PH-Responsive Polyelectrolyte Coatings that Enable Catheter-Mediated Transfer of DNA to the Arterial Wall in Short and Clinically Relevant Inflation Times.

Abstract

We report the design and characterization of pH-responsive polymer coatings that enable catheter balloon-mediated transfer of DNA to arterial tissue in short, clinically relevant inflation times. Our approach exploits the pH-dependent ionization of poly(acrylic acid) (PAA) to promote disassembly and release of plasmid DNA from polyelectrolyte multilayers. We characterized the contact transfer of multilayers composed of PAA, plasmid DNA, and linear poly(ethyleneimine) (LPEI) identified as promising in prior studies on the delivery of DNA to arterial tissue. In contrast to thinner films evaluated previously, we found thicker coatings composed of 32 repeating (LPEI/PAA/LPEI/DNA)x tetralayers to swell substantially in physiologically relevant media (in PBS; pH = 7.4). In some cases, these coatings also disintegrated or delaminated rapidly from their underlying substrates, suggesting the potential for enhanced balloon-mediated transfer. We developed a technically straightforward agarose gel-based hole-insertion model to characterize factors (inflation time, lumen size, etc.) that influence contact transfer of DNA when film-coated balloons are inflated into contact with soft surfaces. Those studies and the results of in vivo experiments using small animal (rat) and large animal (pig) models of peripheral arterial injury revealed catheters coated with these materials to promote robust contact transfer of DNA to soft hydrogel surfaces and the luminal surfaces of arterial tissue using inflation times as short as 30 s. These short inflation times are relevant in the context of clinical vascular interventions in peripheral arteries. Additional studies demonstrated that contact transfer of DNA using these short times can promote subsequent dissemination and transport of DNA to the medial tissue layer, suggesting the potential for use in therapeutically relevant applications of balloon-mediated gene transfer.