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Stabilization of the Nitric Oxide (NO) Prodrugs and Anticancer Leads, PABA/NO and Double JS-K, through Incorporation into PEG-Protected Nanoparticles

  1. Author:
    Kumar, V.
    Hong, S. Y.
    Maciag, A. E.
    Saavedra, J. E.
    Adamson, D. H.
    Prud'homme, R. K.
    Keefer, L. K.
    Chakrapani, H.

  2. Author Address

    [Kumar, Varun; Prud'homme, Robert K.] Princeton Univ, Dept Chem Engn, Princeton, NJ 08544 USA. [Hong, Sam Y.; Keefer, Larry K.] NCI, Chem Sect, Lab Comparat Carcinogenesis, Frederick, MD 21702 USA. [Maciag, Anna E.; Saavedra, Joseph E.] NCI, Basic Sci Program, SAIC Frederick, Frederick, MD 21702 USA. [Adamson, Douglas H.] Univ Connecticut, Dept Chem, Storrs, CT 06269 USA. [Adamson, Douglas H.] Univ Connecticut, Inst Mat Sci, Storrs, CT 06269 USA.;Prud'homme, RK, Princeton Univ, Dept Chem Engn, Princeton, NJ 08544 USA.;prudhomm@princeton.edu harinath@iiserpune.ac.in
    1. Year: 2010
    2. Date: Jan-Feb
  2. Journal: Molecular Pharmaceutics
    1. 7
    2. 1
    3. Pages: 291-298
  4. Type of Article: Article
  5. ISSN: 1543-8384
  1. Abstract:

    We report the stabilization of the nitric oxide (NO) prodrugs and anticancer lead compounds, PABA/NO (O-2-{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-dio l-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.

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  2. DOI: 10.1021/mp900245h
  3. View record in Web of Science®
  4. WOS: 000274015900030

Library Notes

  1. Fiscal Year: FY2009-2010
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