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 tumors 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 tumors 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.
Public Health Relevance Statement: Glioblastoma multiforme (GBM) is the most common and aggressive primary central nervous system tumor malignancy, with an incidence rate of 3.2 per 100,000 population and a 5-year mortality greater than 95%. Reasons why pharmaceutical approaches have failed are multifold, but obstructive tumor intravascular hemodynamics and therapeutic agent toxicity remain major factors. For this Phase I proposal, UNandUP (short for Unmet Needs and Underserved Populations) will develop a technology which leverages the strength of intra-arterially-directed delivery of therapeutic agents immediately proximal to the tumor with a novel magnetic mechanism that overcomes hemodynamic resistance so that greater therapeutic concentrations are better delivered within tumor vasculature.
Project Terms: Acute; Age-Years; Aging; American; animal data; Animal Model; Animals; antitumor agent; arm; base; biomaterial compatibility; Blood; Blood - brain barrier anatomy; Blood flow; Blood Vessels; Brain; Caliber; Cancer Etiology; cancer therapy; Cause of Death; Cells; Central Nervous System Neoplasms; Cessation of life; Characteristics; chemotherapy; Clinical; commercialization; Complex; cost; crystallinity; Cyclic GMP; Data Set; design; Devices; Diagnosis; Diffusion; Distal; Dose; Doxorubicin; Dyes; efficacy study; Embolism; Evans blue stain; Excision; Formulation; four-arm study; Frequencies; Glioblastoma; Goals; Heating; hemodynamics; Hemorrhage; Histopathology; Hospitals; Human; Hypersensitivity; improved; improved outcome; In Vitro; in vivo; Incidence; Intercellular Fluid; Internal carotid artery structure; Intervention; Intravenous; iron oxide; iron oxide nanoparticle; Label; Left; Legal patent; magnetic field; Magnetic nanoparticles; Magnetism; magnetite ferrosoferric oxide; Malignant Neoplasms; Measures; meetings; member; Methodology; Modeling; Morphologic artifacts; Morphology; mortality; Motion; Mus; nanoparticle; nanoparticle delivery; novel; Operative Surgical Procedures; Oral; paraform; particle; Performance; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Photomicrography; Physiological; Polyethylene Glycols; Population; portability; pressure; prevent; prototype; Publishing; Radiation therapy; Reaction; Regulatory Pathway; Reproducibility; Resistance; Risk; Robotics; Roentgen Rays; Safety; safety assessment; safety testing; Shapes; Small Business Innovation Research Grant; standard care; standard of care; Statistical Methods; System; systemic toxicity; Techniques; Technology; Testing; Therapeutic; Therapeutic Agents; tool; Torque; Toxic effect; Treatment Efficacy; Treatment-related toxicity; tumor; tumor vascular supply; Underserved Population; United States; Work
