Nitrile-Functionalized Poly(2-oxazoline)s as a Versatile Platform for the Development of Polymer Therapeutics

Abstract

In recent years, polymers bearing reactive groups have received significant interest for biomedical applications. Numerous functional polymer platforms have been introduced, which allow for the preparation of materials with tailored properties via post-polymerization modifications. However, because of their reactivity, many functional groups are not compatible with the initial polymerization. The nitrile group is a highly interesting and relatively inert functionality that has mainly received attention in radical polymerizations. In this Article, a nitrile-functionalized 2-oxazoline monomer (2-(4-nitrile-butyl)-2-oxazoline, BuNiOx) is introduced, and its compatibility with the cationic ring-opening polymerization is demonstrated. Subsequently, the versatility of nitrile-functionalized poly­(2-oxazoline)­s (POx) is presented. To this end, diverse (co)­polymers are synthesized and characterized by nuclear resonance spectroscopy, size-exclusion chromatography, and mass spectrometry. Amphiphilic block copolymers are shown to efficiently encapsulate the hydrophobic drug curcumin (CUR) in aqueous solution, and the anti-inflammatory effect of the CUR-containing nanostructures is presented in BV-2 microglia. Furthermore, the availability of the BuNiOx repeating units for post-polymerization modifications with hydroxylamine to yield amidoxime (AO)-functionalized POx is demonstrated. These AO-containing POx were successfully applied for the complexation of Fe­(III) in a quantitative manner. In addition, AO-functionalized POx were shown to release nitric oxide intracellularly in BV-2 microglia. Thus nitrile-functionalized POx represent a promising and robust platform for the design of polymer therapeutics for a wide range of applications.

Poly(2‐oxazoline)s: a comprehensive overview of polymer structures and their physical properties—an update

“…The reported nitrile side chain functionalized PBuNiOx 85 was found to be thermally stable up to at least 350 °C which is in line with other PAOxs with linear alkyl side chains. The polymer showed amorphous behaviour with a T g of 18.5 °C as observed from DSC.…”

“…9). 85 CROP also provides straightforward access of PAOxs with 'clickable handles' in the side chain, such as alkene and alkyne groups, as well as in the chain ends, that can be further employed for postpolymerization modification to construct various functional PAOxs via thiol-ene, 105 thiol-yne and copper(I)-catalysed 'click' reactions. 106…”

“…The reported nitrile side chain functionalized PBuNiOx homopolymers are slightly hydrophobic in nature due to the presence of long alkyl side chains and therefore are found to be poorly soluble in water. 85 However, amidoxime functional poly(2-oxazoline) obtained by post-modification of PBuNiOx is soluble in aqueous medium. The aqueous solubility of PBuNiOx can be enhanced by copolymerization of BuNiOx with hydrophilic MeOx or EtOx monomer.…”

“…2). 85 Nitrile functionalized poly(2‐oxazoline)s are indeed interesting as they provide access to further new functionalities via several post‐modification approaches such as nucleophilic addition, reduction, cycloaddition and hydrolysis. The BuNiOx monomer was synthesized from adiponitrile and ethanol amine in the presence of a catalytic amount of Cd(OAc) 2 via the Witte–Seeliger process (Fig.…”

Virtual Issue: Organocatalysis in Polymer Science

“…This nitrile group is not only compatible with the polymerization conditions but also allowed for the introduction of amidoxine moieties into polyoxazolidones, which were shown to release nitric oxide intracellularly in BV-2 microglia. 16 One of the main limitations for the biomedical applications of polyoxazolidones is their lack of biodegradability. In this regard, Hadjichristidis and co-workers found that organocatalysis can be used to prepare biodegradable alternatives to poly(2-oxazoline)s by the ring-opening polymerization of Na c y l a t e d 1 , 4 -o x a z e p a n -7 -o n e s .…”