Localized delivery of diagnostic/therapeutic agents to cerebral aneurysms, lesions in brain arteries, may offer a new treatment paradigm. Since aneurysm rupture leading to subarachnoid hemorrhage is a devastating medical emergency with high mortality, the ability to noninvasively diagnose high-risk aneurysms is of paramount importance. Moreover, treatment of unruptured aneurysms with invasive surgery or minimally invasive neurointerventional surgery poses relatively high risk and there is presently no medical treatment of aneurysms. Here, leveraging the endogenous biophysical properties of brain aneurysms, we develop particulate carriers designed to localize in aneurysm low-shear flows as well as to adhere to a diseased vessel wall, a known characteristic of high-risk aneurysms. We first show, in an in vitro model, flow guided targeting to aneurysms using micron-sized (2 μm) particles, that exhibited enhanced targeting (>7 folds) to the aneurysm cavity while smaller nanoparticles (200 nm) showed no preferable accumulation. We then functionalize the microparticles with glycoprotein VI (GPVI), the main platelet receptor for collagen under low-medium shear, and study their targeting in an in vitro reconstructed patient-specific aneurysm that contained a disrupted endothelium at the cavity. Results in this model showed that GPVI microparticles localize at the injured aneurysm an order of magnitude (>9 folds) more than control particles. Finally, effective targeting to aneurysm sites was also demonstrated in an in vivo rabbit aneurysm model with a disrupted endothelium. Altogether, the presented biophysical strategy for targeted delivery may offer new treatment opportunities for cerebral aneurysms.

中文翻译：

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高风险脑动脉瘤的生物物理靶向


向脑动脉瘤、脑动脉病变局部输送诊断/治疗药物可能会提供一种新的治疗范例。由于动脉瘤破裂导致蛛网膜下腔出血是一种毁灭性的医疗紧急情况，死亡率很高，因此无创诊断高风险动脉瘤的能力至关重要。此外，采用侵入性手术或微创神经介入手术治疗未破裂动脉瘤风险较高，目前尚无针对动脉瘤的药物治疗方法。在这里，利用脑动脉瘤的内源性生物物理特性，我们开发了颗粒载体，旨在定位动脉瘤低剪切流并粘附到患病的血管壁上，这是高风险动脉瘤的已知特征。我们首先在体外模型中展示，使用微米尺寸 (2 μm) 颗粒对动脉瘤进行流引导靶向，对动脉瘤腔表现出增强的靶向性（>7 倍），而较小的纳米颗粒 (200 nm) 则没有表现出更好的积累。然后，我们用糖蛋白 VI (GPVI)（低中剪切力下胶原蛋白的主要血小板受体）对微粒进行功能化，并研究它们在体外重建的患者特异性动脉瘤中的靶向作用，该动脉瘤腔内含有破裂的内皮。该模型中的结果表明，GPVI 微粒在受损动脉瘤处的定位比对照颗粒多一个数量级（>9 倍）。最后，在内皮破裂的体内兔动脉瘤模型中也证明了对动脉瘤部位的有效靶向。总而言之，所提出的靶向递送生物物理策略可能为脑动脉瘤提供新的治疗机会。