Trepanier Chantal M, Burke-Kleinman Jonah, Hou Guangpei, Rubianto Jonathan, Strauss Bradley H, Bendeck Michelle P, Santerre J Paul
Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario M5S 3E3, Canada.
Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research, Toronto, Ontario M5G 1M1, Canada.
ACS Biomater Sci Eng. 2025 Feb 10;11(2):1013-1024. doi: 10.1021/acsbiomaterials.4c02417. Epub 2025 Jan 14.
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 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 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.
血管再狭窄仍然是经皮腔内血管成形术（PTA）后有效维持功能性血流的一个长期限制因素。虽然使用含有抗增殖药物的药物涂层球囊（DCB）改善了患者的治疗效果，但有限的组织转移和较差的治疗靶向能力导致了脱靶细胞毒性，阻碍了内皮的充分修复。在这项研究中，设计并测试了一种DCB系统，以实现抗再狭窄治疗候选药物——钙黏蛋白-2（N-钙黏蛋白）模拟肽（NCad）在动脉中的特定递送，该模拟肽在早期动物PTA模型中已显示出能选择性抑制平滑肌细胞迁移并限制内膜增厚。为了在当前研究中实现成功的组织转移，将先前证明是NCad有效载体的纳米颗粒赋形剂系统与定制的DCB涂层方法相结合，该方法旨在防止递送过程中的治疗药物损失。DCB设计考虑了四个组成部分：（1）血管成形术球囊；（2）聚环氧乙烷（PEO）单层，作为球囊表面与纳米颗粒之间的亲水性间隔层，有助于改善纳米颗粒的释放；（3）负载NCad的表面改性可降解极性疏水离子聚氨酯（D-PHI）纳米颗粒，以促进治疗性肽向血管组织的转运；（4）在纳米颗粒赋形剂层上施加的PEO牺牲涂层，以防止在转运至动脉的过程中过早损失。与单独输注可溶性NCad相比，纳米颗粒-DCB平台成功地将NCad递送至大鼠颈动脉组织，具有更高的疗效和血管壁内增加的渗透性。纳米技术与增强的DCB设计特性相结合，有望推动血管疾病中预防性再狭窄治疗的局部递送。
