title: A nano-enabled cancer-specific ITCH RNAi chemotherapy booster for pancreatic cancer.
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.
  
  
  BACKGROUND
  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.
authors.affiliation: UCL School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX.
authors.forename: Maria
authors.initials: M
authors.lastname: de la Fuente
authors.affiliation: UCL School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Jones
authors.affiliation: UCL School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX.
authors.forename: Manuel J
authors.initials: MJ
authors.lastname: Santander-Ortega
authors.affiliation: UCL School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX.
authors.forename: Anja
authors.initials: A
authors.lastname: Mirenska
authors.affiliation: UCL School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX.
authors.forename: Preethi
authors.initials: P
authors.lastname: Marimuthu
authors.affiliation: UCL School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX.
authors.forename: Ijeoma
authors.initials: I
authors.lastname: Uchegbu
authors.affiliation: UCL School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX. Electronic address: a.schatzlein@ucl.ac.uk.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schätzlein
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011126:Polypropylenes / Q000008:administration & dosage / Q000737:chemistry; D034622:RNA Interference; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D000093542:Gemcitabine
chemical_list: C506111:DAB-Am-16; D011126:Polypropylenes; D012097:Repressor Proteins; D003841:Deoxycytidine; C432966:ITCH protein, human; D044767:Ubiquitin-Protein Ligases; D000093542:Gemcitabine
keywords: Dendrimer; Dendriplex; ITCH; Pancreatic Cancer; Polypropylenimine; p73; shRNA; siRNA