Improved Treatment of Pancreatic Cancer with Drug Delivery Nanoparticles Loaded with a Novel AKT/PDK1 Inhibitor

Joseph E. Kobes, Iman Daryaei, Christine M. Howison, Jordan G. Bontrager, Rachael W. Sirianni, Emmanuelle J. Meuillet, Mark D. Pagel

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Objectives This research study sought to improve the treatment of pancreatic cancer by improving the drug delivery of a promising AKT/PDK1 inhibitor, PHT-427, in poly(lactic-co-glycolic) acid (PLGA) nanoparticles. Methods PHT-427 was encapsulated in single-emulsion and double-emulsion PLGA nanoparticles (SE-PLGA-427 and DE-PLGA-427). The drug release rate was evaluated to assess the effect of the second PLGA layer of DE-PLGA-427. Ex vivo cryo-imaging and drug extraction from ex vivo organs was used to assess the whole-body biodistribution in an orthotopic model of MIA PaCa-2 pancreatic cancer. Anatomical magnetic resonance imaging (MRI) was used to noninvasively assess the effects of 4 weeks of nanoparticle drug treatment on tumor size, and diffusion-weighted MRI longitudinally assessed changes in tumor cellularity. Results DE-PLGA-427 showed delayed drug release and longer drug retention in the pancreas relative to SE-PLGA-427. Diffusion-weighted MRI indicated a consistent decrease in cellularity during drug treatment with both types of drug-loaded nanoparticles. Both SE- and DE-PLGA-427 showed a 6-fold and 4-fold reduction in tumor volume relative to untreated tumors and an elimination of primary pancreatic tumor in 68% of the mice. Conclusions These results indicated that the PLGA nanoparticles improved drug delivery of PHT-427 to pancreatic tumors, which improved the treatment of MIA PaCa-2 pancreatic cancer.

Original languageEnglish (US)
Pages (from-to)1158-1166
Number of pages9
JournalPancreas
Volume45
Issue number8
DOIs
StatePublished - Sep 1 2016

Keywords

  • AKT/PDK1 inhibitor
  • apparent diffusion coefficient (ADC)
  • magnetic resonance imaging (MRI)
  • pancreatic cancer
  • poly(lactic-co-glycolic) acid nanoparticles (PLGA)

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Hepatology
  • Endocrinology

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