Peller Michael, Schwerdt Alenka, Hossann Martin, Reinl Herbert M, Wang Tungte, Sourbron Steven, Ogris Manfred, Lindner Lars H
Josef Lissner Laboratory for Biomedical Imaging, Department of Clinical Radiology, University Hospital, Ludwig-Maximilians University, Munich, Germany.
Invest Radiol. 2008 Dec;43(12):877-92. doi: 10.1097/RLI.0b013e31818768cd.
Thermal dose in tumor tissue is a key factor for regional hyperthermia (HT) combined with chemotherapy and for drug delivery using thermosensitive liposomes (TSL). It influences therapy outcome, affects the accumulation of liposomes, and triggers the content release from TSL in the target tissue. For the development and clinical application of TSL, noninvasive visualization is of critical importance. For this purpose, TSL loaded with MRI contrast agent (CA) have been developed. With increase in temperature, the CA is released from TSL at the phase transition temperature Tm resulting in a relaxation time change, which allows MRI monitoring. The purpose of this study was to examine the feasibility of an in vivo application and MR characterization of Gd-DTPA-BMA-loaded phosphatidylglyceroglycerol-TSL (Gd-TSL) at mild HT conditions in tumor tissue using a clinically relevant setting.
Gd-TSL were characterized in vitro with varying thermal doses between 37 degrees C and 45 degrees C and distinct solvents by MR at 0.5 T and 1.5 T. In vivo studies were performed in C57BL/6 mice bearing BFS-1 fibrosarcomas at 1.5 T. One tumor-bearing leg was immersed in a temperature-controlled water bath (T). Gd-TSL (Tm = 43.5 +/- 0.2 degrees C) were injected either intratumorally or intravenously at T = 37.3 +/- 0.1 degrees C or T = 42.5 +/- 0.3 degrees C. As a control, nonliposomal Gd-DTPA-BMA was injected intravenously at T = 43.1 +/- 0.3 degrees C. A second tumor on the contralateral limb, which remained unheated, served as a control. CA release was monitored by T1-weighted spin-echo.
The in vitro characterization demonstrated at heated and unheated samples a strong increase in T1-relaxivity of Gd-TSL solutions from 0.4 mM-1 s-1 (37.5 degrees C) to 4.2 mM-1 s-1 (43.3 degrees C) at 0.5 T. Thermal dose and solvent affected the rate of relaxation time change significantly. A fast and complete release was observed in samples with serum, whereas Gd-TSL in glucose was only partially released within 1 hour. A dedicated experimental setup was developed for standardized in vivo investigation. Tumor signal intensity changes were detectable in all animals. After intratumoral injection of Gd-TSL, the signal increased heterogeneously (max., +52% +/- 25%) within 3 minutes after temperature increase and decreased strongly thereafter, whereas after i.v. injection, the signal increased homogeneously (+19% +/- 3%) within 2 minutes persisting thereafter. The unheated control tumors on the contralateral legs showed a 10% +/- 3% signal increase within 2 minutes. Injection at 37 degrees C showed a continuous signal increase in "heated" and unheated tumors of up to 8% to 10%. Nonliposomal CA injection demonstrated that tumors were well perfused during HT.
HT-induced CA release from Gd-TSL was monitored and characterized by MRI after i.v. injection in tumor-bearing mice. Higher temperatures resulted in higher signal changes. Immediately after i.v. injection, heated tumor tissue was distinguishable from unheated tumor tissue. The Gd-TSL appears to be suitable for MR monitoring of HT tumor treatment in a clinical MRI setting independent of field strength.
肿瘤组织中的热剂量是区域热疗（HT）联合化疗以及使用热敏脂质体（TSL）进行药物递送的关键因素。它影响治疗效果，影响脂质体的积累，并触发目标组织中TSL的内容物释放。对于TSL的开发和临床应用，无创可视化至关重要。为此，已开发出负载有MRI造影剂（CA）的TSL。随着温度升高，CA在相变温度Tm时从TSL中释放出来，导致弛豫时间发生变化，从而实现MRI监测。本研究的目的是在临床相关环境下，研究负载钆喷酸葡胺 - BMA（Gd - DTPA - BMA）的磷脂酰甘油甘油 - TSL（Gd - TSL）在肿瘤组织轻度HT条件下体内应用和MR表征的可行性。
在0.5 T和1.5 T条件下，通过MR对Gd - TSL在37℃至45℃不同热剂量和不同溶剂中进行体外表征。在1.5 T条件下，对携带BFS - 1纤维肉瘤的C57BL / 6小鼠进行体内研究。将一条荷瘤腿浸入温度可控的水浴（T）中。在T = 37.3±0.1℃或T = 42.5±0.3℃时，将Gd - TSL（Tm = 43.5±0.2℃）瘤内或静脉注射。作为对照，在T = 43.1±0.3℃时静脉注射非脂质体Gd - DTPA - BMA。对侧肢体上未加热的第二个肿瘤用作对照。通过T1加权自旋回波监测CA释放。
体外表征显示，在0.5 T条件下，加热和未加热样品中Gd - TSL溶液的T1弛豫率从0.4 mM - 1 s - 1（37.5℃）大幅增加到4.2 mM - 1 s - 1（43.3℃）。热剂量和溶剂对弛豫时间变化率有显著影响。在含有血清的样品中观察到快速且完全的释放，而葡萄糖中的Gd - TSL在1小时内仅部分释放。开发了一种专门的实验装置用于标准化的体内研究。在所有动物中均可检测到肿瘤信号强度变化。瘤内注射Gd - TSL后，温度升高后3分钟内信号异质性增加（最大，+ 52％±25％），此后强烈下降，而静脉注射后，信号在2分钟内均匀增加（+ 19％±3％），此后持续。对侧腿部未加热的对照肿瘤在2分钟内信号增加10％±3％。在37℃注射显示“加热”和未加热肿瘤中的信号持续增加高达8％至10％。非脂质体CA注射表明在HT期间肿瘤灌注良好。
在荷瘤小鼠静脉注射后，通过MRI监测并表征了HT诱导的Gd - TSL中CA的释放。较高温度导致较高的信号变化。静脉注射后立即，加热的肿瘤组织与未加热的肿瘤组织可区分。Gd - TSL似乎适用于在临床MRI环境中独立于场强对HT肿瘤治疗进行MR监测。
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