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Ribonucleic acid (RNA) interference (RNAi) therapies are promising cancer treatment modalities that can specifically target abnormal proto-oncogenes, thus improving the therapeutic effect. For the treatment of pancreatic cancer, targeting one mutant proto-oncogene by RNAi usually does not yield the desired therapeutic efficiency. Both K-ras gene mutations and Notch1 overexpression are common symptoms in pancreatic cancer patients, and play a crucial role in pancreatic cancer cell drug resistance. In this study, biodegradable charged polyester-based vectors (BCPVs) were synthesized for the co-delivery of K-ras and Notch1 small interfering ribonucleic acid (siRNA) into MiaPaCa-2 cells (pancreatic cancer cell line) to overcome drug resistance to gemcitabine (GEM), a first-line chemotherapeutic drug used in the clinic. BCPVs could effectively absorb negative siRNA to form a capsule-like structure, prevent siRNA from nuclease digestion in the serum, and promote effective siRNA cell internalization and endosomal escape. Through K-ras and Notch1 gene silencing in MiaPaCa-2 cells, BCPV-siRNAK-ras-siRNANotch1 nanocomplexes effectively reversed the epithelia-mesenchymal transition (EMT) in MiaPaCa-2 cells, thereby greatly enhancing the sensitivity of MiaPaCa-2 cells to GEM. MiaPaCa-2 cell proliferation, migration, and invasion were effectively inhibited, and cell apoptosis was also significantly enhanced by the synergistic antitumor effect of BCPV-siRNAK-ras-siRNANotch1 nanocomplexes and GEM. These results suggest that this combination RNAi therapy can be used to improve cancer cell sensitivity to chemotherapeutic drugs. Specifically, this newly developed strategy has a great potential for treating pancreatic cancer.

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Publication history

Received: 17 November 2016
Revised: 04 February 2017
Accepted: 09 February 2017
Published: 09 May 2017
Issue date: September 2017

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© Tsinghua University Press and Springer-Verlag Berlin Heidelberg 2017

Acknowledgements

Acknowledgements

The authors are grateful to Professor Chong Cheng from the University of Buffalo for the original molecular structure design of BCPV. This work has been supported by NTU-A*STAR Silicon Technologies Centre of Excellence under the program grant (No. 11235100003), start-up grant (No. M4080141.040) from Nanyang Technological University, and Grants Tier 2 MOE2010-T2-2-010 (No. M4020020.040 ARC2/11) and Tier 1 (Nos. M4010360.040 RG29/10 and M4010359.040.703012) from Ministry of Education, Singapore, and the research grant (No. MOST104-2221-E-035-078-MY2) from the "Ministry of Science and Technology", and the grants from the National Natural Science Foundation of China (NSFC) (No. 21677102). The authors also appreciate the Precision Instrument Support Center of Feng Chia University in providing the fabrication and measurement facilities.

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Email: nanores@tup.tsinghua.edu.cn

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