An Improved Intra-Arterial Delivery Platform for Glioblastoma Multiforme

到2020年，美国因癌症相关死亡而失去的生命价值预计将超过1.4万亿美元。 多形性胶质母细胞瘤（GBM）是中枢神经系统最具侵袭性的肿瘤之一 超过95%的患者在5年内死亡。如果不治疗，中位生存期只有3个月。 虽然发病率为每10万人年3.2例，但GBM是癌症相关疾病的第三大原因。 15至34岁的人死亡。标准治疗是复杂的，包括手术 切除、放射治疗和化学治疗。尽管几十年来一直在努力改善结果，但GBM仍然存在。 用标准的护理治疗基本上无法治愈，导致中位生存期为15个月。 癌症疗法未能有效地将治疗剂输送到血液中的两个原因是- 脑屏障与剂量相关治疗毒性和不利的肿瘤内血管血流动力学有关。 由于GBM肿瘤内的血流受到异常曲折的血管网和升高的 由于组织间液压力，需要更大的药物剂量来达到有效的治疗浓度， 肿瘤脉管系统，这增加了全身毒性风险。动脉内（IA）输送已探索了70 年来增加肿瘤内的治疗剂浓度。在这种方法中，微导管被导航 靠近肿瘤的血液供应，并给予高剂量的治疗剂。虽然IA显示 与标准口服和静脉注射方法相比， 化疗剂给药策略仍然受到不能递送足够的治疗药物的阻碍 在肿瘤的血管网络内的浓度，以有效地和完全地杀死癌症。 UNANDUP发明了一种新型的磁性纳米颗粒输送平台， 血管血液动力学阻力，使得更大的IA-施用的化疗剂浓度， 在肿瘤内传播。该技术包括一个小型的angiosuite兼容工作站， 磁性搅拌氧化铁纳米颗粒（IONP），使IONP和周围的血液都 更好地在肿瘤内转移。虽然治疗剂的缀合有望显著减少 全身毒性，之前的FDA讨论支持该技术可以在 如果治疗剂是未修饰的和未缀合的，则为CDRH。该团队反映了磁性，机器人，纳米粒子， 临床和癌症专家。对于I期，概念验证将表明肿瘤血流动力学阻力是 克服了IONP和免疫抑制性IA给药的药物。目标包括：1）工作站 构建，2）氧化铁颗粒制剂，3）使用CTA/MRA GBM的体外肿瘤体模有效性研究 数据集，和4）使用已知的GBM动物模型进行IA的急性体内疗效和安全性评估- 定向治疗在第二阶段之前，计划召开FDA会议，通报监管途径。在第二阶段， 将确定和比较最佳的抗肿瘤剂，并进行生物相容性研究。

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.