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

George Mattheolabakis, Ruixue Wang, Basil Rigas, Gerardo Mackenzie

Research output: Contribution to journalArticle

4 Citations (Scopus)

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. Phosphovalproic 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 acidpoly( 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. I n conclusion, P-V is a promising agent against PC, and its formulation in PLLA-PEG nanoparticles enhances its efficacy by improving its pharmacokinetics.

Original languageEnglish (US)
Pages (from-to)1035-1044
Number of pages10
JournalInternational Journal of Oncology
Volume51
Issue number4
DOIs
StatePublished - Oct 1 2017

Fingerprint

Ethylene Glycol
Valproic Acid
Pancreatic Neoplasms
Nanoparticles
Acids
Growth
Milk
Metaplasia
Heterografts
Pharmacokinetics
poly(lactic acid)
Pancreatitis
Antineoplastic Agents
Phosphorylation
Drug Therapy

Keywords

  • Pancreatic Cancer
  • Phospho-Valproic Acid
  • PLLA-PEG Nanoparticles
  • Polymeric Nanoparticles
  • STAT3

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Phospho-valproic acid inhibits pancreatic cancer growth in mice : Enhanced efficacy by its formulation in poly-(L)-lactic acid-poly(ethylene glycol) nanoparticles. / Mattheolabakis, George; Wang, Ruixue; Rigas, Basil; Mackenzie, Gerardo.

In: International Journal of Oncology, Vol. 51, No. 4, 01.10.2017, p. 1035-1044.

Research output: Contribution to journalArticle

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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. Phosphovalproic 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 acidpoly( 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. I n 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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