Redox-responsive nanoplatform for codelivery of miR-519c and gemcitabine for pancreatic cancer therapy

Xiaofei Xin, Virender Kumar, Feng Lin, Vinod Kumar, Rajan Bhattarai, Vijaya R. Bhatt, Chalet Tan, Ram I. Mahato

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Desmoplastic and hypoxic pancreatic cancer microenvironment induces aberrant expression of miRNAs and hypoxia-inducible factor-1α (HIF-1α) responsible for gemcitabine (GEM) resistance. We demonstrated that miR-519c was down-regulated in pancreatic cancer and transfection of miR-519c in GEM-resistant pancreatic cancer cells inhibited HIF-1α level under hypoxia. We synthesized redox-sensitive mPEG-co-P(Asp)-g-DC-g-S-S-GEM polymer, with GEM payload of 14% (w/w) and 90% GEM release upon incubation with l-glutathione. We synthesized mPEGco- P(Asp)-g-TEPA-g-DC for complex formation with miRNA. Chemical modification of miR-519c with 2'-O-methyl phosphorothioate (OMe-PS) at 3' end enhanced its stability and activity without being immunogenic. Epidermal growth factor receptor targeting peptide GE11 decoration increased tumor accumulation of micelles after systemic administration and significantly inhibited orthotopic desmoplastic pancreatic cancer growth in NSG mice by down-regulating HIF-1α and genes responsible for glucose uptake and cancer cell metabolism. Our multifunctional nanomedicine of GEM and OMe-PS-miR-519c offers a novel therapeutic strategy to treat desmoplasia and hypoxia-induced chemoresistance in pancreatic cancer.

Original languageEnglish (US)
Article numbereabd6764
JournalScience Advances
Volume6
Issue number46
DOIs
StatePublished - Nov 11 2020

ASJC Scopus subject areas

  • General

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