Micelles for Delivery of Nitric Oxide

Abstract

We designed block copolymer pro-amphiphiles and amphiphiles for providing very long-term release of nitric oxide (NO). A block copolymer of N-acryloylmorpholine (AM, as a hydrophile) and N-acryloyl-2,5-dimethylpiperazine (AZd, as a hydrophilic precursor) was synthesized. The poly(N-acryloyl-2,5-dimethylpiperazine) (PAZd) is water-soluble, but chemical reaction of the secondary amines with NO to form a N-diazeniumdiolate (NONOate) converts the hydrophilic PAZd into a hydrophobic poly(sodium-1-(N-acryloyl-2,5-dimethylpiperazin-1-yl)diazen-1-ium-1,2-diolate) (PAZd.NONOate), driving aggregation. The PAM block guides this process toward micellization, rather than precipitation, yielding ca. 50 nm spherical micelles. The hydrophobic core of the micelle shielded the NONOate from the presence of water, and thus protons, which are required for NO liberation, delaying release to a remarkable 7 d half-life. Release of the NO returned the original soluble polymer. The very small NO-loaded micelles were able to penetrate complex tissue structures, such as the arterial media, opening up a number of tissue targets to NO-based therapy.

Restenosis Treatments Using Nanoparticle-based Drug Delivery Systems

“…This strategy increased the drug loading efficiency and prolonged drug release by reducing the initial burst release. When tested in a rabbit model, this polymeric drug-eluting stent led to reduced inflammation and in-stent restenosis, while at the same time avoiding delayed reendothelialization due to drug overdose [45]. Micelles have also been used to sustain the release of nitric oxide.…”

“…Micelles have also been used to sustain the release of nitric oxide. Nitric oxide is a potent vasodilator which acts by inducing endothelialdependent relaxation of blood vessels and modulating the tone of SMCs, but limited by its short half-life in tissues (4-15 s) [45]. Jo et al designed a ~50 nm spherical micelle produced from block copolymer pro-amphiphiles and amphiphiles to deliver a nitric oxide donor/prodrug that extended nitric oxide release to a remarkable 7 day half-life [45] (Fig.…”

“…Moreover, these micelle-NO donor conjugates could penetrate complex tissue structures such as arterial media, suggesting their potential for anti-restenotic therapies, possibly as an adjunct to anti-proliferative therapies [45]. Another example is NK911 (Fig.…”

Glucose Sensor Membranes for Mitigating the Foreign Body Response

“…71,72 Since NO is a gas, its storage and delivery has been achieved using NO donors. 73,74 A number of macromolecular scaffolds capable of NO storage and delivery have been reported, including xerogels, [75][76][77] silica nanoparticles, [78][79][80] dendrimers, 81,82 micelles, 83 NO donor-doped polymer matrices, [84][85][86] and synthetic polymers. [87][88][89] The NO release trigger depends on the NO donor employed but may be as simple as water or heat.…”

The formation of an anti-restenotic/anti-thrombotic surface by immobilization of nitric oxide synthase on a metallic carrier

“…In an attempt to develop NO-donors which could provide controlled and prolonged release of NO, several types of NO-donors have been designed and evaluated both in vivo and in vitro [34][35][36][37][38][39][40]. Recently, NO-donors-used as restenosis inhibitors-have also been incorporated into stents [37,[39][40][41][42][43]. Although the release of NO from biomaterials has been shown to reduce neointimal hyperplasia formation, the duration of NO release remains a critical factor.…”