Targeted nano-boron based boron neutron capture therapy for glioma treatment

项目摘要 胶质瘤是最致命和最难治疗的癌症之一。尽管采取了积极的治疗方法， 包括手术切除、放疗和化疗在内，患者的中位生存时间仍然很长 可怜。摘要硼中子俘获疗法是治疗局部侵袭性恶性肿瘤的一种非侵入性治疗方法。 肿瘤，如神经胶质瘤。BNCT是一种强大的治疗方法，具有明显的优势，因为它依赖于核捕获和 裂变反应。尽管有明显的优势，BNCT在临床上并没有那么有效，因为无法 在靶癌细胞中选择性地获得足够量的硼-10(一种活性药物)浓度， 这仍然是一个悬而未决的问题。这里提出的研究旨在通过使用 基于纳米医学的方法，它独特地准备为这一悬而未决的问题提供解决方案。我们有 开发了用于原发和转移性脑肿瘤的成像和治疗的纳米药物。在这里，我们建议 一种新型纳米地毯(Nano-10Boron)，基于一种天然、无毒和可生物降解的过量携带的聚合物 在300个分子中，富含硼-10的4-硼苯丙氨酸(BPA)可以通过血脑屏障(BBB)和 主动靶向并将高浓度的Bopron-10输送到胶质瘤细胞，以实现有效的BNCT。在目标1中，我们将 确定了最佳性能的纳米级硼铅。这将通过合成下一代 不同载量BPA和肿瘤靶向及血脑屏障转运肽Angiopep-2(AP2)的Nano-10Borons。 在我们的初步研究中，我们使用了12个AP2分子和300个BPA分子共价连接到PMLA上 形成第一代Nano-10Boron。我们的目标是在最大允许的情况下制备一种纳米级铅 双酚A分子的数量，以提高细胞内的硼-10浓度，以提高治疗结果。 目标2将集中于建立一个理想的中子通量照射时间窗口，以获得更大的BNCT效应。pk 我们的第一代Nano-10Boron大约是1.44小时(详情见初步结果)，而，PK是免费的 临床研究中使用的双酚A在几分钟内就可以完成。此外，基于PMLA的纳米药物利用活性 靶向并在肿瘤中停留较长时间，同时从体循环中清除 提供更大的肿瘤摄取。这一目标的研究大纲将确定当我们 与周围健康的大脑相比，肿瘤中的硼-10浓度最高，有助于有效的BNCT 反应，同时最大限度地减少对健康大脑的任何潜在的靶向毒性。目标3将利用领先优势 纳米硼对裸鼠脑胶质瘤的治疗能提高其存活率。铅Nano-10Boron将在 低能中子照射治疗脑胶质瘤的最佳剂量 裸露动物，提高生存时间。拟议的工作将解决长期存在的 B-10的交付，从而使BNCT成为治疗胶质瘤的实用疗法，改善患者生存和 提升生活质量。这项研究的结果可能为一种新的治疗方案奠定基础 神经胶质瘤的临床应用。 第1页

Project Summary Gliomas represent one of the most fatal and difficult to treat cancers. Despite the aggressive therapies, including surgical resection, radiotherapy and chemotherapy the median survival time for patients remains very poor. Boron neutron capture therapy (BNCT) is a noninvasive therapy for treating locally invasive malignant tumors such as glioma. BNCT is a robust therapy with clear advantages as it relies on the nuclear capture and fission reactions. Despite clear advantages, BNCT have not been as effective in the clinic due to inability to achieve adequate amounts of Boron-10 (an active drug) concentration selectively in the target cancer cells, which remains an unsolved problem. The studies proposed here are intended to fill a critical void using a nanomedicine-based approach, which is uniquely poised to offer a solution to this unsolved problem. We have developed nanodrugs for imaging and treatment of the primary and metastatic brain tumors. Here we propose a novel nanodrug (Nano-10Boron), based on a natural, nontoxic and biodegradable polymer carrying in excess of 300 molecules of Boron-10 enriched 4-boronophenylalanine (BPA) to cross blood-brain barrier (BBB) and actively target and deliver high Bopron-10 concentration to glioma cells for effective BNCT. In Aim 1, we will establish optimum functionating lead Nano-10Boron. This will be achieved by synthesizing next-generation Nano-10Borons with varied loading of BPA and a tumor targeting and BBB transport peptide Angiopep-2 (Ap2). In our preliminary studies, we used 12 Ap2 molecules and 300 BPA molecules covalently attached to PMLA to form a first-generation Nano-10Boron. Our goal is to prepare a lead Nano-10Boron with maximum allowable number of BPA molecules to enhance intracellular Boron-10 concentrations to boost the treatment outcome. Aim 2 will focus on establishing an ideal time window for neutron flux irradiation for greater BNCT effect. PK of our first-generation Nano-10Boron is about 1.44 h (see preliminary results for details) whereas, PK of free BPA used in clinical studies ranges in few minutes. Additionally, PMLA based nanodrugs utilizes active targeting and remains in tumor for relatively longer period, while clearing out from the systemic circulation providing grater tumor uptake. Studies outlines in this aim will determine the optimum time window when we have the highest Boron-10 concentrations in tumor vs surrounding healthy brain, facilitating effective BNCT response while minimizing any potential off targeting toxicity to the healthy brain. Aim 3 will utilize the lead Nano-10Boron to treat glioma baring mice to improve the survival. Lead Nano-10Boron will be injected at the optimum dose developed in the previous aim followed by irradiation with low energy neutrons to treat glioma baring animals and improve the survival time. The proposed work will solve the long-standing problem of Boron-10 delivery, thereby making BNCT a practical therapy for glioma treatment, improve patient survival and enhance the quality of life. The results of this study could lay the groundwork for a novel treatment option for glioma for clinical applications. Page 1