Joseph E Kobes1, Iman Daryaei, Christine M Howison, Jordan G Bontrager, Rachael W Sirianni, Emmanuelle J Meuillet, Mark D Pagel. 1. 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.
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.
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: Kyle T Householder; Danielle M DiPerna; Eugene P Chung; Gregory M Wohlleb; Harshil D Dhruv; Michael E Berens; Rachael W Sirianni Journal: Int J Pharm Date: 2015-01-03 Impact factor: 5.875
Authors: Y Kawakami; K Inoue; H Hayashi; W J Wang; H Setoyama; Y J Gu; M Imamura; H Iwata; Y Ikada; M Nozawa; J Miyazaki Journal: Cell Transplant Date: 1997 Sep-Oct Impact factor: 4.139
Authors: Vijaya L Damaraju; David Y Bouffard; Clarence K W Wong; Marilyn L Clarke; John R Mackey; Lorraine Leblond; Carol E Cass; Mike Grey; Henriette Gourdeau Journal: BMC Cancer Date: 2007-07-03 Impact factor: 4.430
Authors: Y Higuchi; P Herrera; P Muniesa; J Huarte; D Belin; P Ohashi; P Aichele; L Orci; J D Vassalli; P Vassalli Journal: J Exp Med Date: 1992-12-01 Impact factor: 14.307
Authors: Yiqiao Liu; Madhusudhana Gargesha; Mohammed Qutaish; Zhuxian Zhou; Peter Qiao; Zheng-Rong Lu; David L Wilson Journal: Sci Rep Date: 2021-09-01 Impact factor: 4.996
Authors: Etienne D Foucher; Clément Ghigo; Salem Chouaib; Jérôme Galon; Juan Iovanna; Daniel Olive Journal: Front Immunol Date: 2018-05-14 Impact factor: 7.561