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

Research output: Contribution to journalArticlepeer-review

Authors

  • Maria de la Fuente
  • Manuel J Santander-Ortega
  • Anja Mirenska
  • Preethi Marimuthu
  • Ijeoma Uchegbu
  • Andreas Schätzlein

Colleges, School and Institutes

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.

Bibliographic note

Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Details

Original languageEnglish
Pages (from-to)369-77
Number of pages9
JournalNanomedicine: Nanotechnology, Biology and Medicine
Volume11
Issue number2
Early online date6 Oct 2014
Publication statusPublished - Feb 2015