Nanoparticle delivery of an akt/pdk1 inhibitor improves the therapeutic effect in pancreatic cancer

Armando Lucero-Acuña, Justin J. Jeffery, Edward R. Abril, Raymond B Nagle, Roberto Z Guzman, Mark "Marty" Pagel, Emmanuelle Meuillet

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

The K-ras mutation in pancreatic cancer can inhibit drug delivery and increase drug resistance. This is exemplified by the therapeutic effect of PH-427, a small molecule inhibitor of AKT/PDK1, which has shown a good therapeutic effect against a BxPC3 pancreatic cancer model that has K-ras, but has a poor therapeutic effect against a MiaPaCa-2 pancreatic cancer model with mutant K-ras. To increase the therapeutic effect of PH-427 against the MiaPaCa-2 pancreatic cancer model with mutant K-ras, we encapsulated PH-427 into poly(lactic-co-glycolic acid) nanoparticles (PNP) to form drug-loaded PH-427-PNP. PH-427 showed a biphasic release from PH-427-PNP over 30 days during studies in sodium phosphate buffer, and in vitro stud­ies revealed that the PNP was rapidly internalized into MiaPaCa-2 tumor cells, suggesting that PNP can improve PH-427 delivery into cells harboring mutant K-ras. In vivo studies of an orthotopic MiaPaCa-2 pancreatic cancer model showed reduced tumor load with PH-427-PNP as compared with treatment using PH-427 alone or with no treatment. Ex vivo studies confirmed the in vivo results, suggesting that PNP can improve drug delivery to pancreatic cancer harbor­ing mutant K-ras.

Original languageEnglish (US)
Pages (from-to)5653-5665
Number of pages13
JournalInternational Journal of Nanomedicine
Volume9
Issue number1
DOIs
Publication statusPublished - 2014

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ASJC Scopus subject areas

  • Biophysics
  • Bioengineering
  • Biomaterials
  • Organic Chemistry
  • Drug Discovery

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