Motion Compensated Ultrasound Imaging Allows Thermometry and Image Guided Drug Delivery Monitoring from Echogenic Liposomes.
Motion Compensated Ultrasound Imaging Allows Thermometry and Image Guided Drug Delivery Monitoring from Echogenic Liposomes.
复制标题
DOI：
10.7150/thno.15922
复制
发表时间：
2016
期刊：
影响因子：
12.4
通讯作者：
Ranjan A
中科院分区：
文献类型：
--
作者：
Ektate K;Kapoor A;Maples D;Tuysuzoglu A;VanOsdol J;Ramasami S;Ranjan A
超声成像被广泛用于癌症诊断和评估治疗成功率，但由于其组织对比度弱和市售造影剂的半衰期短，目前无法用于评估运动补偿对比增强肿瘤成像，或用于确定时间分辨的绝对肿瘤温度，同时报告药物递送。本研究的目的是：1）开发回声热敏脂质体（E-LTSL）和非热敏脂质体（E-NTSL），以延长造影剂的半衰期，2）测量运动补偿温度引起的脂质体声阻抗和拉普拉斯压力的状态变化，以监测温度和阿霉素（Dox）向肿瘤的递送。使用一步声致孔方法将含有Dox的LTSL和NTSL与US造影剂（全氟戊烷，PFP）共负载以产生E-LTSL和E-NTSL。为了确定小鼠结肠肿瘤中相对于E-LTSL和E-NTSL的状态变化的温度诱导的强度变化，在42°C、39.5°C和37°C的温度下进行20帧/秒的电影采集约20分钟（或直到洗出）。将刚性旋转和平移应用于每个“关键帧”，以调整由于动物或换能器的运动而产生的任何总体运动。为了评价在各种温度下超声（US）强度变化与Dox释放之间的相关性，一旦肿瘤达到300-400 mm 3的大小，就通过尾静脉施用治疗（5 mg Dox/kg），并且在收集的帧上计算针对每个样品定义的感兴趣区域（ROI）内的平均强度，并在[0，1]的范围内进行归一化。当应用运动补偿技术时，观察到肿瘤的平均图像强度的标准偏差下降> 2倍，使得能够更鲁棒地估计由于E-LTSL和E-NTSL的状态变化而导致的15-20分钟的肿瘤温度的时间变化。因此，与37°C相比，在42°C下的峰强度显著增加，这对应于肿瘤中E-LTSL的增强的Dox递送。我们的研究结果表明，回声脂质体提供了一个可预测的变化，肿瘤血管对比度与温度，这种属性可以适用于纳米监测药物输送在真实的时间。
Ultrasound imaging is widely used both for cancer diagnosis and to assess therapeutic success, but due to its weak tissue contrast and the short half-life of commercially available contrast agents, it is currently not practical for assessing motion compensated contrast-enhanced tumor imaging, or for determining time-resolved absolute tumor temperature while simultaneously reporting on drug delivery. The objectives of this study were to: 1) develop echogenic heat sensitive liposomes (E-LTSL) and non-thermosensitive liposomes (E-NTSL) to enhance half-life of contrast agents, and 2) measure motion compensated temperature induced state changes in acoustic impedance and Laplace pressure of liposomes to monitor temperature and doxorubicin (Dox) delivery to tumors. LTSL and NTSL containing Dox were co-loaded with an US contrast agent (perfluoropentane, PFP) using a one-step sonoporation method to create E-LTSL and E-NTSL. To determine temperature induced intensity variation with respect to the state change of E-LTSL and E-NTSL in mouse colon tumors, cine acquisition of 20 frames/second for about 20 min (or until wash out) at temperatures of 42°C, 39.5°C, and 37°C was performed. A rigid rotation and translation was applied to each of the “key frames” to adjust for any gross motion that arose due to motion of the animal or the transducer. To evaluate the correlation between ultrasound (US) intensity variation and Dox release at various temperatures, treatment (5 mg Dox/kg) was administered via a tail vein once tumors reached a size of 300-400 mm3, and mean intensity within regions of interest (ROIs) defined for each sample was computed over the collected frames and normalized in the range of [0,1]. When the motion compensation technique was applied, a > 2-fold drop in standard deviation in mean image intensity of tumor was observed, enabling a more robust estimation of temporal variations in tumor temperatures for 15-20 min. due to state change of E-LTSL and E-NTSL. Consequently, a marked increase in peak intensity at 42°C compared to 37°C that corresponded with enhanced Dox delivery from E-LTSL in tumors was obtained. Our results suggest that echogenic liposomes provide a predictable change in tumor vascular contrast with temperature, and this property could be applicable to nanomonitoring of drug delivery in real time.