Department of Biomedical Engineering, Biomedical NMR, Eindhoven University of Technology, Eindhoven, 5600 MB Eindhoven, The Netherlands.
Department of Oncology Solutions, Philips Research Eindhoven, 5656 AE Eindhoven, The Netherlands.
Proc Natl Acad Sci U S A. 2017 Jun 13;114(24):E4802-E4811. doi: 10.1073/pnas.1700790114. Epub 2017 May 31.
Several thermal-therapy strategies such as thermal ablation, hyperthermia-triggered drug delivery from temperature-sensitive liposomes (TSLs), and combinations of the above were investigated in a rhabdomyosarcoma rat tumor model ( = 113). Magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) was used as a noninvasive heating device with precise temperature control for image-guided drug delivery. For the latter, TSLs were prepared, coencapsulating doxorubicin (dox) and [Gd(HPDO3A)(HO)], and injected in tumor-bearing rats before MR-HIFU treatment. Four treatment groups were defined: hyperthermia, ablation, hyperthermia followed by ablation, or no HIFU. The intratumoral TSL and dox distribution were analyzed by single-photon emission computed tomography (SPECT)/computed tomography (CT), autoradiography, and fluorescence microscopy. Dox biodistribution was quantified and compared with that of nonliposomal dox. Finally, the treatment efficacy of all heating strategies plus additional control groups (saline, free dox, and Caelyx) was assessed by tumor growth measurements. All HIFU heating strategies combined with TSLs resulted in cellular uptake of dox deep into the interstitial space and a significant increase of tumor drug concentrations compared with a treatment with free dox. Ablation after TSL injection showed [Gd(HPDO3A)(HO)] and dox release along the tumor rim, mirroring the TSL distribution pattern. Hyperthermia either as standalone treatment or before ablation ensured homogeneous TSL, [Gd(HPDO3A)(HO)], and dox delivery across the tumor. The combination of hyperthermia-triggered drug delivery followed by ablation showed the best therapeutic outcome compared with all other treatment groups due to direct induction of thermal necrosis in the tumor core and efficient drug delivery to the tumor rim.
几种热疗策略，如热消融、热敏脂质体（TSL）触发的药物释放、以及上述策略的联合应用，在横纹肌肉瘤大鼠肿瘤模型中进行了研究（= 113）。磁共振引导高强度聚焦超声（MR-HIFU）被用作一种非侵入性加热设备，具有精确的温度控制，用于图像引导药物输送。对于后者，制备了共包封阿霉素（dox）和[Gd（HPDO3A）（HO）]的 TSL，并在 MR-HIFU 治疗前注入荷瘤大鼠体内。定义了四个治疗组：热疗、消融、热疗后消融或无 HIFU。通过单光子发射计算机断层扫描（SPECT）/计算机断层扫描（CT）、放射自显影和荧光显微镜分析肿瘤内 TSL 和 dox 的分布。定量分析 dox 的生物分布，并与非脂质体 dox 进行比较。最后，通过肿瘤生长测量评估所有加热策略加额外对照组（盐水、游离 dox 和 Caelyx）的治疗效果。所有 HIFU 加热策略与 TSL 联合应用可导致 dox 深入细胞间隙摄取，并与游离 dox 治疗相比显著增加肿瘤药物浓度。TSL 注射后消融显示[Gd（HPDO3A）（HO）]和 dox 沿肿瘤边缘释放，反映了 TSL 的分布模式。作为单独的治疗或消融前的热疗可确保 TSL、[Gd（HPDO3A）（HO）]和 dox 在整个肿瘤中的均匀输送。与所有其他治疗组相比，热疗触发药物释放后再消融的组合显示出最佳的治疗效果，这是由于肿瘤核心直接诱导热坏死和高效的药物输送到肿瘤边缘。
