SBIR-STTR Award

Tissue probe measurements and imaging show that tumor hypoxia is common in many cancers including head and neck cancer, cervical cancer, prostate cancer and many other solid tumors. Tumors with low oxygen concentrations are resistant to radiation treatment. New imaging techniques can be used to diagnose tumor hypoxia. A number of methods have been tested to increase tumor oxygenation, but in general without great success. There is as yet no clinically available method of increasing tumor oxygenation to improve response to radiation treatment. The purpose of this Phase I SBIR grant application is to develop a new oxygen carrier based upon dodecaperfluoropentane emulsion (DDFPe) that is active at less than 1/00th the dose of previously described carriers and that will clear from the body shortly after radiation treatment. The Specific Aims are: 1. Develop an optimized DDFPe radiation sensitizer formulation; 2. Characterize the formulation in vitro; 3. Study toxicity/biocompatibility in cell culture; 4. Conduct toxicity studies in mice; 5. Perform radiation sensitization studies in cell culture. DDFPe was previously studied in man for another application, but the surfactant used to stabilize the emulsion was not pure. We have synthesized pure surfactants for stabilizing DDFPe that should be pharmaceutically acceptable. The experiments are designed to test and compare these new surfactants for stabilizing DDFPe. From these preliminary studies we will define prototype DDFPe radiation sensitization product for formal preclinical development. In Phase II we shall conduct animal studies in which we will use imaging to show amelioration in tumor hypoxia pre and post treatment and improvement in tumor response with radiation therapy for hypoxic tumors.

Public Health Relevance:
Tumor hypoxia is common in many cancers including head and neck cancer, cervical cancer, prostate cancer and many other solid tumors. Tumors with low oxygen concentrations are resistant to radiation treatment. This NIH Phase I grant application is directed to development of a new sensitizer that may be much more effective than prior compounds in improving oxygenation of hypoxic cancer cells and improving response of cancer to treatment.

Thesaurus Terms:
After Care; After-Treatment; Aftercare; Animals; Applications Grants; Body Tissues; Cancer Radiotherapy; Cancer Of Cervix; Cancer Of Prostate; Cancer Of The Uterine Cervix; Cancers; Cell Culture Techniques; Cervical Cancer; Cervix Cancer; Development; Diagnosis; Dose; Drug Formulations; Emulsions; Formulation; Formulations, Drug; Grant Proposals; Grants, Applications; Head And Neck Cancer; Hypoxia; Hypoxic; Image; Imaging Procedures; Imaging Techniques; In Vitro; Malignant Cell; Malignant Cervical Neoplasm; Malignant Cervical Tumor; Malignant Head And Neck Neoplasm; Malignant Neoplasm Of The Cervix; Malignant Neoplasms; Malignant Tumor; Malignant Tumor Of The Cervix; Malignant Tumor Of The Cervix Uteri; Malignant Tumor Of The Head And Neck; Malignant Tumor Of The Prostate; Malignant Uterine Cervix Neoplasm; Malignant Uterine Cervix Tumor; Malignant Neoplasm Of Cervix Uteri; Malignant Neoplasm Of Prostate; Malignant Prostatic Tumor; Mammals, Mice; Measurement; Methods; Mice; Murine; Mus; Nih; National Institutes Of Health; National Institutes Of Health (U.S.); O Element; O2 Element; Oxygen; Oxygen Deficiency; Phase; Prostate Ca; Prostate Cancer; Prostatic Cancer; Radiation; Radiation Sensitizers; Radiation Therapy; Radiation-Sensitizing Agents; Radiation-Sensitizing Drugs; Radiosensitizing Agents; Radiosensitizing Drugs; Radiotherapeutics; Radiotherapy; Resistance; Sbir; Sbirs (R43/44); Small Business Innovation Research; Small Business Innovation Research Grant; Solid Neoplasm; Solid Tumor; Technics, Imaging; Testing; Tissues; Toxic Effect; Toxicities; Tumor Oxygenation; United States National Institutes Of Health; Base; Biocompatibility; Biomaterial Compatibility; Cancer Cell; Design; Designing; Experiment; Experimental Research; Experimental Study; Head & Neck Cancer; Head & Neck Tumor; Imaging; Improved; Irradiation; Malignancy; Man; Man's; Neoplasm/Cancer; Novel; Pre-Clinical; Preclinical; Prototype; Public Health Relevance; Radiosensitizer; Ray (Radiation); Research Study; Resistant; Response; Success; Surfactant; Tumor

