.initials: A
authors.lastname: Bilsland
authors.forename: Irina
authors.initials: I
authors.lastname: Proutski
authors.forename: Ijeoma F
authors.initials: IF
authors.lastname: Uchegbu
authors.forename: Andreas G
authors.initials: AG
authors.lastname: Schätzlein
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000737:chemistry / Q000235:genetics / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007763:Lac Operon; D049329:Nanostructures / Q000737:chemistry; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D010957:Plasmids / Q000235:genetics; D011126:Polypropylenes / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D014162:Transfection / Q000379:methods; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D023041:Xenograft Model Antitumor Assays
chemical_list: D011126:Polypropylenes; D014409:Tumor Necrosis Factor-alpha; C443641:poly(propyleneimine)