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.

Multi-stimuli responsive macromolecules and their assemblies

“…44 In this paper, polymeric nanoparticles were prepared by cross-linking aldehyde/disulfide-functionalized copolymers and amine/disulfide-functionalized copolymers (Figure 3) through the formation of benzoic imine and disulfide bonds. It is reported that the benzoic imine bond is stable at pH 7.4 but hydrolyzes in an acidic environment.…”

Schiff's base as a stimuli-responsive linker in polymer chemistry

“…Two copolymers, an aldehyde/disulfide-functionalized copolymer (P1) and an amine/disulfide-functionalized copolymer (P2b), were synthesized as the building blocks to form core crosslinked star (CCS) polymers. 76 To further decorate the CCS polymer, hydrazide end-functionalized poly(ethylene glycol) was synthesized, which could assemble with the CCS polymer based on the formation of a hydrazone bond (Fig. 13).…”

Chitosan-Acrylic Polymeric Nanoparticles with Dynamic Covalent Bonds. Synthesis and Stimuli Behavior

“…Thus, polymerization of monomers M1-M3 in a molar ratio of 1 : 1 : 8 was performed as previously reported, 22) with changes in the monomer with disulfide functionality (M2), which in this work was an acrylate instead of an acrylamide, to obtain the desired polymer P1. Size exclusion chromatography analysis (SEC) of P1 afforded one peak with an average molecular weight (M w ) of 12500 g/mol and a polydispersity index of 2.3.…”

“…[34][35][36] As a matter of fact, this polymer has been used in a wide variety of systems where it has been successfully combined with synthetic polymers having as a result the improvement of various mechanical and biological properties. 37,38) In line with the work of Jackson and Fulton, 22) we wish to report here the synthesis of a a new stimuli-sensitive nanostructured system in which one of the polymeric acrylamide subunits is replaced by thiolate chitosan of semisynthetic origin in order to have a potentially biocompatible material as part of the structural base of the nanoparticles. In addition, the material response towards pH and redox potential stimuli is reported.…”

“…22) This vector has the ability to release the payload when it is exposed to environments with pH under 5.5 and high redox potential. The fact that the carrier must be exposed to two different stimuli at the same time to release the payload represents a tremendous advantage in terms of selectivity of drug release.…”