Glioblastoma multiforme (GBM) is a highly aggressive, malignant brain tumor widely known to be hypoxic and hypoxia is an important factor in the poor response of GBM to treatment. The most common therapy for GBM is surgical excision followed by fractionated RT + chemotherapy. Still, after treatment, GBM patients only survive, on average, about 12 months. A safe, effective technology that raised tumor pO2 and could be administered during each fraction of RT should improve outcomes in GBM patients treated with RT. This proposal is directed to developing such a technology. NVX-108 is a nano-emulsion of dodecafluoropentane (DDFPe). Low doses of NVX-108 raise tumor pO2 by 400% compared to carbogen alone, reverse radiation resistance and increase survival in animals treated with RT. Tumor pO2 continues to rise for up to two hours following administration of NVX-108; the material clears from the body relatively rapidly facilitating repeat administration. NVX-108, a stable formulation of DDFPe, was previously tested as an ultrasound contrast agent (USCA) in 2,000 patients and was safe. The FDA deemed DDFPe approvable but it was never launched due to small size of USCA market. NuvOx had pre-IND meetings with the FDA; the FDA agreed that NuvOx could reference the prior studies of DDFPe in support of clinical trials of NVX-108. This proposal is designed to develop biomarker imaging that can be used to validate tumor re- oxygenation in GBM as well as to confirm efficacy in two relevant preclinical models of GBM. The data from this study will be used to support an IND in the US for a clinical trial in GBM patients treated with RT + NVX-108. The biomarker imaging method developed in this proposal will be incorporated into the study design of the clinical trial to confirm tumor re-oxygenation in the GBM patients. There are two principle objectives to this proposal: 1) to validate tumor re-oxygenation with NVX-108 with imaging biomarkers and 2) to confirm efficacy of NVX-108 + RT + carbogen in treating GBM. In the first objective we will study tumor re-oxygenation with NVX-108 in the C6 glioma model in rats and validate efficacy of TOLD MRI with 18F-EF5 PET. In the second model we will study tumor re- oxygenation with NVX-108 in the GL261 glioma mode in mice and validate TOLD with HypoxiSense" fluorescence imaging and bioluminescence. In the second objective we will confirm efficacy of NVX-108 + RT + carbogen in these two GBM models. In the mouse model we will also treat animals with moderate and severe levels of tumor hypoxia. We hypothesize that NVX-108 will reverse radiation resistance regardless of the level of tumor hypoxia.

Public Health Relevance Statement:


Public Health Relevance:
Glioblastoma multiforme (GBM) is a particularly deadly form of primary brain cancer affecting about 17,000 patients per year in North America and Europe. Standard treatment is primary surgical excision followed by radiation therapy and chemotherapy; survival is then still only about 12 months. This project is directed towards advancing development of NVX-108 nanoparticles to improve outcomes in GBM patients treated with radiation therapy.

Project Terms:
Advanced Development; Affect; Aftercare; Animal Model; Animals; Australia; base; Biological Markers; Bioluminescence; Buffers; Carbogen; Characteristics; chemotherapy; Clinical Research; Clinical Trials; Contrast Media; Data; design; Dose; Drug Formulations; EF5; Europe; Excision; fluorescence imaging; Fluorocarbons; Glioblastoma; Glioma; Hour; Human; Hypoxia; Image; imaging modality; improved; Liquid substance; Magnetic Resonance Imaging; Malignant neoplasm of brain; Marketing; meetings; Methods; Modeling; mouse model; Mus; nanoemulsion; nanoparticle; North America; Operative Surgical Procedures; Outcome; Oxygen; Pancreas; Patients; perfluoropentane; Phase; phase 2 study; Phase II Clinical Trials; Physiological; Positron-Emission Tomography; pre-clinical; Pre-Clinical Model; preclinical study; Primary carcinoma of the liver cells; Prostate; public health relevance; Radiation; radiation resistance; Radiation therapy; Radiation-Sensitizing Agents; Randomized; Rattus; Research Design; Resistance; response; Safety; standard care; Technology; Testing; Therapeutic; Time; tumor; Tumor Oxygenation; tumor xenograft; Ultrasonography; Validation