Blood-tumor barrier opening by MRI-guided transcranial focused ultrasound in a preclinical breast cancer brain metastasis model improves efficacy of combinatorial chemotherapy.
Blood-tumor barrier opening by MRI-guided transcranial focused ultrasound in a preclinical breast cancer brain metastasis model improves efficacy of combinatorial chemotherapy.
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DOI：
10.3389/fonc.2023.1104594
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发表时间：
2023
影响因子：
4.7
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患有转移性乳腺癌的患者具有高且持续增加的脑转移率。在疾病过程中，脑转移可发生在高达30%的这些患者中。在大多数情况下，脑转移瘤是在显著的疾病进展后诊断的。血-肿瘤屏障通过防止化疗药物在转移灶内以治疗有效浓度积聚而增加了治疗脑转移的难度。传统的治疗方法，如手术切除、放疗和化疗，疗效较差，诊断后的中位生存率较低，为5-8%。低强度聚焦超声（LiFUS）是一种新的治疗方法，用于增强药物在脑内的蓄积和脑恶性肿瘤。在这项研究中，我们在三阴性乳腺癌脑转移的临床前模型中阐明了临床LiFUS联合化疗对肿瘤生存和进展的影响。与对照组相比，LiFUS显著增加了14 C-AIB和德克萨斯红的肿瘤蓄积（p< 0.01）。LiFUS介导的BTB开放是大小依赖性的，这与我们以前的研究一致。与其他组相比，接受LiFUS与Doxil和紫杉醇组合的小鼠显示出中位生存期（60天）的显著增加。与单独化疗或单独化疗和LiFUS组合相比，LiFUS加紫杉醇和Doxil的组合化疗也显示出最慢的肿瘤负荷进展。这项研究表明，LiFUS与定时组合化疗治疗相结合是改善脑转移瘤药物递送的潜在策略。
Patients with metastatic breast cancer have high and continually increasing rates of brain metastases. During the course of the disease, brain metastases can occur in up to 30% of these patients. In most cases, brain metastases are diagnosed after significant disease progression. The blood-tumor barrier increases the difficulty of treating brain metastasis by preventing accumulation of chemotherapy within metastases at therapeutically effective concentrations. Traditional therapies, such as surgical resection, radiotherapy, and chemotherapy, have poor efficacy, as reflected by a low median survival rate of 5-8% after post-diagnosis. Low-intensity focused ultrasound (LiFUS) is a new treatment for enhancing drug accumulation within the brain and brain malignancies. In this study, we elucidate the effect of clinical LiFUS combined with chemotherapy on tumor survival and progression in a preclinical model of triple-negative breast cancer metastasis to the brain. LiFUS significantly increased the tumor accumulation of 14C-AIB and Texas Red compared to controls (p< 0.01). LiFUS-mediated opening of the BTB is size-dependent, which is consistent with our previous studies. Mice receiving LiFUS with combinatorial Doxil and paclitaxel showed a significant increase in median survival (60 days) compared to other groups. LiFUS plus combinatorial chemotherapy of paclitaxel and Doxil also showed the slowest progression of tumor burden compared to chemotherapy alone or individual chemotherapy and LiFUS combinations. This study shows that combining LiFUS with timed combinatorial chemotherapeutic treatment is a potential strategy for improving drug delivery to brain metastases.