Enhancing the Efficacy of Drug-loaded Nanocarriers against Brain Tumors by Targeted Radiation Therapy
Enhancing the Efficacy of Drug-loaded Nanocarriers against Brain Tumors by Targeted Radiation Therapy
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DOI：
10.18632/oncotarget.777
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发表时间：
2013-01-01
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影响因子：
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通讯作者：
Dorsey, Jay F.
中科院分区：
文献类型：
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作者：
Baumann, Brian C.;Kao, Gary D.;Dorsey, Jay F.
多形性胶质母细胞瘤（GBM）是一种常见的，通常致命的疾病，中位生存期仅为15个月。它已在临床试验中被证明对化疗药物如紫杉醇具有抗性，紫杉醇在体外非常有效，可能是因为穿过肿瘤血脑屏障（BBB）的药物递送受损。为了增加紫杉醇穿过肿瘤BBB的递送，我们将该药物与由可生物降解的聚（乙二醇）-嵌段-聚（ε-己内酯-r-D，L-丙交酯）制成的新型纤维胶束纳米载体连接，并使用精确准直放射治疗（RT）破坏GBM原位小鼠模型中肿瘤BBB的渗透性。使用非侵入性生物发光成像技术来评估我们模型中的肿瘤负荷和对治疗的反应，我们证明了单独的载药纳米载体（DLN）对立体定向植入的颅内肿瘤无效，但对培养物中的GBM细胞和植入小鼠侧腹的肿瘤非常有效。当靶向颅RT用于调节肿瘤BBB时，负载紫杉醇的纳米载体对颅内肿瘤变得有效。聚焦颅骨RT改善了DLN向颅内肿瘤的输送，显著改善了治疗结局。肿瘤生长延迟或停止，生存期延长>50%（p
Glioblastoma multiforme (GBM) is a common, usually lethal disease with a median survival of only similar to 15 months. It has proven resistant in clinical trials to chemotherapeutic agents such as paclitaxel that are highly effective in vitro, presumably because of impaired drug delivery across the tumor's blood-brain barrier (BBB). In an effort to increase paclitaxel delivery across the tumor BBB, we linked the drug to a novel filomicelle nanocarrier made with biodegradable poly(ethylene-glycol)-block-poly(epsilon-caprolactone-r-D, L-lactide) and used precisely collimated radiation therapy (RT) to disrupt the tumor BBB's permeability in an orthotopic mouse model of GBM. Using a non-invasive bioluminescent imaging technique to assess tumor burden and response to therapy in our model, we demonstrated that the drug-loaded nanocarrier (DLN) alone was ineffective against stereotactically implanted intracranial tumors yet was highly effective against GBM cells in culture and in tumors implanted into the flanks of mice. When targeted cranial RT was used to modulate the tumor BBB, the paclitaxel-loaded nanocarriers became effective against the intracranial tumors. Focused cranial RT improved DLN delivery into the intracranial tumors, significantly improving therapeutic outcomes. Tumor growth was delayed or halted, and survival was extended by >50% (p