Fan Ching-Hsiang, Cheng Yu-Hang, Ting Chien-Yu, Ho Yi-Ju, Hsu Po-Hung, Liu Hao-Li, Yeh Chih-Kuang
1. Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, No. 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan.
2. Department of Electrical Engineering, Chang-Gung University, 259 Wen-Hwa 1st Road, Kuei-Shan, Tao-Yuan 33302, Taiwan.
Theranostics. 2016 Jun 18;6(10):1542-56. doi: 10.7150/thno.15297. eCollection 2016.
One of the greatest challenges in the deployment of chemotherapeutic drugs against brain tumors is ensuring that sufficient drug concentrations reach the tumor, while minimizing drug accumulation at undesired sites. Recently, injection of therapeutic agents following blood-brain barrier (BBB) opening by focused ultrasound (FUS) with microbubbles (MBs) has been shown to enhance drug delivery in targeted brain regions. Nevertheless, the distribution and quantitative deposition of agents delivered to the brain are still hard to estimate. Based on our previous work on superparamagnetic iron oxide (SPIO)-loaded MBs, we present a novel theranostic complex of SPIO-Doxorubicin (DOX)-conjugated MB (SD-MB) for drug delivery to the brain. Magnetic labeling of the drug enables direct visualization via magnetic resonance imaging, and also facilitates magnetic targeting (MT) to actively enhance targeted deposition of the drug. In a rat glioma model, we demonstrated that FUS sonication can be used with SD-MBs to simultaneously facilitate BBB opening and allow dual ultrasound/magnetic targeting of chemotherapeutic agent (DOX) delivery. The accumulation of SD complex within brain tumors can be significantly enhanced by MT (25.7 fold of DOX, 7.6 fold of SPIO). The change in relaxation rate R2 (1/T2) within tumors was highly correlated with SD deposition as quantified by high performance liquid chromatography (R(2) = 0.93) and inductively coupled plasma-atomic emission spectroscopy (R(2) = 0.94), demonstrating real-time monitoring of DOX distribution. Our results suggest that SD-MBs can serve as multifunction agents to achieve advanced molecular theranostics.
在针对脑肿瘤部署化疗药物时，最大的挑战之一是确保足够的药物浓度到达肿瘤部位，同时尽量减少药物在非靶部位的蓄积。最近的研究表明，在聚焦超声（FUS）联合微泡（MBs）打开血脑屏障（BBB）后注射治疗剂，可增强靶向脑区的药物递送。然而，递送至脑内的药剂的分布和定量沉积仍然难以估计。基于我们之前关于负载超顺磁性氧化铁（SPIO）的微泡的研究工作，我们提出了一种新型的用于向脑内递送药物的治疗诊断复合物，即SPIO-阿霉素（DOX）偶联微泡（SD-MB）。药物的磁性标记能够通过磁共振成像直接可视化，还便于磁靶向（MT）以主动增强药物的靶向沉积。在大鼠胶质瘤模型中，我们证明FUS超声处理可与SD-MBs一起使用，以同时促进BBB打开并实现化疗药物（DOX）递送的双超声/磁靶向。MT可显著增强SD复合物在脑肿瘤内的蓄积（DOX的25.7倍，SPIO的7.6倍）。肿瘤内弛豫率R2（1/T2）的变化与通过高效液相色谱法（R(2) = 0.93）和电感耦合等离子体原子发射光谱法（R(2) = 0.94）定量的SD沉积高度相关，证明了DOX分布的实时监测。我们的结果表明，SD-MBs可作为多功能试剂实现先进的分子治疗诊断。
