Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, 37235, USA.
Division of Vascular Surgery, Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
Biomaterials. 2025 Feb;313:122767. doi: 10.1016/j.biomaterials.2024.122767. Epub 2024 Aug 23.
Peripheral artery disease is commonly treated with balloon angioplasty, a procedure involving minimally invasive, transluminal insertion of a catheter to the site of stenosis, where a balloon is inflated to open the blockage, restoring blood flow. However, peripheral angioplasty has a high rate of restenosis, limiting long-term patency. Therefore, angioplasty is sometimes paired with delivery of cytotoxic drugs like paclitaxel to reduce neointimal tissue formation. We pursue intravascular drug delivery strategies that target the underlying cause of restenosis - intimal hyperplasia resulting from stress-induced vascular smooth muscle cell switching from the healthy contractile into a pathological synthetic phenotype. We have established MAPKAP kinase 2 (MK2) as a driver of this phenotype switch and seek to establish convective and contact transfer (coated balloon) methods for MK2 inhibitory peptide delivery to sites of angioplasty. Using a flow loop bioreactor, we showed MK2 inhibition in ex vivo arteries suppresses smooth muscle cell phenotype switching while preserving vessel contractility. A rat carotid artery balloon injury model demonstrated inhibition of intimal hyperplasia following MK2i coated balloon treatment in vivo. These studies establish both convective and drug coated balloon strategies as promising approaches for intravascular delivery of MK2 inhibitory formulations to improve efficacy of balloon angioplasty.
外周动脉疾病通常采用球囊血管成形术治疗，该手术涉及微创、经腔插入导管到狭窄部位，在该处膨胀球囊以打开阻塞物，恢复血流。然而，外周血管成形术的再狭窄率很高，限制了长期通畅性。因此，血管成形术有时与细胞毒性药物（如紫杉醇）联合使用，以减少新生内膜组织的形成。我们追求针对再狭窄根本原因的血管内药物输送策略 - 由应激诱导的血管平滑肌细胞从健康收缩型向病理合成型转变引起的内膜增生。我们已经确定丝裂原激活蛋白激酶激活蛋白激酶 2（MK2）是这种表型转变的驱动因素，并寻求建立用于将 MK2 抑制肽递送到血管成形术部位的对流和接触转移（涂层球囊）方法。使用流动回路生物反应器，我们表明 MK2 抑制在离体动脉中抑制平滑肌细胞表型转变，同时保持血管收缩性。大鼠颈动脉球囊损伤模型表明，MK2i 涂层球囊治疗后体内抑制了内膜增生。这些研究确立了对流和药物涂层球囊策略作为将 MK2 抑制制剂递送到血管内以提高球囊血管成形术疗效的有前途的方法。
