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

基本信息

批准号：
10436070
负责人：
Rameshwar Tukaram Patil
金额：
$ 2.87万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2022-09-20
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10436070
关键词：
Acids Animal Model Animals Binding Biological Biological Assay Biological Markers Biology Blood Blood - brain barrier anatomy Blood Circulation Boron Boron Neutron Capture Therapy Brain Brain Neoplasms Cell Line Cells Chemicals Clinic Clinical Clinical Research DNA Damage Data Dose Drug Kinetics Drug Transport Engineering Excision Exposure to Flow Cytometry Fluorescence Fluorescent Dyes Generations Glioblastoma Glioma Goals High Pressure Liquid Chromatography Human Image In Vitro Indocyanine Green Inductively Coupled Plasma Mass Spectrometry Label Lead Link Malignant Neoplasms Methodology Methods Microscopy Modeling Mus Necrosis Neutrons Newly Diagnosed Normal tissue morphology Nuclear Nuclear Reactors Operative Surgical Procedures Patients Pennsylvania Peptide Transport Peptides Personal Satisfaction Pharmaceutical Preparations Pharmacodynamics Property Quality of life Radiation Radiation therapy Reaction Research Personnel Rhodamine Saline Science Sodium Source Tail Therapeutic Agents Time Tissues Toxic effect Treatment outcome Tumor Tissue Universities Veins Vertebral column Work aggressive therapy alternative treatment base biodegradable polymer blood-brain barrier crossing brain tissue cancer cell chemotherapy clinical application comparison intervention design dosage efficacy study imaging agent improved in vivo irradiation nano nanodrug nanomedicine nanotechnology platform neoplastic cell next generation novel side effect small molecule success survival outcome treatment response tumor uptake

项目摘要

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

项目概要神经胶质瘤是最致命且最难治疗的癌症之一。尽管采取了积极的治疗，包括手术切除、放疗和化疗，患者的中位生存时间仍然很长贫穷的。硼中子俘获疗法（BNCT）是一种治疗局部侵袭性恶性肿瘤的无创疗法。肿瘤，例如神经胶质瘤。 BNCT 是一种强大的疗法，具有明显的优势，因为它依赖于核捕获和裂变反应。尽管 BNCT 具有明显的优势，但由于无法在目标癌细胞中选择性地达到足够量的硼 10（一种活性药物）浓度，这仍然是一个未解决的问题。这里提出的研究旨在利用基于纳米医学的方法，它独特地准备为这个未解决的问题提供解决方案。我们有开发了用于原发性和转移性脑肿瘤成像和治疗的纳米药物。在这里我们建议一种新型纳米药物（Nano-10Boron），基于天然、无毒且可生物降解的聚合物，携带过量 300 个富含硼 10 的分子 4-硼苯丙氨酸 (BPA) 可穿过血脑屏障 (BBB) 积极靶向并向神经胶质瘤细胞输送高浓度的 Bopron-10，以实现有效的 BNCT。在目标 1 中，我们将建立最佳功能的先导 Nano-10Boron。这将通过合成下一代来实现 Nano-10Borons 具有不同负载的 BPA 和肿瘤靶向和 BBB 转运肽 Angiopep-2 (Ap2)。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 形成第一代Nano-10Boron。我们的目标是制备具有最大允许值的铅纳米10硼大量 BPA 分子可增强细胞内硼 10 浓度，从而提高治疗效果。目标 2 将侧重于建立中子通量辐照的理想时间窗口，以实现更大的 BNCT 效果。 PK 我们的第一代 Nano-10Boron 的 PK 约为 1.44 h（详细信息请参见初步结果），而免费的 PK 临床研究中使用的 BPA 在几分钟内即可变化。此外，基于 PMLA 的纳米药物利用活性靶向并在肿瘤中停留相对较长的时间，同时从体循环中清除提供更大的肿瘤摄取。这一目标的研究大纲将确定我们的最佳时间窗口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的非靶向毒性。目标 3 将利用领先优势 Nano-10Boron 治疗患有神经胶质瘤的小鼠以提高存活率。铅纳米10硼将被注入先前目标中开发的最佳剂量，然后用低能中子照射治疗神经胶质瘤裸露动物并提高生存时间。拟议的工作将解决长期存在的问题硼 10 输送，从而使 BNCT 成为神经胶质瘤治疗的实用疗法，提高患者生存率并提高生活质量。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