Kilroy Joseph P, Dhanaliwala Ali H, Klibanov Alexander L, Bowles Douglas K, Wamhoff Brian R, Hossack John A
Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, 22908, USA.
School of Medicine, University of Virginia, Charlottesville, VA, 22908, USA.
Ann Biomed Eng. 2015 Nov;43(11):2642-51. doi: 10.1007/s10439-015-1315-6. Epub 2015 Apr 17.
Potent therapeutic compounds with dose dependent side effects require more efficient and selective drug delivery to reduce systemic drug doses. Here, we demonstrate a new platform that combines intravascular ultrasound (IVUS) and drug-loaded microbubbles to enhance and localize drug delivery, while enabling versatility of drug type and dosing. Localization and degree of delivery with IVUS and microbubbles was assessed using fluorophore-loaded microbubbles and different IVUS parameters in ex vivo swine arteries. Using a swine model of neointimal hyperplasia, reduction of neointima formation following balloon injury was evaluated when using the combination of IVUS and sirolimus-loaded microbubbles. IVUS and microbubble enhanced fluorophore delivery was greatest when applying low amplitude pulses in the ex vivo model. In the in vivo model, neointima formation was reduced by 50% after treatment with IVUS and the sirolimus-loaded microbubbles. This reduction was achieved with a sirolimus whole blood concentration comparable to a commercial drug-eluting stent (0.999 ng/mL). We anticipate this therapy will find clinical use localizing drug delivery for numerous other diseases in addition to serving as an adjunct to stents in treating atherosclerosis.
具有剂量依赖性副作用的强效治疗化合物需要更高效、更具选择性的药物递送方式，以降低全身药物剂量。在此，我们展示了一个新平台，该平台将血管内超声（IVUS）与载药微泡相结合，既能增强药物递送并使其定位，又能实现药物类型和给药方式的多样化。在离体猪动脉中，使用载有荧光团的微泡和不同的IVUS参数评估了IVUS和微泡的定位及递送程度。利用猪内膜增生模型，评估了在使用IVUS与载西罗莫司微泡联合治疗时，球囊损伤后内膜增生的减少情况。在离体模型中，施加低振幅脉冲时，IVUS和微泡增强的荧光团递送效果最佳。在体内模型中，用IVUS和载西罗莫司微泡治疗后，内膜增生减少了50%。实现这种减少所需要的西罗莫司全血浓度与商用药物洗脱支架相当（0.999纳克/毫升）。我们预计，这种疗法除了可作为治疗动脉粥样硬化时支架的辅助手段外，还将在定位药物递送治疗众多其他疾病方面得到临床应用。
