Stabilization of the Nitric Oxide (NO) Prodrugs and Anticancer Leads, PABA/NO and Double JS-K, through Incorporation into PEG-Protected Nanoparticles
- 15 December 2009
- journal article
- research article
- Published by American Chemical Society (ACS) in Molecular Pharmaceutics
- Vol. 7 (1), 291-298
- https://doi.org/10.1021/mp900245h
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.Keywords
This publication has 47 references indexed in Scilit:
- Effects of Branching Architecture and Linker on the Activity of Hyperbranched Polymer−Drug ConjugatesBioconjugate Chemistry, 2009
- Poly(amidoamine) dendrimer–drug conjugates with disulfide linkages for intracellular drug deliveryBiomaterials, 2009
- Novel Role for Glutathione S-Transferase πJournal of Biological Chemistry, 2009
- Aryl Bis(diazeniumdiolates): Potent Inducers of S-Glutathionylation of Cellular Proteins and Their in Vitro Antiproliferative ActivitiesJournal of Medicinal Chemistry, 2008
- Nitric oxide prodrug JS-K inhibits ubiquitin E1 and kills tumor cells retaining wild-type p53Oncogene, 2008
- Synthesis, mechanistic studies, and anti-proliferative activity of glutathione/glutathione S-transferase-activated nitric oxide prodrugsBioorganic & Medicinal Chemistry, 2008
- TIMP-2 mediates the anti-invasive effects of the nitric oxide-releasing prodrug JS-K in breast cancer cellsBreast Cancer Research, 2008
- Synthesis, nitric oxide release, and anti-leukemic activity of glutathione-activated nitric oxide prodrugs: Structural analogues of PABA/NO, an anti-cancer lead compoundBioorganic & Medicinal Chemistry, 2008
- Synthesis and in vitro anti-leukemic activity of structural analogues of JS-K, an anti-cancer lead compoundBioorganic & Medicinal Chemistry Letters, 2008
- JS-K, a GST-activated nitric oxide generator, induces DNA double-strand breaks, activates DNA damage response pathways, and induces apoptosis in vitro and in vivo in human multiple myeloma cellsBlood, 2007