Mechanisms of drug-coated balloon therapy

项目总结 药物涂层球囊(DCB)已发展成为一种有前途的外周动脉介入治疗策略。 疾病(PAD)。而以紫杉醇(PTX)为基础的DCB正在成为介入治疗的标准 许多PAD损害，最近的一项随机试验的荟萃分析表明PTX治疗的晚期死亡率过高 病人。这一结果促使FDA发出警告，最终导致显著减少 DCBs的临床应用。临床和监管机构的这一反应强调了开发 下一代DCB可以显示出更好的疗效和安全性。从我们以前的 与药物洗脱支架相关的研究经验以及最近关于DCB的研究，我们提出了两个假设-- 驱动设计策略，以提高DCB的性能和安全性。AIMS I和II将考虑气球表面 亲水性和涂层成分分别作为关键的DCB设计变量，并寻求确定 这些设计变量、涂层微结构、药物输送效率以及 局部和全身毒性。我们将预测急性和持续给药的最佳DCB设计 使用生物物理接触模型计算DCB过程中确定的界面机械相互作用 部署。我们的材料设计空间包括两种辅料(尿素和虫胶)和两种药物(PTX和 地塞米松(DEX)，考虑到可变的赋形剂与药物比例和新颖的球囊前处理 涂层应用之前的协议。我们将使用兔动脉粥样硬化的活体模型来评估 优化的DCB，为我们增强PTX交付和洞察临床的方法提供支持 DEX作为替代DCB有效载荷的潜力。

PROJECT SUMMARY Drug-coated balloons (DCBs) have evolved as a promising interventional strategy for peripheral arterial disease (PAD). While paclitaxel (PTX)-based DCBs were emerging as the interventional standard of care for many PAD lesions, a recent meta-analysis of randomized trials suggested excess late mortality in PTX-treated patients. This result prompted the FDA to issue a warning that ultimately led to a marked reduction of the clinical use of DCBs. This response by the clinical and regulatory communities underscores a need to develop next-generation DCBs that could show improved efficacy and safety profiles. Drawing from our previous experience related to studies on drug-eluting stents and more recently on DCBs, we propose two hypothesis- driven design strategies to enhance DCB performance and safety. Aims I and II will consider balloon surface hydrophilicity and coating composition, respectively, as critical DCB design variables, and seek to identify mechanistic relations between these design variables, coating microstructure, drug delivery efficacy, as well as local and systemic toxicity. We will predict optimal DCB designs for both acute and sustained drug delivery using a biophysical contact model that computes deterministic interfacial mechanical interactions during DCB deployment. Our material design space includes two excipients (urea and shellac) and two drugs (PTX and dexamethasone (DEX)), with consideration of variable excipient-drug ratios and novel balloon pre-treatment protocols prior to coating applications. We will use an in vivo model of rabbit atherosclerosis to evaluate optimized DCBs, providing support for our approach to enhance PTX delivery and insight into the clinical potential of DEX as an alternate DCB payload.