Targeted delivery of a sonic hedgehog inhibitor for the study of medulloblastoma therapeutics

 美国癌症协会估计，2014年美国将诊断出23，380例脑和脊髓肿瘤。大多数脑肿瘤治疗涉及放疗和化疗，这会导致严重的不良反应。例如，髓母细胞瘤（儿童中最常见的恶性脑肿瘤）的幸存者通常由于放射治疗而具有严重的神经认知缺陷。然而，新药的开发是一个昂贵、耗时的过程;只有万分之一的候选药物能够上市，需要15年和10亿美元的开发时间。尽管在开发位点特异性纳米载体方面已经取得了不断的进展，但是由于血脑屏障（BBB）的防御和缺乏在循环中稳定的位点特异性纳米载体，实现成功的脑肿瘤药物治疗而没有副作用仍然具有挑战性。然而，大多数体外模型的血脑屏障缺乏同时整合的重要功能，包括直接的细胞相互作用。的 本研究的总体目标是设计一种新的纳米载体，其可以穿过BBB，运输音刺猬（SHH）抑制剂，并靶向小鼠中SHH驱动的脑肿瘤的阶段特异性胚胎抗原-1（SSEA-1+）。将在BBB的体外微芯片模型中探测纳米载体的BBB穿越性能，并将在SHH型髓母细胞瘤的SmoA 1/Math 1-GFP小鼠模型中检查靶向递送和抑制功效。工程纳米载体将联合收割机结合高密度脂蛋白（HDL）和脂质聚合物纳米颗粒的特性。HDL是一种天然的纳米颗粒，在循环中具有固有的稳定性，可以穿过BBB并在外周和CNS中执行各种关键功能。PLGA是FDA批准的聚合物，其提供高载药量和缓慢释放所并入的药物内容物。作为概念证明，我们将创建一种新的HDL-PLGA纳米载体，可以运输音刺猬（SHH）抑制剂并靶向小鼠中SHH驱动的脑肿瘤的祖细胞（SSEA-1+）。将在BBB的体外微芯片模型中检查工程化纳米载体的BBB穿越能力。将在SHH型髓母细胞瘤的SmoA 1/Math 1-GFP小鼠模型中研究靶向递送和治疗功效。该项目的成功结果将展示开发新的血脑屏障交叉纳米载体和体外模型血脑屏障系统用于治疗MB和其他脑肿瘤的先进方法。所提出的纳米载体靶向模型是为了在体内测试概念的证明，因此由于SSEA-1/CD 15存在于血细胞上，因此在人类翻译中可能受到限制。为了将其转化为人类临床研究的长期目标，在第二年的最后阶段，我们将在该体外模型中测试额外的人类肿瘤特异性靶向分子，以用于基于这些R21结果的即将到来的R 01应用。

 DESCRIPTION: The American Cancer Society estimates that 23,380 brain and spinal cord tumors will be diagnosed in the United States in 2014. Most brain tumor treatments involve radiation and chemotherapy, which cause serious adverse effects. For example, survivors of medulloblastoma, the most common malignant brain tumor in children, typically have profound neurocognitive deficits due to radiation treatment. However, the development of new drugs is a costly, time-consuming process; only one in ten thousand drug candidates makes it to market, taking fifteen years and one billion dollars to develop. Although continuous progress has been made in developing site-specific nanocarriers, it remains challenging to achieve successful drug treatment of brain tumors without side effect due to the defense of the blood-brain barrier (BBB) and the lack of site-specific nanocarriers stable in circulation. However, most in vitro models of the BBB lack simultaneous integration of vital features including the direct cell interactions. The overall goal of this study is to engineer a new nanocarrier that can cross the BBB, transport a sonic hedgehog (SHH) inhibitor, and target stage-specific embryonic antigen-1 (SSEA-1+) for a SHH-driven brain tumor in the mouse. The BBB-crossing performance of the nanocarrier will be probed in an in vitro microchip model of the BBB, and the targeted delivery and inhibiting efficacy will be examined in an SmoA1/Math1-GFP mouse model of SHH-type medulloblastoma. The engineered nanocarriers will combine the characteristics of high-density lipoprotein (HDL) and lipid-polymer nanoparticles. HDL, a natural nanoparticle transporting lipids with inherent stability in circulation, can traverse the BBB and performs a wide variety of critica functions in the periphery and CNS. PLGA is a FDA approved polymer that provides high drug-loading capacity and slow release of incorporated drug contents. As proof of concept, we will create a new HDL-PLGA nanocarrier that can transport a sonic hedgehog (SHH) inhibitor and target a progenitor cell (SSEA-1+) for a SHH-driven brain tumor in the mouse. BBB-crossing capability of engineered nanocarriers will be examined in an in vitro microchip model of the BBB. The targeted delivery and treating efficacy will be investigated in the SmoA1/Math1-GFP mouse model of SHH-type medulloblastoma. The successful outcomes of this project will demonstrate advanced approaches to the development of new BBB- crossing nanocarriers and in vitro model BBB systems for treating MB and other brain tumors. The nanocarrier targeting model proposed is to test the proof of concept in vivo so may be limited in human translation due to SSEA-1/CD15 being present on blood cells. For our long-term goal of its translation to human clinical studies, at the final stage in Year 2, we will test additional human tumor-specific targeting molecules in this in vitro model for forthcoming R01 application based on these R21 results.