Stabilization of the nitric oxide (NO) prodrugs and anticancer leads, PABA/NO and double JS-K, through incorporation into PEG-protected nanoparticles

Varun Kumar, Sam Y. Hong, Anna E. Maciag, Joseph E. Saavedra, Douglas H. Adamson, Robert K. Prud'homme, Larry K. Keefer, Harinath Chakrapani

Research output: Contribution to journalArticle

60 Scopus citations

Abstract

We report the stabilization of the nitric oxide (NO) prodrugs and anticancer lead compounds, PABA/NO (O2-{2,4-dinitro-5-[4-(N- methylamino)benzoyloxy]phenyl} 1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate) and "Double JS-K" 1,5-bis-{1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen- 1-ium-1,2-diol-2-ato}-2,4-dinitrobenzene, through their incorporation into polymer-protected nanoparticles. The prodrugs were formulated in block copolymer-stabilized nanoparticles with sizes from 220 to 450 nm by a novel rapid precipitation process. The block copolymers, with polyethylene glycol (PEG) soluble blocks, provide a steric barrier against NO prodrug activation by glutathione. Too rapid activation and NO release has been a major barrier to effective administration of this class of compounds. The nanoparticle stabilized PABA/NO are protected from attack by glutathione as evidenced by a significant increase in time taken for 50% decomposition from 15 min (unformulated) to 5 h (formulated); in the case of Double JS-K, the 50% decomposition time was extended from 4.5 min (unformulated) to 40 min (formulated). The more hydrophobic PABA/NO produced more stable nanoparticles and correspondingly more extended release times in comparison with Double JS-K. The hydrophobic blocks of the polymer were either polystyrene or polylactide. Both blocks produced nanoparticles of approximately the same size and release kinetics. This combination of PEG-protected nanoparticles with sizes appropriate for cancer targeting by enhanced permeation and retention (EPR) and delayed release of NO may afford enhanced therapeutic benefit.

Original languageEnglish (US)
Pages (from-to)291-298
Number of pages8
JournalMolecular Pharmaceutics
Volume7
Issue number1
DOIs
StatePublished - Feb 1 2010

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

Keywords

  • Formulation
  • Glutathione
  • Glutathione S-transferase
  • Nanoparticles
  • Nitric oxide
  • PABA/NO

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