4021

Treatment of inaccessible tumors and metastases requires systemic delivery of genes with the help of synthetic or viral vector systems. These nanomedicines have to travel in the blood stream to the tumor, extravasate and traverse the interstitium to reach the cancer cell. A synthetic vector system based on polypropylenimine dendrimer nanocomplexes has the capability to act as a systemic delivery vehicle and mediates efficient transgene expression in tumors after intravenous administration. We have chosen a plasmid expressing the potent cytokine TNFa to explore whether such gene medicines are able to express therapeutically significant amounts of protein. As the TNFa protein is highly toxic on systemic administration we also explored whether such systems when transcriptionally target to the tumor would be able to overcome this toxicity. We found that the systemic tumor necrosis factor alpha (TNFa) 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 TNF alpha expression plasmid regulated by telomerase gene promoters (hTR, 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 extend other common polymeric transfection agents also exhibit plasmid-independent anti-tumor activity, ranging from pronounced growth retardation to complete tumor regression. The genetic therapy as well as treatment with dendrimer alone were well tolerated with no apparent signs of toxicity in the animals. The combination of intrinsic dendrimer activity and transcriptionally targeted TNFa when complexed was significantly more potent than either treatment alone or when both were administered in sequence. Futhermore, the synthetic vector has now also been tested in conjunction with other therapeutic genes such as p53 with good success.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]