Pulsed High-Intensity Focused Ultrasound Enhances Delivery of Doxorubicin in a Preclinical Model of Pancreatic Cancer.
Pulsed High-Intensity Focused Ultrasound Enhances Delivery of Doxorubicin in a Preclinical Model of Pancreatic Cancer.
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DOI：
10.1158/0008-5472.can-15-0296
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发表时间：
2015-09-15
期刊：
影响因子：
11.2
通讯作者：
Hwang JH
中科院分区：
文献类型：
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作者：
Li T;Wang YN;Khokhlova TD;D'Andrea S;Starr F;Chen H;McCune JS;Risler LJ;Mashadi-Hossein A;Hingorani SR;Chang A;Hwang JH
胰腺癌的特点是广泛的间质结缔组织增生，这会减少血液灌注并阻碍化疗的输送。打破基质屏障可以增加灌注并使肿瘤通透，从而增强化疗的渗透。基质的机械破坏可以通过超声波引起的气泡活动（空化）来实现。众所周知，空化会导致微流，并可能具有积极增强扩散到肿瘤中的额外好处。在这里，我们报告了在胰腺导管腺癌基因工程小鼠模型（KPC 小鼠）中使用超声诱导空化增强化疗药物阿霉素 (Dox) 渗透的能力。为了在胰腺肿瘤中诱导局部惯性空化，在给予阿霉素期间或之前使用脉冲高强度聚焦超声（pHIFU）来阐明增强药物递送的机制（主动与被动药物扩散）。对于这两种类型，与高空化活性相关的 PHIFU 暴露导致高度纤维化基质基质的破坏，并使标准化 Dox 浓度与对照相比提高高达 4.5 倍。此外，归一化的 Dox 浓度与空化指标相关（p < 0.01），表明高且持续的空化导致化疗渗透增加。两种类型的结果（即 PHIFU 治疗期间或之后的 Dox 输注）之间没有观察到显着差异，这表明被动扩散到先前透化的组织中是药物浓度增加的主要机制。总之，数据表明，当产生高且持续的空化时，胰腺肿瘤的 PHIFU 治疗可以有效地增强对胰腺肿瘤的化疗递送。
Pancreatic cancer is characterized by extensive stromal desmoplasia which decreases blood perfusion and impedes chemotherapy delivery. Breaking the stromal barrier could both increase perfusion and permeabilize the tumor, enhancing chemotherapy penetration. Mechanical disruption of the stroma can be achieved using ultrasound-induced bubble activity – cavitation. Cavitation is also known to result in microstreaming and could have the added benefit of actively enhancing diffusion into the tumors. Here, we report the ability to enhance chemotherapeutic drug doxorubicin (Dox) penetration using ultrasound-induced cavitation in a genetically engineered mouse model (KPC mouse) of pancreatic ductal adenocarcinoma. To induce localized inertial cavitation in pancreatic tumors, pulsed high intensity focused ultrasound (pHIFU) was used either during or before doxorubicin administration to elucidate the mechanisms of enhanced drug delivery (active versus passive drug diffusion). For both types, the pHIFU exposures which were associated with high cavitation activity resulted in disruption of the highly fibrotic stromal matrix and enhanced the normalized Dox concentration by up to 4.5 fold compared to controls. Furthermore, normalized Dox concentration was associated with the cavitation metrics (p < 0.01), indicating that high and sustained cavitation results in increased chemotherapy penetration. No significant difference between the outcomes of the two types, i.e., Dox infusion during or after pHIFU treatment, was observed, suggesting that passive diffusion into previously permeabilized tissue is the major mechanism for the increase in drug concentration. Together, the data indicate that pHIFU treatment of pancreatic tumors when resulting in high and sustained cavitation can efficiently enhance chemotherapy delivery to pancreatic tumors.