title: Nanoparticle delivery of an AKT/PDK1 inhibitor improves the therapeutic effect in pancreatic cancer.
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.
authors.affiliation: Department of Chemical and Environmental Engineering, University of Arizona, Tucson, AZ, USA.
authors.forename: Armando
authors.initials: A
authors.lastname: Lucero-Acuña
authors.affiliation: Department of Biomedical Engineering, University of Arizona, Tucson, AZ, USA.
authors.forename: Justin J
authors.initials: JJ
authors.lastname: Jeffery
authors.affiliation: University of Arizona Cancer Center, University of Arizona, Tucson, AZ, USA ; Department of Pathology, University of Arizona, Tucson, AZ, USA.
authors.forename: Edward R
authors.initials: ER
authors.lastname: Abril
authors.affiliation: University of Arizona Cancer Center, University of Arizona, Tucson, AZ, USA ; Department of Pathology, University of Arizona, Tucson, AZ, USA.
authors.forename: Raymond B
authors.initials: RB
authors.lastname: Nagle
authors.affiliation: Department of Chemical and Environmental Engineering, University of Arizona, Tucson, AZ, USA.
authors.forename: Roberto
authors.initials: R
authors.lastname: Guzman
authors.affiliation: Department of Biomedical Engineering, University of Arizona, Tucson, AZ, USA ; University of Arizona Cancer Center, University of Arizona, Tucson, AZ, USA ; Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ, USA ; Department of Medical Imaging, University of Arizona, Tucson, AZ, USA.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Pagel
authors.affiliation: University of Arizona Cancer Center, University of Arizona, Tucson, AZ, USA ; Department of Molecular and Cell Biology, University of Arizona, Tucson, AZ, USA ; Department of Nutritional Sciences, University of Arizona, Tucson, AZ, USA.
authors.forename: Emmanuelle J
authors.initials: EJ
authors.lastname: Meuillet
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000737:chemistry; D005260:Female; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry; D051379:Mice; D016513:Mice, SCID; D053758:Nanoparticles / Q000737:chemistry*; D061848:Optical Imaging; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D047428:Protein Kinase Inhibitors; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D051057:Proto-Oncogene Proteins c-akt
keywords: AKT; bioluminescence imaging; drug delivery; nanoparticles; pancreatic cancer