Department of Biomedical Engineering, Biomedical NMR, Eindhoven University of Technology, Eindhoven, The Netherlands.
Invest Radiol. 2013 Jun;48(6):395-405. doi: 10.1097/RLI.0b013e3182806940.
The aim of this study was to investigate the intratumoral distribution of a temperature-sensitive liposomal carrier and its encapsulated compounds, doxorubicin, and a magnetic resonance (MR) imaging contrast agent after high-intensity focused ultrasound (HIFU)-mediated hyperthermia-induced local drug release.
(111)In-labeled temperature-sensitive liposomes encapsulating doxorubicin and [Gd(HPDO3A) (H(2)O)] were injected intravenously in the tail vein of rats (n = 12) bearing a subcutaneous rhabdomyosarcoma tumor on the hind leg. Immediately after the injection, local tumor hyperthermia (2 × 15 minutes) was applied using a clinical 3 T MR-HIFU system. Release of [Gd(HPDO3A)(H(2)O)] was studied in vivo by measuring the longitudinal relaxation rate R(1) with MR imaging. The presence of the liposomal carriers and the intratumoral distribution of doxorubicin were imaged ex vivo with autoradiography and fluorescence microscopy, respectively, for 2 different time points after injection (90 minutes and 48 hours).
In hyperthermia-treated tumors, radiolabeled liposomes were distributed more homogeneously across the tumor than in the control tumors (coefficient of variation(hyp, 90 min) = 0.7 ± 0.2; coefficient of variation(cntrl, 90 min) = 1.1 ± 0.2). At 48 hours after injection, the liposomal accumulation in the tumor was enhanced in the hyperthermia group in comparison with the controls. A change in R(1) was observed in the HIFU-treated tumors, suggesting release of the contrast agent. Fluorescence images showed perivascular doxorubicin in control tumors, whereas in the HIFU-treated tumors, the delivered drug was spread over a much larger area and also taken up by tumor cells at a larger distance from blood vessels.
Treatment with HIFU hyperthermia not only improved the immediate drug delivery, bioavailability, and intratumoral distribution but also enhanced liposomal accumulation over time. The sum of these effects may have a significant contribution to the therapeutic outcome.
本研究旨在探讨高温聚焦超声（HIFU）介导的局部药物释放后，热敏脂质体载体及其包封的化合物阿霉素和磁共振（MR）成像造影剂在肿瘤内的分布。
（111）In 标记的热敏脂质体包封阿霉素和 [Gd（HPDO3A）（H2O）] 被注入后腿皮下横纹肌肉瘤肿瘤模型大鼠尾静脉（n = 12）。注射后立即使用临床 3 T MR-HIFU 系统进行局部肿瘤热疗（2×15 分钟）。通过 MR 成像测量纵向弛豫率 R1 来研究 [Gd（HPDO3A）（H2O）] 的体内释放情况。注射后 90 分钟和 48 小时，通过放射自显影和荧光显微镜分别对脂质体载体的存在和阿霉素的肿瘤内分布进行离体成像。
在热疗处理的肿瘤中，与对照组相比，放射性标记的脂质体在肿瘤内分布更加均匀（变异系数（hyp，90 min）= 0.7±0.2；变异系数（cntrl，90 min）= 1.1±0.2）。注射后 48 小时，与对照组相比，热疗组肿瘤内的脂质体聚集增加。在 HIFU 治疗的肿瘤中观察到 R1 的变化，提示造影剂的释放。荧光图像显示对照组肿瘤中有血管周围的阿霉素，而在 HIFU 治疗的肿瘤中，所给予的药物分布在更大的区域，并且在远离血管的肿瘤细胞中也被摄取。
HIFU 热疗不仅改善了即时药物输送、生物利用度和肿瘤内分布，而且随着时间的推移增强了脂质体的积累。这些效果的总和可能对治疗结果有重大贡献。
