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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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(A) In vivo inhibition of tumor proliferation and AKT. Representative staining is shown for H&E, Ki-67, tAKT, and high-mobility group AT-hook 2 (HMGA2) of control, PH-427-treated, and PH-427-PNP-treated mice (PH-427-PNP, PNP loaded with the PH-427 chemotherapeutic agent). (B) Long scores for HMGA2 staining for control, PH-427, and PH-427-PNP. The values are the means and the error bars are the standard errors (n=2). All images were acquired with 40× magnification.Abbreviations: H&E, hematoxylin and eosin; PNP, poly(lactic-co-glycolic acid) polymeric nanoparticles; tAKT, total AKT.
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f6-ijn-9-5653: (A) In vivo inhibition of tumor proliferation and AKT. Representative staining is shown for H&E, Ki-67, tAKT, and high-mobility group AT-hook 2 (HMGA2) of control, PH-427-treated, and PH-427-PNP-treated mice (PH-427-PNP, PNP loaded with the PH-427 chemotherapeutic agent). (B) Long scores for HMGA2 staining for control, PH-427, and PH-427-PNP. The values are the means and the error bars are the standard errors (n=2). All images were acquired with 40× magnification.Abbreviations: H&E, hematoxylin and eosin; PNP, poly(lactic-co-glycolic acid) polymeric nanoparticles; tAKT, total AKT.

Mentions: We evaluated the antitumor effects of PH-427 and PH-427-PNP in a MiaPaCa-2-LucE orthotopic PCA model using BLI (Figures 5 and 6). The amplitude of the BLI signal is a semiquantitative indication of the pancreatic tumor load. These imaging results were confirmed by ex vivo necropsy analysis (Figure 6). Control mice with no treatment showed high average BLI signal amplitude from the pancreas, indicating a high pancreatic tumor load. Treatment with PH-427 also showed high average BLI signal amplitude, indicating that the drug had no effect on pancreatic tumor load. This result matched our previous studies with PH-427 in the treatment of the orthotopic tumor model of MiaPaCa-2 without the luciferase gene.13 Treatment with PH-427-PNP showed low average BLI signal amplitude, indicating low tumor load and a significant therapeutic effect by the drug-loaded nanoparticles in this tumor model (P<0.001). The standard deviations represented by error bars in Figure 5B were approximately 10% for each group. This indicated that the BLI study was performed with high fidelity, which is critical for interpreting results from this semiquantitative imaging technique. No change in body weight was observed after treatment with PH-427 alone or with PH-427-PNP, and there were no visual signs of toxicity upon gross examination after each treatment. This evidence indicates that PH-427 and PH-427-PNP were not toxic at the dose levels administered during these 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)

(A) In vivo inhibition of tumor proliferation and AKT. Representative staining is shown for H&E, Ki-67, tAKT, and high-mobility group AT-hook 2 (HMGA2) of control, PH-427-treated, and PH-427-PNP-treated mice (PH-427-PNP, PNP loaded with the PH-427 chemotherapeutic agent). (B) Long scores for HMGA2 staining for control, PH-427, and PH-427-PNP. The values are the means and the error bars are the standard errors (n=2). All images were acquired with 40× magnification.Abbreviations: H&E, hematoxylin and eosin; PNP, poly(lactic-co-glycolic acid) polymeric nanoparticles; tAKT, total AKT.
© Copyright Policy
Related In: Results  -  Collection

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

f6-ijn-9-5653: (A) In vivo inhibition of tumor proliferation and AKT. Representative staining is shown for H&E, Ki-67, tAKT, and high-mobility group AT-hook 2 (HMGA2) of control, PH-427-treated, and PH-427-PNP-treated mice (PH-427-PNP, PNP loaded with the PH-427 chemotherapeutic agent). (B) Long scores for HMGA2 staining for control, PH-427, and PH-427-PNP. The values are the means and the error bars are the standard errors (n=2). All images were acquired with 40× magnification.Abbreviations: H&E, hematoxylin and eosin; PNP, poly(lactic-co-glycolic acid) polymeric nanoparticles; tAKT, total AKT.
Mentions: We evaluated the antitumor effects of PH-427 and PH-427-PNP in a MiaPaCa-2-LucE orthotopic PCA model using BLI (Figures 5 and 6). The amplitude of the BLI signal is a semiquantitative indication of the pancreatic tumor load. These imaging results were confirmed by ex vivo necropsy analysis (Figure 6). Control mice with no treatment showed high average BLI signal amplitude from the pancreas, indicating a high pancreatic tumor load. Treatment with PH-427 also showed high average BLI signal amplitude, indicating that the drug had no effect on pancreatic tumor load. This result matched our previous studies with PH-427 in the treatment of the orthotopic tumor model of MiaPaCa-2 without the luciferase gene.13 Treatment with PH-427-PNP showed low average BLI signal amplitude, indicating low tumor load and a significant therapeutic effect by the drug-loaded nanoparticles in this tumor model (P<0.001). The standard deviations represented by error bars in Figure 5B were approximately 10% for each group. This indicated that the BLI study was performed with high fidelity, which is critical for interpreting results from this semiquantitative imaging technique. No change in body weight was observed after treatment with PH-427 alone or with PH-427-PNP, and there were no visual signs of toxicity upon gross examination after each treatment. This evidence indicates that PH-427 and PH-427-PNP were not toxic at the dose levels administered during these 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