‘Charge-Shifting’ Polymers: Control of Ionic Interactions in Polyelectrolyte Assemblies

Cationic polymers interact with anionic materials in aqueous environments to form ionically-crosslinked aggregates and assemblies, and have thus been investigated widely as materials for the non-viral delivery of DNA (and for a range of other applications). Unfortunately, however, the same charge-based interactions that promote the formation of these ionically-crosslinked assemblies also introduce fundamental and significant obstacles to the subsequent disassembly of these complexes (and, thus, a barrier to the effective release of DNA or other agents). The extent to which charge-based interactions between anionic polymers and cationic materials can (or cannot) be controlled underpins the success (or failure) of many conventional approaches to the delivery of DNA, and is, in general, important in a broad range of other fundamental, industrial, and commercial contexts.

We have developed new molecular-level approaches that can be used to disrupt or change the nature of ionic interactions between cationic and anionic polymers in physiologically relevant environments. These efforts have focused on the design and synthesis of new classes of ‘charge-shifting’ cationic polymers that undergo dynamic changes in charge density (e.g., from cationic to anionic, or from cationic to ‘less cationic’) by the chemical hydrolysis of masked anionic side-chain functionality. This approach presents a departure from the design of conventional cationic polymers, which generally have charge densities that are either fixed at the time of synthesis, or that vary only upon changes to pH, ionic strength, etc.

We have demonstrated in several different contexts that these charge-shifting materials can be used to provide control over the assembly and disassembly of aggregates formed with DNA, both in solution and at surfaces and interfaces. For example, the structures of these polymers can be manipulated to provide control over the rates and extents of disassembly of nanoparticle-based polymer/DNA aggregates (e.g., ‘polyplexes’; over periods ranging from hours to weeks), and, as a consequence, to provide control over levels of in vitro cell transfection. These ‘charge-shifting’ materials also provide new mechanisms for control over the disruption of ionic interactions in polyelectrolyte multilayers (PEMs), and can be used to promote and modulate the long-term release of agents (e.g., DNA) from these thin film materials (e.g., over periods of up to 3 months). In this respect, our accomplishments and goals in this area of research are also aligned closely with those of our broader efforts to develop new approaches to surface-mediated drug and gene delivery (discussed in more detail here). We have also extended this approach to the design of anionic charge-shifting polymers that provide opportunities to disrupt ionic interactions and fabricate assemblies that promote the release of cationic agents (e.g., cationic peptides, proteins, polymers, nanoparticles, etc.) from self-assembled nanoparticles or film-coated surfaces.

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