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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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Schematic of the procedure for creating PLGA polymeric nanoparticles loaded with the PH-427 chemotherapeutic agent (PH-427-PNP). Emulsification in dichloromethane and water was facilitated by sonication, followed by solvent evaporation and purification using centrifugation.Abbreviations: PLGA, poly(lactic-co-glycolic acid); PVA, poly(vinyl alcohol); PNP, PLGA polymeric nanoparticles.
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f1-ijn-9-5653: Schematic of the procedure for creating PLGA polymeric nanoparticles loaded with the PH-427 chemotherapeutic agent (PH-427-PNP). Emulsification in dichloromethane and water was facilitated by sonication, followed by solvent evaporation and purification using centrifugation.Abbreviations: PLGA, poly(lactic-co-glycolic acid); PVA, poly(vinyl alcohol); PNP, PLGA polymeric nanoparticles.

Mentions: PH-427-PNP and Rhodamine-6G in PNP (Rhodamine-PNP) were prepared with PLGA using a single emulsification method followed by solvent evaporation (Figure 1).21,23 Briefly, 50 mg of PLGA and 2.5 mg of PH-427 or 2.5 mg of Rhodamine-6G were dissolved in 5 mL of dichloromethane. Next, 10 mL of aqueous 5% poly(vinyl alcohol) was added to the organic phase. The mixture was emulsified in an ice bath with an XL2020 ultrasonicator (Misonix Inc., Farmingdale, NY, USA) operating at 55 W power output for 1 minute. The organic solvent was removed with a rotary evaporator operated at 38°C and low agitation velocity for 1 hour. Next, a 10-minute centrifugation cycle at 850 rcf was employed to remove agglomerations, using an IEC Centra-4B centrifuge (International Equipment Inc., Nashville, TN, USA). The solution was washed by three centrifugation cycles at 4,900 rcf for 50 minutes. During the first two centrifugation cycles, the supernatant was removed and PH-427-PNP or Rhodamine-PNP was resuspended in 10 mL of distilled water. On the final centrifugation cycle, the nanoparticles were resuspended in 0.3 mL of 10 mM sodium phosphate buffer with a pH of 7.4.


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)

Schematic of the procedure for creating PLGA polymeric nanoparticles loaded with the PH-427 chemotherapeutic agent (PH-427-PNP). Emulsification in dichloromethane and water was facilitated by sonication, followed by solvent evaporation and purification using centrifugation.Abbreviations: PLGA, poly(lactic-co-glycolic acid); PVA, poly(vinyl alcohol); PNP, PLGA polymeric nanoparticles.
© Copyright Policy
Related In: Results  -  Collection

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

f1-ijn-9-5653: Schematic of the procedure for creating PLGA polymeric nanoparticles loaded with the PH-427 chemotherapeutic agent (PH-427-PNP). Emulsification in dichloromethane and water was facilitated by sonication, followed by solvent evaporation and purification using centrifugation.Abbreviations: PLGA, poly(lactic-co-glycolic acid); PVA, poly(vinyl alcohol); PNP, PLGA polymeric nanoparticles.
Mentions: PH-427-PNP and Rhodamine-6G in PNP (Rhodamine-PNP) were prepared with PLGA using a single emulsification method followed by solvent evaporation (Figure 1).21,23 Briefly, 50 mg of PLGA and 2.5 mg of PH-427 or 2.5 mg of Rhodamine-6G were dissolved in 5 mL of dichloromethane. Next, 10 mL of aqueous 5% poly(vinyl alcohol) was added to the organic phase. The mixture was emulsified in an ice bath with an XL2020 ultrasonicator (Misonix Inc., Farmingdale, NY, USA) operating at 55 W power output for 1 minute. The organic solvent was removed with a rotary evaporator operated at 38°C and low agitation velocity for 1 hour. Next, a 10-minute centrifugation cycle at 850 rcf was employed to remove agglomerations, using an IEC Centra-4B centrifuge (International Equipment Inc., Nashville, TN, USA). The solution was washed by three centrifugation cycles at 4,900 rcf for 50 minutes. During the first two centrifugation cycles, the supernatant was removed and PH-427-PNP or Rhodamine-PNP was resuspended in 10 mL of distilled water. On the final centrifugation cycle, the nanoparticles were resuspended in 0.3 mL of 10 mM sodium phosphate buffer with a pH of 7.4.

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