Mechanisms of drug-coated balloon therapy

项目摘要 药物涂层球囊（DCB）已发展为外周动脉的有前途的介入策略 疾病（PAD）。虽然基于紫杉醇（PTX）的DCB正在成为 许多PAD病变，最近的一项随机试验荟萃分析表明，PTX治疗的晚期死亡率过高。 患者这一结果促使FDA发出警告，最终导致了 DCB的临床应用临床和监管机构的这种反应强调了开发 下一代DCB可以显示出更好的疗效和安全性。从我们以前的 根据药物洗脱支架和最近DCB研究的相关经验，我们提出两个假设- 驱动的设计策略，以提高DCB的性能和安全性。目标I和II将考虑球囊表面 亲水性和涂层成分，分别作为关键DCB设计变量，并寻求确定 这些设计变量、涂层微观结构、药物递送功效以及 局部和全身毒性。我们将预测最佳DCB设计的急性和持续的药物输送 使用生物物理接触模型计算DCB期间确定性界面机械相互作用 部署.我们的材料设计空间包括两种赋形剂（尿素和虫胶）和两种药物（PTX和 地塞米松（DEX）），同时考虑到不同的赋形剂-药物比例和新型球囊预处理 在涂层应用之前的方案。我们将使用兔动脉粥样硬化的体内模型来评估 优化DCB，为我们增强PTX输送和深入了解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.