title: Improved Treatment of Pancreatic Cancer With Drug Delivery Nanoparticles Loaded With a Novel AKT/PDK1 Inhibitor.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: From the *Biomedical Engineering Graduate Interdisciplinary Program, University of Arizona, Tucson, AZ; †Chemistry/Life Science Department, United States Military Academy, West Point, NY; Departments of ‡Chemistry and Biochemistry and §Biomedical Engineering, University of Arizona, Tucson, AZ; ∥Barrow Brain Tumor Research Center, Barrow Neurological Institute, Phoenix; and ¶University of Arizona Cancer Center and #Department of Medical Imaging, University of Arizona, Tucson, AZ.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Kobes
authors.forename: Iman
authors.initials: I
authors.lastname: Daryaei
authors.forename: Christine M
authors.initials: CM
authors.lastname: Howison
authors.forename: Jordan G
authors.initials: JG
authors.lastname: Bontrager
authors.forename: Rachael W
authors.initials: RW
authors.lastname: Sirianni
authors.forename: Emmanuelle J
authors.initials: EJ
authors.lastname: Meuillet
authors.forename: Mark D
authors.initials: MD
authors.lastname: Pagel
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D019344:Lactic Acid; D051379:Mice; D053758:Nanoparticles; D010190:Pancreatic Neoplasms; D011100:Polyglycolic Acid; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D014018:Tissue Distribution
chemical_list: C000631433:Pdk1 protein, mouse; D047428:Protein Kinase Inhibitors; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011100:Polyglycolic Acid; D019344:Lactic Acid; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt