Limits...
Nanoparticle delivery of an AKT/PDK1 inhibitor improves the therapeutic effect in pancreatic cancer.

Lucero-Acuña A, Jeffery JJ, Abril ER, Nagle RB, Guzman R, Pagel MD, Meuillet EJ - Int J Nanomedicine (2014)

Bottom Line: To increase the therapeutic effect of PH-427 against the MiaPaCa-2 pancreatic cancer model with mutant K-ras, we encapsulated PH-427 into poly(lactic-co-glycolic acid) nanoparticles (PNP) to form drug-loaded PH-427-PNP.In vivo studies of an orthotopic MiaPaCa-2 pancreatic cancer model showed reduced tumor load with PH-427-PNP as compared with treatment using PH-427 alone or with no treatment.Ex vivo studies confirmed the in vivo results, suggesting that PNP can improve drug delivery to pancreatic cancer harboring mutant K-ras.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical and Environmental Engineering, University of Arizona, Tucson, AZ, USA.

ABSTRACT
The K-ras mutation in pancreatic cancer can inhibit drug delivery and increase drug resistance. This is exemplified by the therapeutic effect of PH-427, a small molecule inhibitor of AKT/PDK1, which has shown a good therapeutic effect against a BxPC3 pancreatic cancer model that has K-ras, but has a poor therapeutic effect against a MiaPaCa-2 pancreatic cancer model with mutant K-ras. To increase the therapeutic effect of PH-427 against the MiaPaCa-2 pancreatic cancer model with mutant K-ras, we encapsulated PH-427 into poly(lactic-co-glycolic acid) nanoparticles (PNP) to form drug-loaded PH-427-PNP. PH-427 showed a biphasic release from PH-427-PNP over 30 days during studies in sodium phosphate buffer, and in vitro studies revealed that the PNP was rapidly internalized into MiaPaCa-2 tumor cells, suggesting that PNP can improve PH-427 delivery into cells harboring mutant K-ras. In vivo studies of an orthotopic MiaPaCa-2 pancreatic cancer model showed reduced tumor load with PH-427-PNP as compared with treatment using PH-427 alone or with no treatment. Ex vivo studies confirmed the in vivo results, suggesting that PNP can improve drug delivery to pancreatic cancer harboring mutant K-ras.

Show MeSH

Related in: MedlinePlus

Fluorescence images show that Rhodamine-PNP were internalized in MiaPaCa-2 pancreatic cancer cells following 1 hour and 24 hours of treatment of the cells. Cells were visualized by detecting a 4′,6-diamidino-2-phenylindole (DAPI) stain (top), and Rhodamine-labeled PNP were visualized by detecting Rhodamine (bottom).Abbreviation: PNP, poly(lactic-co-glycolic acid) polymeric nanoparticles.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4263440&req=5

f3-ijn-9-5653: Fluorescence images show that Rhodamine-PNP were internalized in MiaPaCa-2 pancreatic cancer cells following 1 hour and 24 hours of treatment of the cells. Cells were visualized by detecting a 4′,6-diamidino-2-phenylindole (DAPI) stain (top), and Rhodamine-labeled PNP were visualized by detecting Rhodamine (bottom).Abbreviation: PNP, poly(lactic-co-glycolic acid) polymeric nanoparticles.

Mentions: Using fluorescence microscopy, MiaPaCa-2 cells treated with Rhodamine-PNP demonstrated cellular uptake of PNP within 1 hour, as demonstrated by Rhodamine fluorescence surrounding and within the cell nuclei that was localized with DAPI fluorescence (Figure 3). Cells retained fluorescence after 24 hours of incubation with Rhodamine-PNP. These results demonstrated the cellular uptake of the PNP, and suggested that an intracellular environment surrounded the PNP during the in vitro studies, which differed from the purely aqueous environment used to test the release of PH-427 during chemical solution studies.


Nanoparticle delivery of an AKT/PDK1 inhibitor improves the therapeutic effect in pancreatic cancer.

Lucero-Acuña A, Jeffery JJ, Abril ER, Nagle RB, Guzman R, Pagel MD, Meuillet EJ - Int J Nanomedicine (2014)

Fluorescence images show that Rhodamine-PNP were internalized in MiaPaCa-2 pancreatic cancer cells following 1 hour and 24 hours of treatment of the cells. Cells were visualized by detecting a 4′,6-diamidino-2-phenylindole (DAPI) stain (top), and Rhodamine-labeled PNP were visualized by detecting Rhodamine (bottom).Abbreviation: PNP, poly(lactic-co-glycolic acid) polymeric nanoparticles.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4263440&req=5

f3-ijn-9-5653: Fluorescence images show that Rhodamine-PNP were internalized in MiaPaCa-2 pancreatic cancer cells following 1 hour and 24 hours of treatment of the cells. Cells were visualized by detecting a 4′,6-diamidino-2-phenylindole (DAPI) stain (top), and Rhodamine-labeled PNP were visualized by detecting Rhodamine (bottom).Abbreviation: PNP, poly(lactic-co-glycolic acid) polymeric nanoparticles.
Mentions: Using fluorescence microscopy, MiaPaCa-2 cells treated with Rhodamine-PNP demonstrated cellular uptake of PNP within 1 hour, as demonstrated by Rhodamine fluorescence surrounding and within the cell nuclei that was localized with DAPI fluorescence (Figure 3). Cells retained fluorescence after 24 hours of incubation with Rhodamine-PNP. These results demonstrated the cellular uptake of the PNP, and suggested that an intracellular environment surrounded the PNP during the in vitro studies, which differed from the purely aqueous environment used to test the release of PH-427 during chemical solution studies.

Bottom Line: To increase the therapeutic effect of PH-427 against the MiaPaCa-2 pancreatic cancer model with mutant K-ras, we encapsulated PH-427 into poly(lactic-co-glycolic acid) nanoparticles (PNP) to form drug-loaded PH-427-PNP.In vivo studies of an orthotopic MiaPaCa-2 pancreatic cancer model showed reduced tumor load with PH-427-PNP as compared with treatment using PH-427 alone or with no treatment.Ex vivo studies confirmed the in vivo results, suggesting that PNP can improve drug delivery to pancreatic cancer harboring mutant K-ras.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical and Environmental Engineering, University of Arizona, Tucson, AZ, USA.

ABSTRACT
The K-ras mutation in pancreatic cancer can inhibit drug delivery and increase drug resistance. This is exemplified by the therapeutic effect of PH-427, a small molecule inhibitor of AKT/PDK1, which has shown a good therapeutic effect against a BxPC3 pancreatic cancer model that has K-ras, but has a poor therapeutic effect against a MiaPaCa-2 pancreatic cancer model with mutant K-ras. To increase the therapeutic effect of PH-427 against the MiaPaCa-2 pancreatic cancer model with mutant K-ras, we encapsulated PH-427 into poly(lactic-co-glycolic acid) nanoparticles (PNP) to form drug-loaded PH-427-PNP. PH-427 showed a biphasic release from PH-427-PNP over 30 days during studies in sodium phosphate buffer, and in vitro studies revealed that the PNP was rapidly internalized into MiaPaCa-2 tumor cells, suggesting that PNP can improve PH-427 delivery into cells harboring mutant K-ras. In vivo studies of an orthotopic MiaPaCa-2 pancreatic cancer model showed reduced tumor load with PH-427-PNP as compared with treatment using PH-427 alone or with no treatment. Ex vivo studies confirmed the in vivo results, suggesting that PNP can improve drug delivery to pancreatic cancer harboring mutant K-ras.

Show MeSH
Related in: MedlinePlus