Journal
NANO RESEARCH
Volume 10, Issue 9, Pages 3049-3067Publisher
TSINGHUA UNIV PRESS
DOI: 10.1007/s12274-017-1521-7
Keywords
pancreatic cancer; small interfering ribonucleic acid (siRNA); biodegradable charged polyester-based vector (BCPV); gemcitabine (GEM); epithelia-mesenchymal transition (EMT)
Categories
Funding
- NTU-AstarSTAR Silicon Technologies Centre of Excellence [11235100003]
- Nanyang Technological University [M4080141.040]
- Ministry of Education, Singapore [M4020020.040 ARC2/11, M4010360.040 RG29/10, M4010359.040.703012]
- Ministry of Science and Technology [MOST104-2221-E-035-078-MY2]
- National Natural Science Foundation of China (NSFC) [21677102]
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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-siRNA(K-ras)-siRNA(Notch1) 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-siRNA(K-ras)-siRNA(Notch1) 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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