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

65 Citations (Scopus)

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

Fingerprint

gemcitabine
Micelles
MicroRNAs
Pancreatic Neoplasms
Tumors
Neoplasms
Drug Stability
Cell proliferation
Cell death
Stem cells
Complexation
Neoplastic Stem Cells
Metabolism
Growth
Assays
Particle Size
Animals
Copolymers
Particle size
Transfection

Keywords

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

ASJC Scopus subject areas

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

Cite this

Efficacy of gemcitabine conjugated and miRNA-205 complexed micelles for treatment of advanced pancreatic cancer. / Mittal, Anupama; Chitkara, Deepak; Behrman, Stephan W.; Mahato, Ram I.

In: Biomaterials, Vol. 35, No. 25, 08.2014, p. 7077-7087.

Research output: Contribution to journalArticle

Mittal, Anupama ; Chitkara, Deepak ; Behrman, Stephan W. ; Mahato, Ram I. / Efficacy of gemcitabine conjugated and miRNA-205 complexed micelles for treatment of advanced pancreatic cancer. In: Biomaterials. 2014 ; Vol. 35, No. 25. pp. 7077-7087.
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