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

TitleA nano-enabled cancer-specific ITCH RNAi chemotherapy booster for pancreatic cancer.
Publication TypeJournal Article
Year of Publication2015
Authorsde la Fuente M, Jones M-C, Santander-Ortega MJ, Mirenska A, Marimuthu P, Uchegbu I, Schätzlein A
JournalNanomedicine
Volume11
Issue2
Pagination369-77
Date Published2015 Feb
ISSN1549-9642
KeywordsApoptosis, Cell Line, Tumor, Cell Proliferation, Deoxycytidine, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic, Humans, Pancreatic Neoplasms, Polypropylenes, Repressor Proteins, RNA Interference, Ubiquitin-Protein Ligases
Abstract

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.

URLhttp://www.nanomedjournal.com/article/S1549-9634(14)00533-4/pdf
DOI10.1016/j.nano.2014.09.010
Alternate JournalNanomedicine
PubMed ID25267700