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

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.

• Authors: Joseph E Kobes, Iman Daryaei, Christine M Howison, Jordan G Bontrager, Rachael W Sirianni, Emmanuelle J Meuillet, Mark D Pagel
• Journal: Pancreas (Pancreas) Vol. 45 Issue 8 Pg. 1158-66 (09 2016) ISSN: 1536-4828 [Electronic] United States
• PMID: 26918875 (Publication Type: Journal Article)

Chemical References

• Pdk1 protein, mouse
• Protein Kinase Inhibitors
• Pyruvate Dehydrogenase Acetyl-Transferring Kinase
• Polyglycolic Acid
• Lactic Acid
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Cell Line, Tumor
• Lactic Acid
• Mice
• Nanoparticles
• Pancreatic Neoplasms
• Polyglycolic Acid
• Protein Kinase Inhibitors
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• Pyruvate Dehydrogenase Acetyl-Transferring Kinase
• Tissue Distribution