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

Biomaterials. 2014 Aug;35(25):7077-87. doi: 10.1016/j.biomaterials.2014.04.053. Epub 2014 May 14.

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 in vivo efficacy in a pancreatic cancer ectopic tumor model developed using gemcitabine resistant MIA PaCa-2(R) cells. Combination formulations showed mean a particle size of <100 nm 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-2(R) and CAPAN-1(R) 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.

Keywords: Cancer; Gemcitabine; Micelles; Pancreas; miR-205; miRNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / pharmacology
  • Drug Delivery Systems / methods
  • Drug Resistance, Neoplasm
  • Drug Stability
  • Humans
  • Immunohistochemistry
  • Ligands
  • Male
  • Mice, Nude
  • Micelles*
  • MicroRNAs / chemistry*
  • MicroRNAs / pharmacology*
  • Pancreatic Neoplasms / drug therapy*
  • Particle Size
  • Polyethylene Glycols / chemical synthesis
  • Polymers / chemistry
  • Transfection
  • Xenograft Model Antitumor Assays

Substances

  • Ligands
  • MIRN205 microRNA, human
  • Micelles
  • MicroRNAs
  • Polymers
  • Deoxycytidine
  • Polyethylene Glycols
  • gemcitabine