Biodegradable nanocarriers for small interfering ribonucleic acid (siRNA) co-delivery strategy increase the chemosensitivity of pancreatic cancer cells to gemcitabine

• Published in: Nano research Vol. 10; no. 9; pp. 3049 - 3067
• Main Authors: Yang, Chengbin, Chan, Kok Ken, Lin, Wen-Jen, Soehartono, Alana Mauluidy, Lin, Guimiao, Toh, Huiting, Yoon, Ho Sup, Chen, Chih-Kuang, Yong, Ken-Tye
• Format: Journal Article
• Language: English
• Published: Beijing Tsinghua University Press 01.09.2017; Springer Nature B.V
• Subjects: Anticancer properties; Antitumor activity; Apoptosis; Atomic/Molecular Structure and Spectra; Biodegradability; Biodegradation; Biomedicine; Biotechnology; Cancer; Cell migration; Cell proliferation; Chemistry and Materials Science; Condensed Matter Physics; Drug resistance; Gemcitabine; Gene expression; Gene silencing; Internalization; K-Ras protein; Materials Science; Mesenchyme; Mutation; Nanotechnology; Notch1 protein; Nuclease; Pancreatic cancer; Proto-oncogenes; Research Article; Ribonucleic acid; RNA; RNA-mediated interference; Sensitivity enhancement; siRNA; pancreatic cancer; epithelia-mesenchymal transition (EMT); gemcitabine (GEM); small interfering ribonucleic acid (siRNA); biodegradable charged polyester-based vector (BCPV)
• ISSN: 1998-0124; 1998-0000
• DOI: 10.1007/s12274-017-1521-7

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.