TY - JOUR
T1 - Improved Treatment of Pancreatic Cancer with Drug Delivery Nanoparticles Loaded with a Novel AKT/PDK1 Inhibitor
AU - Kobes, Joseph E.
AU - Daryaei, Iman
AU - Howison, Christine M.
AU - Bontrager, Jordan G.
AU - Sirianni, Rachael W.
AU - Meuillet, Emmanuelle J.
AU - Pagel, Mark D.
N1 - Funding Information:
This study was supported by National Institutes of Health grants R01CA167183-01 and P50 CA95060. J.E.K. acknowledges support from the United States Army Advanced Civil Schooling Program. E.J.M. has financial interests in PHusis Therapeutics, Inc (San Diego, CA), and the other authors have no conflicts of interest to declare.
Publisher Copyright:
Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
PY - 2016/9/1
Y1 - 2016/9/1
N2 - 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.
AB - 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.
KW - AKT/PDK1 inhibitor
KW - apparent diffusion coefficient (ADC)
KW - magnetic resonance imaging (MRI)
KW - pancreatic cancer
KW - poly(lactic-co-glycolic) acid nanoparticles (PLGA)
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U2 - 10.1097/MPA.0000000000000607
DO - 10.1097/MPA.0000000000000607
M3 - Article
C2 - 26918875
AN - SCOPUS:84959244390
SN - 0885-3177
VL - 45
SP - 1158
EP - 1166
JO - Pancreas
JF - Pancreas
IS - 8
ER -