Department of Molecular Science and Technology, Ajou University, Suwon, Republic of Korea.
Division of Cardiology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
Acta Biomater. 2024 Jan 1;173:314-324. doi: 10.1016/j.actbio.2023.11.001. Epub 2023 Nov 9.
In-stent restenosis (ISR) after percutaneous coronary intervention is a major reason for limited long-term patency due to complex neointimal proliferation caused by vascular injury. Drug-coated balloon (DCB) has been developed to treat various cardiovascular diseases including ISR by providing anti-proliferative drugs into blood vessel tissues. However, a significant proportion of the drug is lost during balloon tracking, resulting in ineffective drug delivery to the target region. In this study, we report an everolimus-coated balloon (ECB) using everolimus-loaded gelatin-hydroxyphenyl propionic acid microgel (GM) with enhanced everolimus delivery to vascular walls for long-term patency. GM with high drug loading (> 97%) was simply prepared by homogenizing enzyme-mediated crosslinked hydrogels. The optimal condition to prepare GM-coated ECB (GM-ECB) was established by changing homogenization time and ethanol solvent concentration (30 ∼ 80%). In vitro sustained everolimus release for 30 d, and cellular efficacy using smooth muscle cells and vascular endothelial cells were evaluated. Additionally, an in vivo drug transfer levels of GM-ECB using rabbit femoral arteries were assessed with reduced drug loss and efficient drug delivery capability. Finally, using ISR-induced porcine models, effective in vivo vascular patency 4 weeks after treatment of ECBs was also confirmed. Thus, this study strongly demonstrates that GM can be used as a potential drug delivery platform for DCB application. STATEMENT OF SIGNIFICANCE: We report an ECB using everolimus-loaded GM prepared by homogenization of enzymatic cross-linked hydrogel. GM showed efficient drug loading (> 97 %) and controllable size. GM-ECB exhibited potential to deliver everolimus in a sustained manner to target area with drug efficacy and viability against SMC and EC. Although GM-ECB had much lower drug content compared to controls, animal study demonstrated enhanced drug transfer and reduced drug loss of GM-ECB due to the protection of encapsulated drugs by GM, and the possible interaction between GM and endothelium. Finally, vascular patency and safety were assessed using ISR-induced porcine models. We suggest an advanced DCB strategy to alleviate rapid drug clearance by bloodstream while improving drug delivery for a long-term vascular patency.
经皮冠状动脉介入治疗后的支架内再狭窄（ISR）是由于血管损伤导致的复杂新生内膜增殖而导致长期通畅性有限的主要原因。药物涂层球囊（DCB）已被开发用于治疗各种心血管疾病，包括通过将抗增殖药物递送至血管组织中的 ISR。然而，在球囊跟踪过程中，相当一部分药物丢失，导致药物无法有效递送至目标区域。在这项研究中，我们报告了一种依维莫司涂层球囊（ECB），该球囊使用载有依维莫司的明胶-对羟基苯丙酸微凝胶（GM），通过增强药物向血管壁的递送来实现长期通畅。通过均匀化酶介导的交联水凝胶，简单制备了具有高载药量（>97%）的 GM。通过改变匀浆时间和乙醇溶剂浓度（30∼80%），确定了制备 GM 涂层 ECB（GM-ECB）的最佳条件。对 GM-ECB 进行了 30 天的持续依维莫司释放和细胞功效评估，使用平滑肌细胞和血管内皮细胞。此外，还评估了使用兔股动脉的 GM-ECB 的体内药物转移水平，减少了药物损失并提高了药物递送能力。最后，在 ISR 诱导的猪模型中，还证实了治疗后 ECB 的有效体内血管通畅性可维持 4 周。因此，本研究强烈表明 GM 可作为 DCB 应用的潜在药物递送平台。 意义声明：我们报告了一种使用通过酶交联水凝胶的匀浆制备的载有依维莫司的 GM 的 ECB。GM 显示出高效的载药量（>97%）和可控的尺寸。GM-ECB 具有以持续方式将依维莫司递送至靶区的潜力，具有针对 SMC 和 EC 的药物功效和活力。尽管 GM-ECB 的药物含量与对照组相比要低得多，但动物研究表明，由于 GM 对包封药物的保护以及 GM 与内皮之间的可能相互作用，GM-ECB 增强了药物转移并减少了药物损失。最后，使用 ISR 诱导的猪模型评估了血管通畅性和安全性。我们提出了一种先进的 DCB 策略，通过改善长期血管通畅性来缓解血流引起的快速药物清除，同时改善药物递送。
