Aryal Muna, Park Juyoung, Vykhodtseva Natalia, Zhang Yong-Zhi, McDannold Nathan
Department of Physics, Boston College, 221 Longwood Avenue, Boston, MA 02115, USA. Department of Radiology, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Phys Med Biol. 2015 Mar 21;60(6):2511-27. doi: 10.1088/0031-9155/60/6/2511. Epub 2015 Mar 6.
Effective drug delivery to brain tumors is often challenging because of the heterogeneous permeability of the 'blood tumor barrier' (BTB) along with other factors such as increased interstitial pressure and drug efflux pumps. Focused ultrasound (FUS) combined with microbubbles can enhance the permeability of the BTB in brain tumors, as well as the blood-brain barrier in the surrounding tissue. In this study, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used to characterize the FUS-induced permeability changes of the BTB in a rat glioma model at different times after implantation. 9L gliosarcoma cells were implanted in both hemispheres in male rats. At day 9, 14, or 17 days after implantation, FUS-induced BTB disruption using 690 kHz ultrasound and definity microbubbles was performed in one tumor in each animal. Before FUS, liposomal doxorubicin was administered at a dose of 5.67 mg kg(-1). This chemotherapy agent was previously shown to improve survival in animal glioma models. The transfer coefficient Ktrans describing extravasation of the MRI contrast agent Gd-DTPA was measured via DCE-MRI before and after sonication. We found that tumor doxorubicin concentrations increased monotonically (823 ± 600, 1817 ± 732 and 2432 ± 448 ng g(-1)) in the control tumors at 9, 14 and 17 d. With FUS-induced BTB disruption, the doxorubicin concentrations were enhanced significantly (P < 0.05, P < 0.01, and P < 0.0001 at days 9, 14, and 17, respectively) and were greater than the control tumors by a factor of two or more (2222 ± 784, 3687 ± 796 and 5658 ± 821 ng g(-1)) regardless of the stage of tumor growth. The transfer coefficient Ktrans was significantly (P < 0.05) enhanced compared to control tumors only at day 9 but not at day 14 or 17. These results suggest that FUS-induced enhancements in tumor drug delivery are relatively consistent over time, at least in this tumor model. These results are encouraging for the use of large drug carriers, as they suggest that even large/late-stage tumors can benefit from FUS-induced drug enhancement. Corresponding enhancements in Ktrans were found to be variable in large/late-stage tumors and not significantly different than controls, perhaps reflecting the size mismatch between the liposomal drug (~100 nm) and Gd-DTPA (molecular weight: 938 Da; hydrodynamic diameter: ≃2 nm). It may be necessary to use a larger MRI contrast agent to effectively evaluate the sonication-induced enhanced permeabilization in large/late-stage tumors when a large drug carrier such as a liposome is used.
由于“血瘤屏障”（BTB）的渗透性不均一，以及诸如间质压力增加和药物外排泵等其他因素，向脑肿瘤有效递送药物往往具有挑战性。聚焦超声（FUS）联合微泡可增强脑肿瘤中BTB以及周围组织中血脑屏障的通透性。在本研究中，动态对比增强磁共振成像（DCE-MRI）用于表征在大鼠胶质瘤模型中植入后不同时间FUS诱导的BTB通透性变化。将9L胶质肉瘤细胞植入雄性大鼠的双侧半球。在植入后第9、14或17天，对每只动物的一个肿瘤进行使用690kHz超声和Definity微泡的FUS诱导的BTB破坏。在FUS之前，以5.67mg kg⁻¹的剂量给予脂质体阿霉素。这种化疗药物先前已显示可提高动物胶质瘤模型的生存率。通过DCE-MRI在超声处理前后测量描述MRI造影剂钆喷酸葡胺外渗的转运系数Ktrans。我们发现，在第9、14和17天时，对照肿瘤中的肿瘤阿霉素浓度单调增加（823±600、1817±732和2432±448ng g⁻¹）。随着FUS诱导的BTB破坏，阿霉素浓度显著提高（分别在第9、14和17天时P<0.05、P<0.01和P<0.0001），并且比对照肿瘤高两倍或更多（2222±784、3687±796和5658±821ng g⁻¹），与肿瘤生长阶段无关。转运系数Ktrans仅在第9天时与对照肿瘤相比显著（P<0.05）提高，而在第14天或17天时未提高。这些结果表明，FUS诱导的肿瘤药物递送增强在一段时间内相对一致，至少在该肿瘤模型中如此。这些结果对于使用大型药物载体是令人鼓舞的，因为它们表明即使是大型/晚期肿瘤也可从FUS诱导的药物增强中获益。发现在大型/晚期肿瘤中Ktrans的相应增强是可变的，并且与对照无显著差异，这可能反映了脂质体药物（~100nm）与钆喷酸葡胺（分子量：938Da；流体动力学直径：≃2nm）之间大小不匹配。当使用诸如脂质体这样的大型药物载体时，可能有必要使用更大的MRI造影剂来有效评估大型/晚期肿瘤中超声处理诱导的增强通透性。
