Triggering Polymeric Nanoparticle Disassembly through the Simultaneous Application of Two Different Stimuli

Abstract

Polymeric nanoparticles whose disassembly into their component polymer chains is triggered by the simultaneous application of two different stimuli are described. Reversible addition–fragmentation chain transfer (RAFT) polymerization was utilized to prepare acrylamide-based linear copolymers displaying pyridyl disulfide appendages and either aldehyde or amine functional groups. These copolymer chains were intermolecularly cross-linked through imine bond formation at pH 8.0 and then through disulfide bond formation to afford polymeric nanoparticles possessing hydrodynamic radii of 76 nm consisting of multiple polymer chains cross-linked through both imine and disulfide bonds. By performing the cross-linking reactions in the presence of the hydrophobic dye Nile Red, it was demonstrated that these polymeric nanoparticles could encapsulate a cargo of small hydrophobic molecules. The disassembly of the polymeric nanoparticles into their component polymer chains was accomplished by lowing the pH to 5.5 in the presence of the disulfide reducing agent tris(2-carboxyethyl)phosphine (TCEP), causing hydrolysis of the imine cross-links and cleavage of the disulfide cross-links, respectively, and demonstrating that the simultaneous application of both low pH and a reducing environment are required to trigger the disassembly process. It was shown that application of either a low pH or the application of the reducing agent TCEP does not trigger the disassembly of the polymeric nanoparticle as there is sufficient density of the remaining imine or disulfide cross-links which are able to maintain the structural integrity of the polymeric nanoparticle. The formation and disassembly processes of these polymeric nanoparticles was monitored by gel permeation chromatography, and the release of the dye was monitored using fluorescence spectroscopy. A 5 kDa poly(ethylene glycol) was grafted onto the polymeric nanoparticle, demonstrating the potential of these polymeric nanoparticles to undergo post-assembly functionalization.