Institute of Biomedical Engineering, Department of Engineering Science, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, UK.
Institute of Biomedical Engineering, Department of Engineering Science, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, UK.
J Control Release. 2014 Mar 28;178:101-7. doi: 10.1016/j.jconrel.2013.12.016. Epub 2013 Dec 22.
The encapsulation of cytotoxic drugs within liposomes enhances pharmacokinetics and allows passive accumulation within tumors. However, liposomes designed to achieve good stability during the delivery phase often have compromised activity at the target site. This problem of inefficient and unpredictable drug release is compounded by the present lack of low-cost, non-invasive methods to measure such release. Here we show that focused ultrasound, used at pressures similar to those applied during diagnostic ultrasound scanning, can be utilised to both trigger and monitor release of payload from liposomes. Notably, drug release was influenced by liposome composition and the presence of SonoVue® microbubbles, which provided the nuclei for the initiation of an event known as inertial cavitation. In vitro studies demonstrated that liposomes formulated with a high proportion of 1,2 distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) released up to 30% of payload following ultrasound exposure in the presence of SonoVue®, provided that the exposure created sufficient inertial cavitation events, as characterised by violent bubble collapse and the generation of broadband acoustic emissions. In contrast a 'Doxil'-like liposome formulation gave no such triggered release. In pre-clinical studies, ultrasound was used as a non-invasive, targeted stimulus to trigger a 16-fold increase in the level of payload release within tumors following intravenous delivery. The inertial cavitation events driving this release could be measured remotely in real-time and were a reliable predictor of drug release.
脂质体将细胞毒性药物包封后，增强了药物的药代动力学性质，使其能够被动地在肿瘤内积累。然而，设计用于在递药阶段实现良好稳定性的脂质体，往往在靶部位的活性受到影响。这种药物释放效率低下和不可预测的问题，因目前缺乏低成本、非侵入性的方法来测量这种释放而变得更加复杂。在这里，我们展示了聚焦超声可以在类似于诊断性超声扫描所施加的压力下，被用于触发和监测脂质体中有效载荷的释放。值得注意的是，药物释放受到脂质体组成和 SonoVue®微泡的影响，后者为被称为惯性空化的起始事件提供了核。体外研究表明，在 SonoVue®存在的情况下，用 1,2 二硬脂酰-sn-甘油-3-磷酸乙醇胺（DSPE）的高比例配制的脂质体，在超声暴露后可释放高达 30%的有效载荷，前提是暴露产生足够的惯性空化事件，如剧烈的气泡崩溃和宽带声发射所表征的那样。相比之下，“Doxil”-样脂质体配方则不会产生这种触发释放。在临床前研究中，超声被用作非侵入性、靶向刺激物，在静脉给药后，可在肿瘤内引发 16 倍的有效载荷释放。驱动这种释放的惯性空化事件可以实时远程测量，并且是药物释放的可靠预测指标。
