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最难治疗的癌症之一。尽管有积极的治疗， 包括手术切除、放疗和化疗，患者的中位生存时间仍然非常短， 扶贫硼中子俘获治疗（BNCT）是一种治疗局部浸润性恶性肿瘤的无创治疗方法， 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， 裂变反应尽管有明显的优势，BNCT在临床上并不有效，因为它不能 在靶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。这里提出的研究旨在填补一个关键的空白， 基于纳米医学的方法，这是唯一准备提供一个解决方案，这一悬而未决的问题。我们有 开发了用于成像和治疗原发性和转移性脑肿瘤的纳米药物。在这里我们建议 一种新的纳米药物（纳米-10硼），基于一种天然的，无毒的和可生物降解的聚合物， 300分子硼-10富集的4-硼苯丙氨酸（BPA）穿过血脑屏障（BBB）， 主动靶向并向胶质瘤细胞递送高浓度的Bopron-10以用于有效的BNCT。在目标1中，我们 建立了最佳功能化铅纳米10硼。这将通过合成下一代 纳米-10硼具有不同的BPA负载和肿瘤靶向和血脑屏障转运肽Angiopep-2（Ap 2）。 在我们的初步研究中，我们使用了12个Ap 2分子和300个BPA分子共价连接到PMLA上 形成第一代纳米10硼我们的目标是准备最大允许量的铅纳米-10Boron BPA分子的数量，以提高细胞内硼-10浓度，从而提高治疗效果。 目标2将侧重于建立一个理想的时间窗口中子通量照射更大的BNCT效果。PK 我们的第一代纳米10硼的PK约为1.44小时（详见初步结果），而游离的 临床研究中使用的BPA范围在几分钟内。此外，基于PMLA的纳米药物利用活性 靶向并在肿瘤中保留相对较长的时间，同时从体循环中清除 提供更大的肿瘤摄取。在这一目标的研究概述将确定最佳的时间窗口，当我们 与周围健康大脑相比，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非靶向毒性。目标3将利用铅 纳米-10硼治疗胶质瘤裸小鼠以提高生存率。铅纳米-10硼将注入在 在先前的目标中开发了最佳剂量，然后用低能中子照射治疗胶质瘤 使动物裸露并提高存活时间。拟议的工作将解决长期存在的问题， 硼-10递送，从而使BNCT成为胶质瘤治疗的实用疗法，改善患者存活率， 提高生活质量。这项研究的结果可以为一种新的治疗选择奠定基础， 神经胶质瘤的临床应用。 第1页