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

用于神经胶质瘤治疗的靶向纳米硼硼中子捕获疗法

• 批准号: 10731166
• 负责人: Rameshwar Tukaram Patil
• 金额: $ 25.12万
• 依托单位: LOMA LINDA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10731166
• 关键词: Targeted; nano; boron; based; neutron

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

项目摘要 神经胶质瘤是最致命和难以治疗的癌症之一。尽管采取了积极的疗法， 包括手术切除，放疗和化学疗法的患者中位生存时间仍然非常 贫穷的。硼中子捕获疗法（BNCT）是一种用于治疗局部侵入性恶性肿瘤的无创疗法 肿瘤，例如神经胶质瘤。 BNCT是一种健壮的疗法，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，但由于无法 在目标癌细胞中选择性地实现足够量的硼-10（活性药物）浓度， 这仍然是一个未解决的问题。此处提出的研究旨在使用A填充关键空隙 基于纳米医学的方法，该方法唯一准备为这种未解决的问题提供解决方案。我们有 开发了用于对原发性和转移性脑肿瘤进行成像和治疗的纳米果。我们在这里提出 一种新型的纳米果（Nano-10boron），基于自然，无毒和可生物降解的聚合物，其携带过量的聚合物 富含4-硼苯丙氨酸（BPA）的300个硼-10分子的分子，以交叉血脑屏障（BBB）和 积极靶向并向胶质瘤细胞授予高生物Bopron-10浓度，以进行有效的BNCT。在AIM 1中，我们将 建立最佳功能性铅Nano-10boron。这将通过综合下一代来实现 BPA负载和肿瘤靶向和BBB转运肽AngiOpep-2（AP2）的纳米10木体。 在我们的初步研究中，我们使用了12个AP2分子和300 BPA分子共价附加到PMLA 形成第一代Nano-10boron。我们的目标是准备最大允许的铅Nano-10boron BPA分子的数量以增强细胞内硼-10浓度以提高治疗结果。 AIM 2将集中于建立一个理想的中子通量照射的时间窗口，以提高BNCT效应。 PK 我们的第一代Nano-10boron中的大约1.44 h（有关详细信息，请参见初步结果），而PK则是免费的 BPA在临床研究中使用了几分钟。此外，基于PMLA的纳米果还利用了活动 靶向并保持在肿瘤中相对较长的时期，同时从全身循环中清除 提供刨丝肿瘤的吸收。研究中的研究将确定我们的最佳时间窗口 在健康大脑周围的肿瘤中，硼-10浓度最高，促进有效的BNCT 响应同时最大程度地降低了针对健康大脑毒性的任何潜力。 AIM 3将利用铅 纳米10boron治疗胶神经胶质瘤小鼠以改善生存率。铅纳米10boron将被注入 最佳剂量在上一个目标中产生的，然后用低能量中子照射以治疗神经胶质瘤 野蛮动物并改善生存时间。拟议的工作将解决长期存在的问题 硼10分娩，从而使BNCT成为神经胶质瘤治疗的实用疗法，改善患者的生存和 提高生活质量。这项研究的结果可以为新的治疗选择奠定基础 用于临床应用的神经瘤。 第1页