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-coglycolic) acid (PLGA) nanoparticles.Methods-PHT-427 was encapsulated in single-emulsion and double-emulsion PLGA nanoparticles . 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 MiaPaCa-2 pancreatic cancer. Anatomical MRI was used to noninvasively assess the effects of four 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 HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript 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.