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 down-regulation of target genes with chemotherapy drugs, is expected to improve the 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. PEG-Polyethyleneimine (PEI)-Magnetic iron oxide nanoparticles (PEG-PEI-IONPs) were employed to co-deliver ASO-miR-21 and Gem. An anti-CD44v6 single chain variable fragment (scFv_CD44v6) 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 up-regulation of the tumor-suppressor genes PDCD4 and PTEN and the suppression of the epithelial-mesenchymal transformation (EMT), 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 the single ASO-miR-21 or Gem treatment in vitro. In animal tests, more scFv_CD44v6-PEG-PEI/ASO-IONP/Gem (scFv-ASO-Gem-NPs) accumulated at the tumor site than non-targeted NPs and induced a potent inhibition of tumor proliferation and metastasis. MR imaging was used to observed tumor homing of nanoparticles. These results imply that the combination of miR-21 gene silencing and Gem therapy using scFv-functionalized nanoparticle carrier exerted synergistic anti-tumour effects on pancreatic cancer cells, which is a promising strategy for pancreatic cancer therapy.

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