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

Abstract

Here we report the stabilization of the nitric oxide (NO) prodrugs and anti-cancer 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 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.

A competitive aggregation model for Flash NanoPrecipitation

“…Thus, as long as there are enough unimers in the system to provide sufficient 'heterogeneous nucleation' sites for the organic, the FNP process should be nearly independent of the chemical composition of the organic (provided that it is at most weakly soluble in the non-solvent). This observation is consistent with experiments [13,[17][18][19][20][21][22][23].…”

“…A promising alternative is Flash NanoPrecipitation (FNP) [13][14][15], wherein the PSD is controlled by co-precipitating an amphiphilic di-block copolymer. The FNP process has been used to produce nanoparticles from a wide range of organic compounds [16][17][18][19][20][21][22][23]. In the FNP process, the organic compound and the block copolymer are initially dissolved in a good solvent in either a pre-mixed or in separate feed streams [13].…”

A comparison of implicit- and explicit-solvent simulations of self-assembly in block copolymer and solute systems

“…1 One solution to this problem is to use amphiphilic block copolymer micelles as "containers" to carry such molecules. [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] The hydrophilic block forms a corona that sterically stabilizes the particles. In order to be useful, such particles must be sufficiently small (50-400 nm in diameter) and biocompatible.…”

Modulated nitric oxide delivery in three-dimensional biomaterials for vascular functionality

“…In mice model biodegradable polymeric particles have been found to increase blood circulation time with reduced liver accumulation. [91] Kumar et al [92] reported the synthesis of NO-releasing PEGylated NPs from different PEG-based block copolymers. The block copolymers were mixed with the NONOate adducts (PABA/NO or Double JS-K) and subjected to processes of a rapid micromixing and precipitation followed with a block-copolymer-directed encapsulation.…”