Micellar delivery of cyclopamine and gefitinib for treating pancreatic cancer

Deepak Chitkara, Saurabh Singh, Virender Kumar, Michael Danquah, Stephen W. Behrman, Neeraj Kumar, Ram I Mahato

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Hedgehog (Hh) and epidermal growth factor receptor (EGFR) signaling are involved in pancreatic cancer progression. Targeting these pathways simultaneously with cyclopamine (Hh inhibitor) and gefitinib (EGFR inhibitor) is a promising approach for treating pancreatic cancer. However, the major limitation for effective clinical translation of these molecules is their low aqueous solubility. We have previously demonstrated that methoxy polyethyleneglycol-b-poly(carbonate-co-lactic acid) {mPEG-b-P(CB-co-LA)} copolymer solubilizes hydrophobic anticancer drugs and has the potential to deliver to tumors by an enhanced permeability and retention (EPR) effect. In this study, using the nanoprecipitation method, cyclopamine and gefitinib were efficiently loaded into mPEG-b-P(CB-co-LA) micelles with encapsulation efficiencies of 94.4 and 88.6%, respectively. These micelles had a narrow particle size distribution with a mean particle size of 54.3 nm and a PDI of 0.14. Combination therapy showed a synergistic effect against L3.6pl cells but an additive effect against MIA PaCa-2cells. Caspase 3/7 activity was also increased when this combination therapy was used, indicating apoptotic cell death. Gene and protein expression analysis indicated cross-talk between Hh and EGFR signaling. Furthermore, the combination decreased tumor growth rate in L3.6pl-derived xenograft mouse tumors. These data suggest the applicability of our micellar system to effectively load and deliver cyclopamine and gefitinib for combination chemotherapy.

Original languageEnglish (US)
Pages (from-to)2350-2357
Number of pages8
JournalMolecular Pharmaceutics
Volume9
Issue number8
DOIs
StatePublished - Aug 6 2012

Fingerprint

Hedgehogs
Pancreatic Neoplasms
Epidermal Growth Factor Receptor
Carbonates
Micelles
Particle Size
Lactic Acid
Caspase 7
Neoplasms
Combination Drug Therapy
Heterografts
Caspase 3
Solubility
Permeability
Cell Death
Gene Expression
Therapeutics
Growth
Pharmaceutical Preparations
gefitinib

Keywords

  • combination
  • cyclopamine
  • drug delivery
  • gefitinib
  • micelles
  • pancreatic cancer

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

Cite this

Chitkara, D., Singh, S., Kumar, V., Danquah, M., Behrman, S. W., Kumar, N., & Mahato, R. I. (2012). Micellar delivery of cyclopamine and gefitinib for treating pancreatic cancer. Molecular Pharmaceutics, 9(8), 2350-2357. https://doi.org/10.1021/mp3002792

Micellar delivery of cyclopamine and gefitinib for treating pancreatic cancer. / Chitkara, Deepak; Singh, Saurabh; Kumar, Virender; Danquah, Michael; Behrman, Stephen W.; Kumar, Neeraj; Mahato, Ram I.

In: Molecular Pharmaceutics, Vol. 9, No. 8, 06.08.2012, p. 2350-2357.

Research output: Contribution to journalArticle

Chitkara, D, Singh, S, Kumar, V, Danquah, M, Behrman, SW, Kumar, N & Mahato, RI 2012, 'Micellar delivery of cyclopamine and gefitinib for treating pancreatic cancer', Molecular Pharmaceutics, vol. 9, no. 8, pp. 2350-2357. https://doi.org/10.1021/mp3002792
Chitkara D, Singh S, Kumar V, Danquah M, Behrman SW, Kumar N et al. Micellar delivery of cyclopamine and gefitinib for treating pancreatic cancer. Molecular Pharmaceutics. 2012 Aug 6;9(8):2350-2357. https://doi.org/10.1021/mp3002792
Chitkara, Deepak ; Singh, Saurabh ; Kumar, Virender ; Danquah, Michael ; Behrman, Stephen W. ; Kumar, Neeraj ; Mahato, Ram I. / Micellar delivery of cyclopamine and gefitinib for treating pancreatic cancer. In: Molecular Pharmaceutics. 2012 ; Vol. 9, No. 8. pp. 2350-2357.
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