UV-mediated thiol-ene click reactions for the synthesis of drug-loadable and degradable gels based on copoly(2-oxazoline)s

Abstract

An 80-membered library of gels composed of monofunctional 2-ethyl-2-oxazoline and 2-nonyl-2-oxazoline and one of four selected difunctional 2-oxazolines (containing either ether or ester bonds) were synthesized by microwave-assisted ring-opening polymerizations. The difunctional 2-oxazolines were prepared from the thiol-ene reaction of glycol dimercaptoacetate or 2,2′-(ethylenedioxy)diethanethiol and 2-but-3′-enyl-2-oxazoline or 2-dec-9′-enyl-2-oxazoline. 53 of the gels exhibited glass-transition temperatures, which ranged from −5.9 to 45.3 °C. 13 Derivatives exhibited glass-transition temperatures in the range from 20 to 30 °C, which renders them stiff at room temperature and flexible at body temperature. The gels that did not contain any 2-ethyl-2-oxazoline acted as lipogels, whereas the gels that did not contain any 2-nonyl-2-oxazoline acted as hydrogels; all other gels may be classified as amphigels. The swelling degrees were measured by gravimetry and maximum swelling degrees of 6 (in water) were observed for the gels with the lowest degrees of crosslinking. In a second approach, the synthesis of crosslinked networks had been achieved by performing the polymeranalogous thiol-ene reaction of copoly(2-oxazoline)s containing olefinic side-chains and glycol dimercaptoacetate. This soft strategy enabled the straightforward loading of such gels with active pharmaceutical ingredients without altering them. This method delivered gels with selected composition exhibiting a targeted disc-shape and loaded with active pharmaceutical ingredients from one-step syntheses. The maximum swelling degrees of these specimens were found to be in accordance with the ones from the first route investigated. Preliminary degradation studies were performed at 25 °C; these types of gels were found to be degraded in alkaline media as well as by esterases.

Poly(2‐oxazoline) Hydrogels: State‐of‐the‐Art and Emerging Applications

“…Wiesbrock and co‐workers have demonstrated this approach by making libraries of hydrogels incorporating ethyl, butenyl, nonyl, and decenyl side‐chains that were used to encapsulate active pharmaceutical ingredients. They used two routes to synthesize the hydrogels—either using bifunctional monomers prepared via thiol‐ene photochemistry of alkene functional 2‐oxazoline monomers with dithiols including an ester as degradable linker followed by microwave assisted polymerization, or first the formation of polymers followed by thiol‐ene photocross‐linking.…”

New Developments in Material Preparation Using a Combination of Ionic Liquids and Microwave Irradiation

“…Cationic ring opening polymerization (CROP) is an easy route to synthesize poly(2-oxazoline)s (POxs) [91,92,93]. POxs are functionalized polymers with various applications, however, they often have low polymerization rates and high VOC emissions during their production which limits their vast development [94,95,96].…”

Polythioethers with Controlled α,ω‐End Groups Prepared by Visible Light Induced Thiol–Ene Click Polymerization of Dithiol and Divinyl Ether with 4‐(N,N‐diphenylamino)benzaldehyde as Organocatalyst

“…The thiol–ene click reaction could be activated by either heat or light without metal catalysts, it has penetrated into many fields such as medicine, biology, and automotive industry. [ 12–22 ] The reaction of thiols with enes, whether proceeding by a radical (termed thiol–ene reaction) or anionic chain (termed thiol Michael addition) reactions. [ 5 ] The ideal thiol–ene radical reaction revolves around the alternation between thiyl radical propagation across the ene functional group and the chain‐transfer reaction.…”