Hadinger Kyle P, Marshalek Joseph P, Sheeran Paul S, Dayton Paul A, Matsunaga Terry O
Department of Medical Imaging, University of Arizona, Tucson, Arizona, USA.
Physical Sciences Department, Sunnybrook Research Institute, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Ultrasound Med Biol. 2018 Dec;44(12):2728-2738. doi: 10.1016/j.ultrasmedbio.2018.08.003. Epub 2018 Sep 15.
Breast cancer remains a leading cause of death for women throughout the world. Recent advances in medical imaging technologies and tumor targeting agents signify vast potential for progress toward improved management of this global problem. Phase-change contrast agents (PCCAs) are dynamic imaging agents with practical applications in both the research and clinical settings. PCCAs possess characteristics that allow for cellular uptake where they can be converted from liquid-phase PCCAs to gaseous microbubbles via ultrasound energy. Previously, we reported successful internalization of folate-targeted PCCAs in MDA-MB-231 breast cancer cells followed by ultrasound-mediated activation to produce internalized microbubbles. This study examines the binding, internalization and activation of folate-receptor targeted PCCAs in MDA-MB-231 breast cancer cells as a function of gaseous core compositions, incubation time and ultrasound exposure period. In vitro results indicate that internalization and ultrasound-mediated activation of PCCAs were significantly greater using a 50:50 mixture of decafluorobutane:dodecafluoropentane compared with other core compositions: 50:50 octafluoropropane:decafluorobutane (p < 0.0001), decafluorobutane (p < 0.04) and dodecafluoropentane (p < 0.0001). Furthermore, it was found that PCCAs composed of perfluorocarbons with higher boiling points responded with greater activation efficiency when exposed to 12 s of ultrasound exposure as opposed to 4 s of ultrasound exposure. When evaluating different incubation times, it was found that incubating the PCCAs with breast cancer cells for 60 min did not produce significantly greater internalization and activation compared with incubation for 10 min; this was concluded after comparing the number of microbubbles present per cell before ultrasound versus post-ultrasound, and finding a ratio of intracellular microbubbles post-ultrasound/pre-ultrasound, 3.46 versus 3.14, respectively. The data collected in this study helps illustrate further optimization of folate-receptor targeted PCCAs for breast cancer targeting and imaging.
乳腺癌仍然是全球女性死亡的主要原因。医学成像技术和肿瘤靶向剂的最新进展表明，在改善对这一全球性问题的管理方面取得进展具有巨大潜力。相变造影剂（PCCA）是一种动态成像剂，在研究和临床环境中都有实际应用。PCCA具有能够被细胞摄取的特性，在超声能量作用下，它们可以从液相PCCA转化为气态微泡。此前，我们报道了叶酸靶向PCCA在MDA-MB-231乳腺癌细胞中的成功内化，随后通过超声介导激活产生内化微泡。本研究考察了叶酸受体靶向PCCA在MDA-MB-231乳腺癌细胞中的结合、内化和激活情况，作为气态核心成分、孵育时间和超声暴露时间的函数。体外实验结果表明，与其他核心成分相比，使用十氟丁烷：十二氟戊烷50:50的混合物时，PCCA的内化和超声介导激活显著更高：八氟丙烷：十氟丁烷50:50（p < 0.0001）、十氟丁烷（p < 0.04）和十二氟戊烷（p < 0.0001）。此外，研究发现，与暴露于4秒超声相比，暴露于12秒超声时，由沸点较高的全氟化碳组成的PCCA反应时激活效率更高。在评估不同孵育时间时发现，将PCCA与乳腺癌细胞孵育60分钟与孵育10分钟相比，并未产生显著更高的内化和激活；这是在比较超声处理前和超声处理后每个细胞中存在的微泡数量，并发现超声处理后/超声处理前细胞内微泡的比例分别为3.46和3.14后得出的结论。本研究收集的数据有助于进一步优化叶酸受体靶向PCCA用于乳腺癌靶向和成像。
