Co-delivery of microRNA-21 antisense oligonucleotides and gemcitabine using nanomedicine for pancreatic cancer therapy.

Abstract

Tumor metastasis occurs naturally in pancreatic cancer, and the efficacy of chemotherapy is usually poor. Precision medicine, combining downregulation of target genes with chemotherapy drugs, is expected to improve therapeutic effects. Therefore, we developed a combined therapy of microRNA-21 antisense oligonucleotides (ASO-miR-21) and gemcitabine (Gem) using a targeted co-delivery nanoparticle (NP) carrier and investigated the synergistic inhibitory effects on pancreatic cancer cells metastasis and growth. Polyethylene glycol-polyethylenimine-magnetic iron oxide NPs were used to co-deliver ASO-miR-21 and Gem. An anti-CD44v6 single-chain variable fragment (scFvCD44v6 ) was used to coat the particles to obtain active and targeted delivery. Our results showed that the downregulation of the oncogenic miR-21 by ASO resulted in upregulation of the tumor-suppressor genes PDCD4 and PTEN and the suppression of epithelial-mesenchymal transition, which inhibited the proliferation and induced the clonal formation, migration, and invasion of pancreatic cancer cells in vitro. The co-delivery of ASO-miR-21 and Gem induced more cell apoptosis and inhibited the growth of pancreatic cancer cells to a greater extent than single ASO-miR-21 or Gem treatment in vitro. In animal tests, more scFvCD44v6 -PEG-polyethylenimine/ASO-magnetic iron oxide NP/Gem accumulated at the tumor site than non-targeted NPs and induced a potent inhibition of tumor proliferation and metastasis. Magnetic resonance imaging was used to observed tumor homing of NPs. These results imply that the combination of miR-21 gene silencing and Gem therapy using an scFv-functionalized NP carrier exerted synergistic antitumor effects on pancreatic cancer cells, which is a promising strategy for pancreatic cancer therapy.

• Authors: Yaqing Li, Yinting Chen, Jiajia Li, Zuoquan Zhang, Chumei Huang, Guoda Lian, Kege Yang, Shaojie Chen, Ying Lin, Lingyun Wang, Kaihong Huang, Linjuan Zeng
• Journal: Cancer science (Cancer Sci) Vol. 108 Issue 7 Pg. 1493-1503 (Jul 2017) ISSN: 1349-7006 [Electronic] England
• PMID: 28444967 (Publication Type: Journal Article)
• Copyright: © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Chemical References

• CD44v6 antigen
• Drug Carriers
• Ferric Compounds
• Hyaluronan Receptors
• MIRN21 microRNA, human
• MicroRNAs
• Oligonucleotides, Antisense
• Single-Chain Antibodies
• Deoxycytidine
• ferric oxide
• Polyethylene Glycols
• Polyethyleneimine
• Gemcitabine

Topics

• Animals
• Deoxycytidine (administration & dosage, analogs & derivatives)
• Drug Carriers (administration & dosage, chemistry)
• Female
• Ferric Compounds
• Genetic Therapy (methods)
• Humans
• Hyaluronan Receptors (administration & dosage)
• Metal Nanoparticles (chemistry)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• MicroRNAs (antagonists & inhibitors)
• Molecular Targeted Therapy (methods)
• Nanomedicine (methods)
• Oligonucleotides, Antisense (administration & dosage)
• Pancreatic Neoplasms (pathology)
• Polyethylene Glycols
• Polyethyleneimine
• Precision Medicine (methods)
• Single-Chain Antibodies (administration & dosage)
• Xenograft Model Antitumor Assays
• Gemcitabine