Laboratory of Drug and Gene Delivery Research, Faculty of Pharma-Science, Teikyo University, Tokyo, Japan.
Laboratory of Theranostics, Faculty of Pharma-Science, Teikyo University, Tokyo, Japan.
J Control Release. 2019 Oct;311-312:65-73. doi: 10.1016/j.jconrel.2019.08.023. Epub 2019 Aug 25.
The combination of Ultrasound (US) and US contrast agent (microbubbles, MBs), which is gas stabilized by a shell such as phospholipids or proteins, has potential as a useful innovative diagnostic and therapeutic tool. Previous studies have evaluated how particle size or shell components of MBs affect their physical characteristics, imaging ability, and drug delivery efficacy. We reported that MBs composed of neutral, anionic phospholipids, and polyethylene glycol-conjugated phospholipids at appropriate ratios were highly stable for US imaging. However, the effects of encapsulated gas on stability and drug delivery efficacy have not been characterized. Therefore, we developed several gas-loaded MBs with identical shell compositions and assessed their stability by US imaging (LOGIQ E9 with ML6-15 probe, MI 0.20). In addition, we assessed the effects of gas encapsulated in MBs on brain-targeted drug delivery, because the brain requires an efficient drug delivery system. Perfluoropropane and perfluorobutane-loaded MBs (MB-CF and MB-CF) showed sustained US imaging in vitro and in vivo compared with sulfur hexafluoride-loaded MBs (MB-SF). In addition, treatment of MB-CF and MB-CF with non-focused US efficiently delivered Evans blue, which was used as a model drug, to the brain to a greater extent than MB-SF. In these treatments, notable damage to brain was not observed, which was assessed by HE staining and denatured neuron staining. Our results suggested that perfluoropropane and perfluorobutane could be useful for the production of MBs with high stability to allow for US imaging and drug delivery.
超声（US）与超声造影剂（微泡，MB）的联合应用具有成为一种有用的创新诊断和治疗工具的潜力，MB 由壳稳定的气体组成，例如磷脂或蛋白质。先前的研究已经评估了 MB 的颗粒大小或壳成分如何影响其物理特性、成像能力和药物输送效果。我们曾报道过，由中性、阴离子磷脂和聚乙二醇化磷脂以适当比例组成的 MB 在超声成像方面具有高度稳定性。然而，包封气体对稳定性和药物输送效果的影响尚未得到表征。因此，我们开发了几种具有相同壳组成的载气 MB，并通过超声成像（LOGIQ E9 与 ML6-15 探头，MI 0.20）评估其稳定性。此外，我们评估了 MB 中包封气体对脑靶向药物输送的影响，因为大脑需要高效的药物输送系统。与六氟化硫载 MB（MB-SF）相比，全氟丙烷和全氟丁烷载 MB（MB-CF 和 MB-CF）在体外和体内均显示出持续的超声成像。此外，用非聚焦超声处理 MB-CF 和 MB-CF 可以更有效地将作为模型药物的 Evans 蓝递送到大脑，效果优于 MB-SF。在这些治疗中，通过 HE 染色和变性神经元染色评估，未观察到明显的脑损伤。我们的结果表明，全氟丙烷和全氟丁烷可用于生产具有高稳定性的 MB，以允许进行 US 成像和药物输送。
