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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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Relative in vitro cell survival following drug treatments.Notes: (A, B) BxPC3 and MiaPaCa-2 cell lines were treated once with PH-427 alone, and then evaluated with a methylthiazole tetrazolium (MTT) assay each day for 7 consecutive days. The results showed a lower therapeutic response for MiaPaCa-2 cells than for BxPC3 cells (P<0.001). (C, D) BxPC3 and MiaPaCa-2 cell lines were treated once with PNP loaded with the PH-427 chemotherapeutic agent (PH-427-PNP). The concentration of PH-427 was assumed to be the concentration recorded following the biphasic release effect. The percent cell survival was measured daily with a standard MTT microcytotoxicity assay for 7 consecutive days. These results showed that encapsulating PH-427 in the PNP improved the therapeutic efficacy in MiaPaCa-2 pancreatic cancer (B versus D; P<0.01), and had the same therapeutic efficacy against BxPC3 pancreatic cancer (A versus C; P>0.05), relative to treatment with PH-427 alone. (E, F) Results for C and D were re-evaluated by assuming that the concentration of PH-427 was the total concentration of drug in the PNP that was added to the cell system. Encapsulating PH-427 in the PNP did not improve therapeutic efficacy against MiaPaCa-2 pancreatic cancer (B versus F; P>0.05), and inclusion of PNP reduced the therapeutic efficacy against BxPC3 pancreatic cancer (A versus E; P<0.01). The error bars in each graph represent the standard deviation of each measurement (n=4).Abbreviation: PNP, poly(lactic-co-glycolic acid) polymeric nanoparticles.
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f4-ijn-9-5653: Relative in vitro cell survival following drug treatments.Notes: (A, B) BxPC3 and MiaPaCa-2 cell lines were treated once with PH-427 alone, and then evaluated with a methylthiazole tetrazolium (MTT) assay each day for 7 consecutive days. The results showed a lower therapeutic response for MiaPaCa-2 cells than for BxPC3 cells (P<0.001). (C, D) BxPC3 and MiaPaCa-2 cell lines were treated once with PNP loaded with the PH-427 chemotherapeutic agent (PH-427-PNP). The concentration of PH-427 was assumed to be the concentration recorded following the biphasic release effect. The percent cell survival was measured daily with a standard MTT microcytotoxicity assay for 7 consecutive days. These results showed that encapsulating PH-427 in the PNP improved the therapeutic efficacy in MiaPaCa-2 pancreatic cancer (B versus D; P<0.01), and had the same therapeutic efficacy against BxPC3 pancreatic cancer (A versus C; P>0.05), relative to treatment with PH-427 alone. (E, F) Results for C and D were re-evaluated by assuming that the concentration of PH-427 was the total concentration of drug in the PNP that was added to the cell system. Encapsulating PH-427 in the PNP did not improve therapeutic efficacy against MiaPaCa-2 pancreatic cancer (B versus F; P>0.05), and inclusion of PNP reduced the therapeutic efficacy against BxPC3 pancreatic cancer (A versus E; P<0.01). The error bars in each graph represent the standard deviation of each measurement (n=4).Abbreviation: PNP, poly(lactic-co-glycolic acid) polymeric nanoparticles.

Mentions: PCA cell viabilities following treatment with PH-427 or PH-427-PNP were evaluated with BxPC3 and MiaPaCa-2 PCA cell lines (Figure 4A and B). PH-427 caused greater cytotoxicity in BxPC3 PCA with wild-type K-ras relative to MiaPaCa-2 PCA with mutant K-ras (Figure 4A and B), which agreed with our previous results.12,13 The average IC50 value for PH-427 against BxPC3 and MiaPaCa-2 PCA was 46.5±2.5 μM and 93.8±2.7 μM, respectively, with a statistically significant difference (P<0.001).


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)

Relative in vitro cell survival following drug treatments.Notes: (A, B) BxPC3 and MiaPaCa-2 cell lines were treated once with PH-427 alone, and then evaluated with a methylthiazole tetrazolium (MTT) assay each day for 7 consecutive days. The results showed a lower therapeutic response for MiaPaCa-2 cells than for BxPC3 cells (P<0.001). (C, D) BxPC3 and MiaPaCa-2 cell lines were treated once with PNP loaded with the PH-427 chemotherapeutic agent (PH-427-PNP). The concentration of PH-427 was assumed to be the concentration recorded following the biphasic release effect. The percent cell survival was measured daily with a standard MTT microcytotoxicity assay for 7 consecutive days. These results showed that encapsulating PH-427 in the PNP improved the therapeutic efficacy in MiaPaCa-2 pancreatic cancer (B versus D; P<0.01), and had the same therapeutic efficacy against BxPC3 pancreatic cancer (A versus C; P>0.05), relative to treatment with PH-427 alone. (E, F) Results for C and D were re-evaluated by assuming that the concentration of PH-427 was the total concentration of drug in the PNP that was added to the cell system. Encapsulating PH-427 in the PNP did not improve therapeutic efficacy against MiaPaCa-2 pancreatic cancer (B versus F; P>0.05), and inclusion of PNP reduced the therapeutic efficacy against BxPC3 pancreatic cancer (A versus E; P<0.01). The error bars in each graph represent the standard deviation of each measurement (n=4).Abbreviation: PNP, poly(lactic-co-glycolic acid) polymeric nanoparticles.
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Related In: Results  -  Collection

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

f4-ijn-9-5653: Relative in vitro cell survival following drug treatments.Notes: (A, B) BxPC3 and MiaPaCa-2 cell lines were treated once with PH-427 alone, and then evaluated with a methylthiazole tetrazolium (MTT) assay each day for 7 consecutive days. The results showed a lower therapeutic response for MiaPaCa-2 cells than for BxPC3 cells (P<0.001). (C, D) BxPC3 and MiaPaCa-2 cell lines were treated once with PNP loaded with the PH-427 chemotherapeutic agent (PH-427-PNP). The concentration of PH-427 was assumed to be the concentration recorded following the biphasic release effect. The percent cell survival was measured daily with a standard MTT microcytotoxicity assay for 7 consecutive days. These results showed that encapsulating PH-427 in the PNP improved the therapeutic efficacy in MiaPaCa-2 pancreatic cancer (B versus D; P<0.01), and had the same therapeutic efficacy against BxPC3 pancreatic cancer (A versus C; P>0.05), relative to treatment with PH-427 alone. (E, F) Results for C and D were re-evaluated by assuming that the concentration of PH-427 was the total concentration of drug in the PNP that was added to the cell system. Encapsulating PH-427 in the PNP did not improve therapeutic efficacy against MiaPaCa-2 pancreatic cancer (B versus F; P>0.05), and inclusion of PNP reduced the therapeutic efficacy against BxPC3 pancreatic cancer (A versus E; P<0.01). The error bars in each graph represent the standard deviation of each measurement (n=4).Abbreviation: PNP, poly(lactic-co-glycolic acid) polymeric nanoparticles.
Mentions: PCA cell viabilities following treatment with PH-427 or PH-427-PNP were evaluated with BxPC3 and MiaPaCa-2 PCA cell lines (Figure 4A and B). PH-427 caused greater cytotoxicity in BxPC3 PCA with wild-type K-ras relative to MiaPaCa-2 PCA with mutant K-ras (Figure 4A and B), which agreed with our previous results.12,13 The average IC50 value for PH-427 against BxPC3 and MiaPaCa-2 PCA was 46.5±2.5 μM and 93.8±2.7 μM, respectively, with a statistically significant difference (P<0.001).

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