Phospho-valproic acid inhibits pancreatic cancer growth in mice: enhanced efficacy by its formulation in poly-(L)-lactic acid-poly(ethylene glycol) nanoparticles Corrigendum in /10.3892/ijo.2018.4584

Mattheolabakis,George; Wang,Ruixue; Rigas,Basil; Mackenzie,Gerardo   G.

doi:10.3892/ijo.2017.4103

Phospho-valproic acid inhibits pancreatic cancer growth in mice: enhanced efficacy by its formulation in poly-(L)-lactic acid-poly(ethylene glycol) nanoparticles

Corrigendum in: /10.3892/ijo.2018.4584

Authors:
- George Mattheolabakis
- Ruixue Wang
- Basil Rigas
- Gerardo G. Mackenzie
View Affiliations

Affiliations: Department of Medicine, Stony Brook University, Stony Brook, NY 11794-8175, USA, Department of Family, Population and Preventive Medicine, Stony Brook University, Stony Brook, NY 11794-8175, USA
Published online on: August 25, 2017 https://doi.org/10.3892/ijo.2017.4103
Pages: 1035-1044
Copyright: © Mattheolabakis et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Pancreatic cancer (PC) is one of the most difficult cancers to treat. Since the current chemotherapy is inadequate and various biological approaches have failed, the need for agents that have a potential to treat PC is pressing. Phospho-valproic acid (P-V), a novel anticancer agent, is efficacious in xenograft models of human PC and is apparently safe. In the present study, we evaluated whether formulating P-V in nanoparticles could enhance its anticancer efficacy. In a mouse model of Kras/pancreatitis-associated PC, P-V, orally administered, inhibited the incidence of acinar-to-ductal metaplasia by 60%. To improve its efficacy, we formulated P-V in five different polymeric nanoparticles. Poly-(L)-lactic acid- poly(ethylene glycol) (PLLA-PEG) nanoparticles proved the optimal formulation. PLLA-PEG improved P-V's pharmacokinetics in mice enhancing the levels of P-V in blood. Compared to control, P-V formulated in PLLA-PEG suppressed the growth of MIA PaCa-2 xenografts by 81%, whereas P-V alone reduced it by 51% (p<0.01). Furthermore, P-V formulated in PLLA-PEG inhibited acinar-to-ductal metaplasia in mice with activated Kras, reducing it by 87% (p<0.02). In both disease models, P-V suppressed STAT3 phosphorylation at the Ser727 and Tyr705 residues; STAT3 is the pivotal molecular target of P-V. In conclusion, P-V is a promising agent against PC, and its formulation in PLLA-PEG nanoparticles enhances its efficacy by improving its pharmacokinetics.

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