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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.

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Characterization of the nanoparticles.Notes: (A) Scanning electron microscopy images show a smooth surface for PLGA polymeric nanoparticles and drug-loaded PH-427-PNP. (B) Dynamic light scattering spectra of PNP and PH-427-PNP were used to determine the average diameter and polydispersity index of each nanoparticle, based on an average of ten measurements. (C) Experimental release of PH-427 from the PNP was performed in phosphate-buffered saline at pH 7.4 and 37°C, and then fit to a model that evaluates initial burst and slow relaxation of drug release.Abbreviation: PLGA, poly(lactic-co-glycolic acid); PNP, poly(lactic-co-glycolic acid) polymeric nanoparticles.
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f2-ijn-9-5653: Characterization of the nanoparticles.Notes: (A) Scanning electron microscopy images show a smooth surface for PLGA polymeric nanoparticles and drug-loaded PH-427-PNP. (B) Dynamic light scattering spectra of PNP and PH-427-PNP were used to determine the average diameter and polydispersity index of each nanoparticle, based on an average of ten measurements. (C) Experimental release of PH-427 from the PNP was performed in phosphate-buffered saline at pH 7.4 and 37°C, and then fit to a model that evaluates initial burst and slow relaxation of drug release.Abbreviation: PLGA, poly(lactic-co-glycolic acid); PNP, poly(lactic-co-glycolic acid) polymeric nanoparticles.

Mentions: The PNP was synthesized with 1% w/w PH-427 following a single nanoemulsion method to create PH-427-PNP, resulting in an 18.8% encapsulation efficiency (Figure 1). Both PNP had a smooth surface as depicted by scanning electron microscopy (Figure 2A). Dynamic light scattering spectra confirmed the average diameter of PNP to be 165±2.2 nm with a polydispersity index of 0.063±0.001, while the average diameter of PH-427-PNP was 274±0.9 nm with a polydispersity index of 0.39±0.027 (Figure 2B).


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)

Characterization of the nanoparticles.Notes: (A) Scanning electron microscopy images show a smooth surface for PLGA polymeric nanoparticles and drug-loaded PH-427-PNP. (B) Dynamic light scattering spectra of PNP and PH-427-PNP were used to determine the average diameter and polydispersity index of each nanoparticle, based on an average of ten measurements. (C) Experimental release of PH-427 from the PNP was performed in phosphate-buffered saline at pH 7.4 and 37°C, and then fit to a model that evaluates initial burst and slow relaxation of drug release.Abbreviation: PLGA, poly(lactic-co-glycolic acid); PNP, poly(lactic-co-glycolic acid) polymeric nanoparticles.
© Copyright Policy
Related In: Results  -  Collection

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

f2-ijn-9-5653: Characterization of the nanoparticles.Notes: (A) Scanning electron microscopy images show a smooth surface for PLGA polymeric nanoparticles and drug-loaded PH-427-PNP. (B) Dynamic light scattering spectra of PNP and PH-427-PNP were used to determine the average diameter and polydispersity index of each nanoparticle, based on an average of ten measurements. (C) Experimental release of PH-427 from the PNP was performed in phosphate-buffered saline at pH 7.4 and 37°C, and then fit to a model that evaluates initial burst and slow relaxation of drug release.Abbreviation: PLGA, poly(lactic-co-glycolic acid); PNP, poly(lactic-co-glycolic acid) polymeric nanoparticles.
Mentions: The PNP was synthesized with 1% w/w PH-427 following a single nanoemulsion method to create PH-427-PNP, resulting in an 18.8% encapsulation efficiency (Figure 1). Both PNP had a smooth surface as depicted by scanning electron microscopy (Figure 2A). Dynamic light scattering spectra confirmed the average diameter of PNP to be 165±2.2 nm with a polydispersity index of 0.063±0.001, while the average diameter of PH-427-PNP was 274±0.9 nm with a polydispersity index of 0.39±0.027 (Figure 2B).

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