Layer-by-Layer Assembly of Thin Films and Coatings: Drug Delivery and Other Applications
Methods for the alternating, layer-by-layer (LbL) adsorption of oppositely charged polymers on surfaces provide nanometer-scale control over the compositions and structures of multilayered polymer thin films (or ‘polyelectrolyte multilayers’, PEMs). These methods are also entirely aqueous, and can thus be used to incorporate biologically active polyelectrolytes (such as proteins and DNA) into assemblies fabricated at a range of complex surfaces and interfaces. Provided that these materials can be fabricated in ways that also permit for controlled disruption, these methods present unique opportunities to design thin films and coatings that provide control over the release of proteins, DNA, and other agents from surfaces. Our group has developed new synthetic polyelectrolytes with the functionality required to exert such control in physiologically relevant environments, and we have demonstrated, in a range of contexts, the application of this ‘multilayered’ approach to provide platforms for the surface-mediated delivery of plasmid DNA and other agents.
A significant amount of our work in this area has exploited the properties of PEMs fabricated using synthetic poly(beta-amino ester)s, a class of polyamines that degrade by chemical hydrolysis in aqueous environments. The incorporation of degradable polyamines into a PEM introduces (i) a mechanism for promoting controlled disruption of ionic interactions in these assemblies, (ii) a means of promoting the subsequent release of incorporated agents (e.g., ‘layers’), and, in the context of applications in the area of gene delivery, (iii) a potential means of promoting the polymer-mediated internalization and processing of DNA by cells.
We have demonstrated that thin films (~100 nm thick) fabricated from alternating layers of these polymers and DNA erode gradually in physiological media and promote surface-mediated cell transfection in vitro and in vivo. We have also demonstrated that small changes in polymer structure can be used to influence the functional properties of these erodible assemblies. For example, systematic changes in hydrophobicity, side chain structure, or charge density can be used to fabricate films that erode and release DNA (or other agents) over periods ranging from several hours to several days or weeks. In combination with new classes of ‘charge-shifting’ cationic polymers developed in our laboratory (described in more detail here), this layer-by-layer approach can also be used to design PEMs that promote the extended release of DNA (e.g., over 3 months) or to fabricate films with ‘hierarchical’ nanostructures that permit control over the release of multiple different DNA constructs with separate, distinct, and predictable release profiles (e.g., rapid release of one DNA construct followed by the slower, sustained release of a second construct).
We have demonstrated that this ‘multilayered’ approach can be used to localize the release and delivery of DNA from the surfaces of implantable medical devices (e.g., intravascular stents and catheter balloons) and other objects (e.g., microneedle arrays and polymer microspheres) both in vitro and in vivo (e.g., in cell culture media and in rat, rabbit, and pig models for vascular gene delivery). With further development, this approach to materials design could contribute to the development of thin films and coatings capable of delivering precise and well-defined quantities of multiple different functional DNA constructs (or combinations of DNA and other therapeutic agents) in a range of fundamental and applied contexts. Ongoing studies in our laboratory are extending the potential reach of this approach to materials that promote the controlled and surface-mediated release of therapeutic DNA constructs, siRNA constructs, proteins, peptides, and small molecule drug-like agents.
- Azlactone-Functionalized Polymers: Reactive Platforms for the Design of Advanced Materials
- Redox-Based Control of DNA Delivery Using Ferrocene-Containing Cationic Lipids
- Surfaces that Prevent Bacterial Communication and Biofilm Growth
- ‘Charge-Shifting’Polymers: Control of Ionic Interactions in Polyelectrolyte Assemblies