Background

Calcific atherosclerosis is a major challenge to intraluminal drug delivery in peripheral artery disease (PAD).

Objectives

We evaluated the effects of orbital atherectomy on intraluminal paclitaxel delivery to human peripheral arteries with substantial calcified plaque.

Methods

Diagnostic angiography and 3-D rotational imaging of five fresh human lower limbs revealed calcification in all main arteries. The proximal or distal segment of each artery was treated using an orbital atherectomy system (OAS) under simulated blood flow and fluoroscopy. Explanted arterial segments underwent either histomorphometric assessment of effect or tracking of ¹⁴C-labeled or fluorescent–labeled paclitaxel. Radiolabeled drug quantified bulk delivery and fluorescent label established penetration of drug over finer spatial domain in serial microscopic sections. Results were interpreted using a mathematical model of binding-diffusion mediated arterial drug distribution.

Results

Lesion composition affected paclitaxel absorption and distribution in cadaveric human peripheral arteries. Pretreatment imaging calcium scores in control femoropopliteal arterial segments correlated with a log-linear decline in the bulk absorption rate-constant of ¹⁴C-labeled, declining 5.5-fold per calcified quadrant (p = 0.05, n = 7). Compared to controls, OAS-treated femoropopliteal segments exhibited 180 μm thinner intima (p < 0.001), 45% less plaque calcification, and 2 log orders higher paclitaxel bulk absorption rate-constants. Correspondingly, fluorescent paclitaxel penetrated deeper in OAS-treated femoropopliteal segments compared to controls, due to a 70% increase in diffusivity (p < 0.001).

Conclusions

These data illustrate that calcified plaque limited intravascular drug delivery, and controlled OAS treatment of calcific plaques resulted in greater drug permeability and improved adjunct drug delivery to diseased arteries.

中文翻译：

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钙化斑块修饰可改变周围动脉粥样硬化的局部给药

背景

钙化动脉粥样硬化是外周动脉疾病（PAD）中腔内给药的主要挑战。

目标

我们评估了眼眶斑块切除术对腔内紫杉醇向实质性钙化斑块的人外周动脉递送的影响。

方法

五个新鲜人类下肢的诊断性血管造影和3-D旋转成像显示所有主要动脉均钙化。在模拟血流和荧光检查下，使用眶动脉斑块切除术系统（OAS）对每条动脉的近端或远端段进行治疗。对移植的动脉节段进行效果的组织形态计量学评估或跟踪¹⁴ C标记或荧光标记的紫杉醇。放射性标记的药物定量了整体递送，荧光标记确定了在连续显微切片中药物在更精细的空间域上的渗透。使用结合扩散介导的动脉药物分布的数学模型解释结果。

结果

病变组成影响紫杉醇在尸体人外周动脉中的吸收和分布。对照股pop动脉节段中的预处理影像学钙评分与¹⁴ C标记的总体吸收速率常数的对数线性下降相关，每钙化象限下降5.5倍（p = 0.05，n = 7）。与对照组相比，OAS治疗的股pop段显示出更薄的180μm内膜（p <0.001），斑块钙化减少了45％和紫杉醇整体吸收速率常数提高了2个对数阶。相应地，与对照组相比，荧光紫杉醇在OAS处理的股pop节段中的渗透更深，这是由于扩散率增加了70％（p <0.001）。

结论

这些数据表明，钙化斑块限制了血管内药物的递送，而钙化斑块的受控OAS治疗导致更大的药物渗透性和改善了向患病动脉的辅助药物递送。