The dendritic polymer DAB-Am16 as a novel tumoricidal compound

In the 21st century, cancer is becoming the curse of the ageing population in developed countries. No satisfactory therapies are available for many tumour types, and application of existing therapies is limited by severe side effects. Thus, there is a great need of new approaches in cancer treatment. DAB-Am16 is a dendritic polymer with a globular structure, consisting of poly(propylene imine) branches that emerge from a diaminobutane core. Its intrinsic tumoricidal activity in mouse models was published in 2005, but no information on the mechanism of action was available. This thesis presents novel findings on the pathways underlying the anti-cancer activity of this dendrimer in vitro and in vivo. Extensive chemical characterisation of DAB-Am16 confirmed its stability and purity. Severe time- and concentration-dependent cytotoxicity was observed for a panel of human tumour cell lines, while a small population of persisters was identified. Toxicity was accompanied by a delayed or abrogated cell cycle. There was an increased number of S phase cells, while the ability to synthesise DNA or to undergo mitosis was progressively lost with increasing DAB-Am16 concentration. The following cell death was found to be apoptotic and was biased in a cell cycle phase dependent manner. The order of apoptotic events upon DAB-Am16 exposure was determined. Finally, an in vivo experiment confirmed that DAB-Am16 has a pronounced effect against human pancreatic cancer xenografts in mice, while being well tolerated by the animals. Post mortem examination of tumour tissue revealed cell cycle blockage of tumour cells from DAB-Am16-treated mice. However, disposition for further proliferation was not diminished, and no significant difference in tumour vascularisation was observed

A nano-enabled cancer-specific ITCH RNAi chemotherapy booster for pancreatic cancer

UNLABELLED: Gemcitabine is currently the standard therapy for pancreatic cancer. However, growing concerns over gemcitabine resistance mean that new combinatory therapies are required to prevent loss of efficacy with prolonged treatment. Here, we suggest that this could be achieved through co-administration of RNA interference agents targeting the ubiquitin ligase ITCH. Stable anti-ITCH siRNA and shRNA dendriplexes with a desirable safety profile were prepared using generation 3 poly(propylenimine) dendrimers (DAB-Am16). The complexes were efficiently taken up by human pancreatic cancer cells and produced a 40-60% decrease in ITCH RNA and protein expression in vitro (si/shRNA) and in a xenograft model of pancreatic cancer (shRNA). When co-administered with gemcitabine (100 mg/kg/week) at a subtherapeutic dose, treatment with ITCH-shRNA (3x 50 mg/week) was able to fully suppress tumour growth for 17 days, suggesting that downregulation of ITCH mediated by DAB-Am16/shRNA sensitizes pancreatic cancer to gemcitabine in an efficient and specific manner. FROM THE CLINICAL EDITOR: Gemcitabine delivery to pancreatic cancer often results in the common problem of drug resistance. This team overcame the problem through co-administration of siRNA and shRNA dendriplexes targeting the ubiquitin ligase ITCH

A nano-enabled cancer-specific ITCH RNAi chemotherapy booster for pancreatic cancer

Gemcitabine is currently the standard therapy for pancreatic cancer. However, growing concerns over gemcitabine resistance mean that new combinatory therapies are required to prevent loss of efficacy with prolonged treatment. Here, we suggest that this could be achieved through co-administration of RNA interference agents targeting the ubiquitin ligase ITCH. Stable anti-ITCH siRNA and shRNA dendriplexes with a desirable safety profile were prepared using generation 3 poly(propylenimine) dendrimers (DAB-Am16). The complexes were efficiently taken up by human pancreatic cancer cells and produced a 40-60% decrease in ITCH RNA and protein expression in vitro (si/shRNA) and in a xenograft model of pancreatic cancer (shRNA). When co-administered with gemcitabine (100 mg/kg/week) at a subtherapeutic dose, treatment with ITCH-shRNA (3x 50 mg/week) was able to fully suppress tumour growth for 17 days, suggesting that downregulation of ITCH mediated by DABAm16/shRNA sensitizes pancreatic cancer to gemcitabine in an efficient and specific manner