Imaging Division, University Medical Center Utrecht, Utrecht, Netherlands.
Institut de Mathématiques de Bordeaux, UMR 5251, CNRS, Université de Bordeaux, Bordeaux, France.
Contrast Media Mol Imaging. 2019 Mar 7;2019:2645928. doi: 10.1155/2019/2645928. eCollection 2019.
In solid tumors, rapid local intravascular release of anticancer agents, e.g., doxorubicin (DOX), from thermosensitive liposomes (TSLs) can be an option to overcome poor extravasation of drug nanocarriers. The driving force of DOX penetration is the drug concentration gradient between the vascular compartment and the tumor interstitium. In this feasibility study, we used fibered confocal fluorescence microscopy (FCFM) to monitor in real-time DOX penetration in the interstitium of a subcutaneous tumor after its intravascular release from TSLs, Thermodox®. Cell uptake kinetics of the released DOX was quantified, along with an in-depth assessment of released-DOX penetration using an evolution model. A subcutaneous rat R1 rhabdomyosarcoma xenograft was used. The rodent was positioned in a setup including a water bath, and FCFM identification of functional vessels in the tumor tissue was applied based on AngioSense. The tumor-bearing leg was immersed in the 43°C water for preheating, and TSLs were injected intravenously. Real-time monitoring of intratumoral (i.t.) DOX penetration could be performed, and it showed the progressing DOX wave front via its native fluorescence, labeling successively all cell nuclei. Cell uptake rates (1/k) of 3 minutes were found (=241 cells), and a released-DOX penetration in the range of 2500 m·s was found in the tumor extravascular space. This study also showed that not all vessels, identified as functional based on AngioSense, gave rise to local DOX penetration.
在实体瘤中，从热敏脂质体（TSL）中快速局部血管内释放抗癌药物，例如阿霉素（DOX），可以作为克服药物纳米载体外渗不良的一种选择。DOX 渗透的驱动力是血管腔室和肿瘤间质之间的药物浓度梯度。在这项可行性研究中，我们使用纤维共聚焦荧光显微镜（FCFM）实时监测 DOX 从 TSL（Thermodox®）血管内释放后在皮下肿瘤间质中的渗透情况。我们量化了释放的 DOX 的细胞摄取动力学，并使用演化模型对释放的 DOX 渗透进行了深入评估。使用皮下大鼠 R1 横纹肌肉瘤异种移植模型。将啮齿动物置于包括水浴的设置中，并基于 AngioSense 应用 FCFM 识别肿瘤组织中的功能血管。将带瘤腿浸入 43°C 的水中进行预热，并静脉注射 TSL。可以实时监测肿瘤内（i.t.）DOX 渗透情况，通过其固有荧光显示逐渐推进的 DOX 波前，依次标记所有细胞核。发现细胞摄取率（1/k）为 3 分钟（=241 个细胞），并且在肿瘤血管外空间中发现了 2500 m·s 的释放 DOX 渗透范围。这项研究还表明，并非所有根据 AngioSense 鉴定为功能的血管都会导致局部 DOX 渗透。
