Cancer therapy is currently limited by the difficulty to efficiently deliver therapeutic molecules or genes to remote tumours and metastases by systemic administration. We have recently reported that “Synfect” (generation 3 polypropylenimine dendrimers) can efficiently mediate transfection in vitro. Here we show that the intravenously administered gene medicine, consisting of the intrinsically active dendrimer complexing a tumour necrosis factor (TNFα) expression plasmid driven by a tumour-specific promoter, leads to transgene expression, regression of established xenograft tumours and long-term survival of a high proportion of the mice. Groups of female nude mice (n=5) bearing established subcutaneous human A431 epidermoid carcinoma xenografts were treated by intravenous injection of nanoparticles containing a TNFα expression plasmid (pORF9 mTNFα). Furthermore, specificity of tumour gene delivery was increased through transcriptional targeting based on promoter fragments for telomerase (human telomerase RNA hTR and human telomerase reverse transcriptase hTERT). Body weight (as a surrogate marker of toxicity) and tumour volume (from calliper measurements) were recorded daily. Synfect nanoparticles carrying active TNFα expression lead to significant tumour regression within 1-2 days in 100 % of the treated animals and excellent long term response (17 weeks; analogous to RECIST) with hTR driven plasmid leading to 80% complete and 20% partial response. hTERT-driven gene medicine also lead to a regression in 40% of the tumours (30% of them completely disappeared) and to a stabilization in 30% of the tumours. These therapeutic effects were comparable with the regression induced with complexes driven by non-specific promoter, occurring in 100% of tumours, and were also observed in other established xenografts (C33a, LS174T). This anti-tumour activity appears to be the result of synergies of the intrinsic cytostatic effect of the dendrimer combined with the expression of TNFα. The dendrimer alone lead to a complete growth retardation of the tumours and long term regression in 50% of tumours. Complexes of TNFα expression plasmid with other cationic transfection agents delayed tumour growth compared to the untreated control, but only Synfect lead to a significant tumour ablation. The lack of apparent toxicity and significant weight loss compared to untreated controls suggests the treatment to be relatively well tolerated and safe. In conclusion we have demonstrated for the first time that systemic treatment of remote tumours using a gene medicine exploiting synergies between an intrinsically active Synfect transfection agent and a transcriptionally targeted TNFα expression plasmid is a highly efficacious and safe treatment strategy with a high percentage of tumour regression and long-term survival in a murine animal model.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]