Focused ultrasound-facilitated brain drug delivery using optimized nanodroplets: vaporization efficiency dictates large molecular delivery
Focused ultrasound-facilitated brain drug delivery using optimized nanodroplets: vaporization efficiency dictates large molecular delivery
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DOI：
10.1088/1361-6560/aaa30d
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发表时间：
2018-02-01
影响因子：
3.5
通讯作者：
Konofagou, Elisa E.
中科院分区：
文献类型：
--
作者：
Wu, Shih-Ying;Fix, Samantha M.;Konofagou, Elisa E.
与微泡相比，具有纳米液滴的聚焦超声可以促进汽化后的局部药物递送，具有潜在的改善的体内稳定性、药物有效载荷和焦点区域外的最小干扰。虽然先前已经报道了使用纳米液滴打开血脑屏障（BBB）的可行性，但是尚未实现相关递送的表征。据推测，药物递送的结果与液滴对声能的敏感性相关，并且可以用液核的沸点来调制。因此，在这项研究中，八氟丙烷（OFP）和十氟丁烷（DFB）纳米液滴在体外用于评估它们的相对汽化效率与高速显微镜，并在体内用于提供分子的大小相关的蛋白质（40 kDa葡聚糖）到小鼠大脑。在体外研究中发现，与较高压力（750-900 kPa）下的DFB液滴相比，在低压（300-450 kPa）下，OFP液滴蒸发成更多数量的微泡。在体内研究中，使用1/4剂量，在300 kPa和450 kPa下用OFP液滴实现成功递送，而没有空化损伤的证据，与在900 kPa下的DFB液滴相比，在900 kPa下，组织学指示由于惯性空化导致的组织损伤。总之，纳米液滴的蒸发效率积极影响递送到大脑的分子量。与DFB液滴相比，由于更高的蒸发效率，OFP液滴用作更好的声学剂以将大分子有效地递送到大脑。
Focused ultrasound with nanodroplets could facilitate localized drug delivery after vaporization with potentially improved in vivo stability, drug payload, and minimal interference outside of the focal zone compared with microbubbles. While the feasibility of blood-brain barrier (BBB) opening using nanodroplets has been previously reported, characterization of the associated delivery has not been achieved. It was hypothesized that the outcome of drug delivery was associated with the droplet's sensitivity to acoustic energy, and can be modulated with the boiling point of the liquid core. Therefore, in this study, octafluoropropane (OFP) and decafluorobutane (DFB) nanodroplets were used both in vitro for assessing their relative vaporization efficiency with high-speed microscopy, and in vivo for delivering molecules with a size relevant to proteins (40 kDa dextran) to the murine brain. It was found that at low pressures (300-450 kPa), OFP droplets vaporized into a greater number of microbubbles compared to DFB droplets at higher pressures (750-900 kPa) in the in vitro study. In the in vivo study, successful delivery was achieved with OFP droplets at 300 kPa and 450 kPa without evidence of cavitation damage using 1/4 dosage, compared to DFB droplets at 900 kPa where histology indicated tissue damage due to inertial cavitation. In conclusion, the vaporization efficiency of nanodroplets positively impacted the amount of molecules delivered to the brain. The OFP droplets due to the higher vaporization efficiency served as better acoustic agents to deliver large molecules efficiently to the brain compared with the DFB droplets.