An Improved Intra-Arterial Delivery Platform for Glioblastoma Multiforme

改进的多形性胶质母细胞瘤动脉内输送平台

基本信息

批准号：
9904911
负责人：
Francis Milton Creighton
金额：
$ 29.99万
依托单位：
UNANDUP, LLC
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-07 至 2022-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9904911
关键词：
Acute Age-Years Aging American Animal Model Animals Blood Blood - brain barrier anatomy Blood Vessels Blood flow Brain Caliber Cancer Etiology Cause of Death Cells Central Nervous System Neoplasms Cessation of life Characteristics Clinical Complex Cyclic GMP Data Set Devices Diagnosis Diffusion Distal Dose Doxorubicin Dyes Embolism Evans blue stain Excision Formulation Frequencies Glioblastoma Goals Heating Hemorrhage Histopathology Hospitals Human Hypersensitivity In Vitro Incidence Intercellular Fluid Internal carotid artery structure Intervention Intravenous Label Left Legal patent Magnetic nanoparticles Magnetism Malignant Neoplasms Measures Methodology Modeling Morphologic artifacts Morphology Motion Mus Operative Surgical Procedures Oral Performance Persons Pharmaceutical Preparations Pharmacologic Substance Phase Photomicrography Physiological Polyethylene Glycols Population Publishing Radiation therapy Reaction Regulatory Pathway Reproducibility Resistance Risk Robotics Roentgen Rays Safety Shapes Small Business Innovation Research Grant Statistical Methods System Techniques Technology Testing Therapeutic Therapeutic Agents Torque Toxic effect Treatment Efficacy Treatment-related toxicity Underserved Population United States Work animal data antitumor agent arm base biomaterial compatibility cancer therapy chemotherapy commercialization cost crystallinity design efficacy study four-arm study hemodynamics improved improved outcome in vivo iron oxide iron oxide nanoparticle magnetic field magnetite ferrosoferric oxide meetings member mortality nanoparticle nanoparticle delivery novel paraform particle portability pressure prevent prototype safety assessment safety testing standard care standard of care systemic toxicity tool tumor tumor vascular supply

项目摘要

The value of lives lost to cancer-related deaths in the United States is expected to exceed $1.4 trillion by 2020. Of all cancers, glioblastoma multiforme (GBM) is one of the most aggressive types of central nervous system tumors with more than 95% of victims dying within 5 years. Left untreated, median survival is only 3 months. While the incidence rate is 3.2 per 100,000 person-years, GBM is the third leading cause of cancer-related death for those between 15 and 34 years of age. Standard treatment is complex and includes surgical resection, radiation therapy, and chemotherapy. Despite decades of effort to improve outcomes, GBM remains largely incurable with standard-of-care treatment resulting in a median survival of 15 months. Two reasons why cancer therapies have failed to effectively deliver therapeutic agents across the blood- brain barrier relate to dose-related therapeutic toxicity and adverse intra-tumor vascular hemodynamics. Because blood flow within GBM tumors is impeded by abnormal tortuous vascular networks and elevated interstitial fluid pressures, larger drug doses are needed to achieve effective therapeutic concentrations within tumor vasculature, which increases systemic toxicity risks. Intra-arterial (IA) delivery has been explored for 70 years to increase therapeutic agent concentration within tumors. In this approach, a microcatheter is navigated near the tumor’s blood supply and a high dose of the therapeutic agent is administered. While IA shows promise in reducing systemic toxicity compared to standard oral and intravenous methodologies, all current chemotherapeutics administration strategies remain hindered by an inability to deliver enough therapeutic concentrations within the tumor’s vascular network to effectively and completely kill the cancer. UNandUP has invented a novel magnetic nanoparticle-delivery platform that overcomes intra-tumor vascular hemodynamic resistance so that greater IA-administered chemotherapeutic concentrations are conveyed within the tumor. The technology consists of a small, angiosuite-compatible workstation which magnetically agitates iron oxide nanoparticles (IONPs) so that both the IONPs and the surrounding blood are better conveyed within the tumor. While conjugation of therapeutic agents promises to substantially reduce systemic toxicity, prior FDA discussions support that the technology could be potentially evaluated under the CDRH if therapeutics are unmodified and unconjugated. The team reflects magnetics, robotics, nanoparticle, clinical, and cancer experts. For Phase I, proof of concept will be shown that tumor hemodynamic resistance is overcome for the IONPs and the adjunctive IA-administrated agent. The aims include 1) workstation construction, 2) iron oxide particle formulation, 3) in vitro tumor phantom efficacy studies using CTA/MRA GBM datasets, and 4) acute in vivo efficacy and safety assessments using a known GBM animal model for IA- directed therapy. Prior to Phase II, an FDA meeting is planned to inform the regulatory pathway. In Phase II, the best anti-tumor agents will be identified and compared, and biocompatibility studies will be conducted.

到 2020 年，美国因癌症相关死亡而损失的生命价值预计将超过 1.4 万亿美元。在所有癌症中，多形性胶质母细胞瘤 (GBM) 是中枢神经系统最具侵袭性的类型之一如果不治疗，超过 95% 的患者会在 5 年内死亡，中位生存期仅为 3 个月。虽然发病率为每 10 万人年 3.2 例，但 GBM 是癌症相关的第三大原因 15 至 34 岁之间的死亡标准治疗很复杂，包括手术。尽管数十年来一直在努力改善预后，但 GBM 仍然存在。标准护理治疗基本上无法治愈，中位生存期为 15 个月。癌症疗法未能有效地通过血液传递治疗剂的两个原因是：脑屏障与剂量相关的治疗毒性和不利的肿瘤内血管血流动力学有关。因为 GBM 肿瘤内的血流受到异常曲折的血管网络和升高的阻碍间质液压力，需要更大的药物剂量才能在体内达到有效的治疗浓度动脉内 (IA) 给药已被探索了 70 年。几年来增加肿瘤内的治疗剂浓度。在这种方法中，通过微导管进行导航。 IA 显示，肿瘤的血液供应附近，并施用高剂量的治疗剂。与标准口服和静脉注射方法相比，所有当前的方法都有望减少全身毒性化疗给药策略仍然因无法提供足够的治疗而受到阻碍肿瘤血管网络内的浓度，有效并完全杀死癌症。 UNandUP 发明了一种新型磁性纳米粒子递送平台，克服了肿瘤内血管血流动力学阻力，因此更高的 IA 化疗浓度该技术由一个小型的、与血管套件兼容的工作站组成。磁力搅拌氧化铁纳米粒子 (IONP)，使 IONP 和周围的血液都更好地在肿瘤内传递，而治疗剂的结合有望大大减少。系统毒性，FDA 之前的讨论支持该技术可能会根据 CDRH 如果治疗方法未经修饰且未结合，则该团队会磁力反射、机器人技术、纳米粒子、对于第一阶段，概念验证将表明肿瘤血流动力学阻力是临床和癌症专家。 IONP 和辅助 IA 管理代理要克服的问题目标包括 1) 工作站。构建，2) 氧化铁颗粒配方，3) 使用 CTA/MRA GBM 进行体外肿瘤模型功效研究数据集，以及 4) 使用已知的 GBM 动物模型进行急性体内疗效和安全性评估在第二阶段之前，计划召开 FDA 会议以告知监管途径。将鉴定和比较最好的抗肿瘤药物，并进行生物相容性研究。