de Gracia Lux C, Vezeridis A M, Lux J, Armstrong A M, Sirsi S R, Hoyt K, Mattrey R F
Department of Radiology, Translational Research in Ultrasound Theranostics (TRUST) Program, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Department of Radiology, University of California, La Jolla, San Diego, CA 92093, USA.
RSC Adv. 2017;7(77):48561-48568. doi: 10.1039/C7RA08971F. Epub 2017 Oct 16.
Microbubble (MB) contrast agents have positively impacted the clinical ultrasound (US) community worldwide. Their use in molecular US imaging applications has been hindered by their limited distribution to the vascular space. Acoustic droplet vaporization (ADV) of nanoscale superheated perfluorocarbon nanodroplets (NDs) demonstrates potential as an extravascular contrast agent that could facilitate US-based molecular theranostic applications. However these agents are metastable and difficult to manufacture with high yields. Here, we report a new formulation technique that yields reliable, narrowly dispersed sub-300 nm decafluorobutane (DFB) or octafluoropropane (OFP)-filled phospholipid-coated NDs that are stable at body temperature, using small volume microfluidization. Final droplet concentration was high for DFB and lower for OFP (>10 >10 NDs per mL). Superheated ND stability was quantified using tunable resistive pulse sensing (TRPS) and dynamic light scattering (DLS). DFB NDs were stable for at least 2 hours at body temperature (37 °C) without spontaneous vaporization. These NDs are activatable when exposed to diagnostic US pressures delivered by a clinical system to become visible microbubbles. The DFB NDs were suficiently stable to allow their processing into functionalized NDs with anti-epithelial cell adhesion molecule (EpCAM) antibodies to target EpCAM positive cells.
微泡（MB）造影剂对全球临床超声（US）领域产生了积极影响。它们在分子超声成像应用中的使用受到其在血管空间分布有限的阻碍。纳米级过热全氟化碳纳米液滴（NDs）的声滴汽化（ADV）显示出作为血管外造影剂的潜力，可促进基于超声的分子诊疗应用。然而，这些试剂是亚稳态的，难以高产率制造。在此，我们报告一种新的制剂技术，该技术使用小体积微流化法，可产生可靠的、窄分布的、填充十氟丁烷（DFB）或八氟丙烷（OFP）的、磷脂包被的亚300 nm纳米液滴，这些纳米液滴在体温下稳定。DFB的最终液滴浓度较高，OFP的较低（每毫升>10>10个纳米液滴）。使用可调电阻脉冲传感（TRPS）和动态光散射（DLS）对过热纳米液滴的稳定性进行了量化。DFB纳米液滴在体温（37°C）下至少稳定2小时，无自发汽化。当暴露于临床系统提供的诊断超声压力下时，这些纳米液滴可被激活成为可见微泡。DFB纳米液滴足够稳定，能够将其加工成用抗上皮细胞粘附分子（EpCAM）抗体功能化的纳米液滴，以靶向EpCAM阳性细胞。
