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，美国与癌症相关死亡的生命价值预计将超过1.4万亿美元。在所有癌症中，胶质母细胞瘤多形（GBM）是中枢神经系统中最具侵略性的类型之一在5年内，恐怖死亡的肿瘤超过95％。未经治疗的中位生存期只有3个月。虽然事件率为每100,000人年3.2 15至34岁之间的死亡。标准治疗很复杂，包括手术切除，放射疗法和化学疗法。尽管数十年来改善结果，但GBM仍然存在在标准治疗中基本无法治愈，导致中位生存期15个月。癌症疗法未能有效地传递热量剂的两个原因与剂量相关的治疗毒性和肿瘤内血管血流动力学不良的脑屏障。因为GBM肿瘤内的血流受到异常曲折的血管网络的阻碍，并且升高间质液压力，需要较大的药物剂量来实现有效的治疗浓度肿瘤脉管系统，增加了全身毒性风险。动脉内（IA）的交付已经探索了70 年以增加肿瘤内治疗剂浓度的年份。在这种方法中，微导管导航在肿瘤的血液供应和高剂量的治疗剂附近。 ia显示与标准口服和静脉注射方法相比，有望降低全身毒性，所有当前无法提供足够的治疗的化学治疗剂策略仍然阻碍肿瘤的血管网络中的浓度有效并完全杀死了癌症。 UnAndup发明了一个新型的磁性纳米粒子交付平台，该平台克服了肿瘤内血管血流动力学抗性，以使更高的IA辅助化学治疗浓度是在肿瘤内输送。该技术由一个小型的，可徒兼容的工作站组成，该工作站磁搅拌氧化铁纳米颗粒（IONPS），以使IONP和周围的血液都是更好地在肿瘤内传达。虽然治疗剂的结合有望大大减少系统性毒性，先前的FDA讨论支持该技术可以在该技术下进行评估 CDRH如果理论未修改并且未缀合。该团队反映了磁性，机器人技术，纳米颗粒，临床和癌症专家。对于第一阶段，概念证明将表明肿瘤血液动力学抗性为克服IONPS和辅助IA-ADMIDISTAMED代理。目的包括1）工作站结构，2）使用CTA/MRA GBM的体外肿瘤幻影效率研究3）数据集和4）使用已知的GBM动物模型进行IA-急性体内效率和安全评估定向治疗。在第二阶段之前，计划举行一次FDA会议，以告知监管途径。在第二阶段，将确定和比较最佳的抗肿瘤药物，并将进行生物相容性研究。