title: Stabilization of the nitric oxide (NO) prodrugs and anticancer leads, PABA/NO and Double JS-K, through incorporation into PEG-protected nanoparticles.
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-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.
authors.affiliation: Department of Chemical Engineering, Princeton University, Princeton, New Jersey 08544, USA.
authors.forename: Varun
authors.initials: V
authors.lastname: Kumar
authors.forename: Sam Y
authors.initials: SY
authors.lastname: Hong
authors.forename: Anna E
authors.initials: AE
authors.lastname: Maciag
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Saavedra
authors.forename: Douglas H
authors.initials: DH
authors.lastname: Adamson
authors.forename: Robert K
authors.initials: RK
authors.lastname: Prud'homme
authors.forename: Larry K
authors.initials: LK
authors.lastname: Keefer
authors.forename: Harinath
authors.initials: H
authors.lastname: Chakrapani
mesh_terms: D010129:4-Aminobenzoic Acid / Q000008:administration & dosage / Q000737:chemistry; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001391:Azo Compounds / Q000008:administration & dosage / Q000737:chemistry; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003692:Delayed-Action Preparations; D004355:Drug Stability; D006801:Humans; D053758:Nanoparticles; D020030:Nitric Oxide Donors / Q000008:administration & dosage* / Q000737:chemistry; D010316:Particle Size; D010879:Piperazines / Q000008:administration & dosage / Q000737:chemistry; D011092:Polyethylene Glycols; D011355:Prodrugs / Q000008:administration & dosage* / Q000737:chemistry; D062366:para-Aminobenzoates
chemical_list: D000970:Antineoplastic Agents; D001391:Azo Compounds; D003692:Delayed-Action Preparations; D020030:Nitric Oxide Donors; C485370:O(2)-(2,4-dinitro-5-(N-methyl-N-4-carboxyphenylamino)phenyl 1-N,N-dimethylamino)diazen-1-ium-1,2-diolate; C474958:O(2)-(2,4-dinitrophenyl) 1-((4-ethoxycarbonyl)piperazin-1-yl)diazen-1-ium-1,2-diolate; D010879:Piperazines; D011355:Prodrugs; D062366:para-Aminobenzoates; D011092:Polyethylene Glycols; D010129:4-Aminobenzoic Acid