Delivery of N-Cadherin Targeting Peptides to Vascular Tissues by Surface-Modified Polyurethane Nanoparticles via a Drug-Coated Balloon

Restenosis remains a long-standing limitation to effectively maintain functional blood flow after percutaneous transluminal angioplasty (PTA). While the use of drug-coated balloons (DCBs) containing antiproliferative drugs has improved patient outcomes, limited tissue transfer and poor therapeutic targeting capabilities contribute to off-target cytotoxicity, precluding adequate endothelial repair. In this work, a DCB system was designed and tested to achieve defined arterial delivery of an antirestenosis therapeutic candidate, cadherin-2 (N-cadherin) mimetic peptides (NCad), shown to selectively inhibit smooth muscle cell migration in vitro and limit intimal thickening in early animal PTA models. To enable successful tissue transfer in the current work, a nanoparticle excipient system previously demonstrated to be an effective carrier of NCad in vitro was integrated with customized DCB coating methodologies designed to prevent therapeutic loss during delivery. DCB design took into consideration four components: (1) the angioplasty balloon; (2) a poly(ethylene oxide) (PEO) monolayer acting as a hydrophilic spacer between the balloon surface and the nanoparticles to assist with improved nanoparticle release; (3) surface-modified degradable polar hydrophobic ionic polyurethane (D-PHI) nanoparticles loaded with NCad to facilitate the transport of the therapeutic peptide into vascular tissue; and (4) a PEO sacrificial coating applied over the nanoparticle excipient layer to prevent premature losses during transit to the artery. The nanoparticle-DCB platform successfully delivered NCad to rat carotid tissue, with superior efficacy and increased permeation within the vessel wall compared with soluble NCad infusion alone. Nanoscale technologies in conjunction with enhanced DCB design properties hold promise in advancing the localized delivery of preventive restenosis therapies in vascular disease.