Efficacy of gemcitabine conjugated and miRNA-205 complexed micelles for treatment of advanced pancreatic cancer

Anupama Mittal, Deepak Chitkara, Stephan W. Behrman, Ram I. Mahato

Research output: Contribution to journalArticle

73 Scopus citations

Abstract

Clinical effectiveness of gemcitabine in pancreatic cancer is hindered due to its rapid plasma metabolism and development of chemo-resistance. We have previously delineated the significant role of miRNAs in mediating the growth and proliferation of cancer stem cells (CSCs) which in turn result in chemo-resistance, invasion and metastasis. Here, we designed self-assembling, gemcitabine conjugated cationic copolymers for co-delivery of a tumor suppressor miRNA-205 (miR-205) and evaluated their invivo efficacy in a pancreatic cancer ectopic tumor model developed using gemcitabine resistant MIA PaCa-2R cells. Combination formulations showed mean a particle size of <100nm and gemcitabine payload of >10% w/w, exhibited miRNA complexation at N/P ratio of 4/1, sustained release of gemcitabine for >10 days, transfection efficiency of >90%, extended miRNA and drug stability in serum. Functional assays in gemcitabine resistant MIA PaCa-2R and CAPAN-1R pancreatic cancer cells revealed that the combination formulations effectively reversed chemo-resistance, invasion and migration. In pancreatic tumor model, the combination formulation treated group showed significant inhibition of tumor growth. Immuno-hiostochemical analysis revealed decreased tumor cell proliferation with increased apoptosis in the animals treated with miR-205 and gemcitabine combination.

Original languageEnglish (US)
Pages (from-to)7077-7087
Number of pages11
JournalBiomaterials
Volume35
Issue number25
DOIs
StatePublished - Aug 2014

Keywords

  • Cancer
  • Gemcitabine
  • MiR-205
  • MiRNA
  • Micelles
  • Pancreas

ASJC Scopus subject areas

  • Bioengineering
  • Ceramics and Composites
  • Biophysics
  • Biomaterials
  • Mechanics of Materials

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