Nitric oxide release: part I. Macromolecular scaffolds

Abstract

The roles of nitric oxide (NO) in physiology and pathophysiology merit the use of NO as a therapeutic for certain biomedical applications. Unfortunately, limited NO payloads, too rapid NO release, and the lack of targeted NO delivery have hindered the clinical utility of NO gas and low molecular weight NO donor compounds. A wide-variety of NO-releasing macromolecular scaffolds has thus been developed to improve NO's pharmacological potential. In this tutorial review, we provide an overview of the most promising NO release scaffolds including protein, organic, inorganic, and hybrid organic-inorganic systems. The NO release vehicles selected for discussion were chosen based on their enhanced NO storage, tunable NO release characteristics, and potential as therapeutics.

Figure 1

Representation of macromolecular vesicles encapsulating A) gaseous NO or B) LMW NO donor compounds (blue spheres). Nitric oxide freely diffuses from the scaffold when encapsulated as a gas, but water diffusion through the scaffold shell is necessary to initiate NO release when LMW NO donors are employed.

Figure 2

Representation of generation 3 polyamidoamine (PAMAM) dendrimer as a typical dendritic scaffold exhibiting highly branched and defined architecture with resulting surface functionalities modified as NO donors (blue spheres)..

Figure 3

Representations of A) a MOF with chemisorbed NO at its metal sites (red spheres) and B) of IRMOF-3 with diazeniumdiolate formation on its organic bridging ligands.

Figure 4

Representations of NO-releasing silica particles modified with NO donors (blue spheres) A) via surface grafting, B) after particle synthesis and C) on silane precursors before particle synthesis via sol-gel chemistry. Cross section of particle interior depicts a lack of functionality within surface-grafted particles and the presence of non-modified precursor functionalities (white circles) within traditional sol-gel synthesized particles.

Figure 5

Representations of strategies to fabricate NO-releasing surfaces including A) doping of LMW NO donors (small blue spheres), B) covalent tethering of NO donor functionalities to the polymer backbone, and C) doping of NO-releasing macromolecular scaffolds (large blue spheres) within the polymer. Leaching of LMW dopants and the limited NO reservoir of covalently-modified polymers are schematically depicted.

Figure 6

Representation of a multifunctionalized NO release scaffold outfitted with multiple NO donors (blue spheres), fluorescent labels (pink stars) for vehicle tracking, and targeting ligands (orange cubes) and a magnetic core (green sphere) for targeted NO delivery.

Scheme 1

N-Diazeniumdiolate formation and decomposition of representative secondary amine-bearing compounds, illustrating the difference between metal cation and protonated amine formation and stabilization.

Scheme 2

S-Nitrosothiol formation and decomposition.