Many pharmaceutical agents are highly potent, but are unable to exert substantial therapeutic activity against disorders of the brain, because the blood-brain barrier (BBB) effectively prevents their access to the site of intracerebral disease. For example, the majority of glioblastoma patients, despite the best efforts of current medical care, die within two years after diagnosis. Hence, there is a great medical need for novel approaches to effective brain drug delivery, in particular for malignant brain cancers, but other diseases as well. As a solution to this medical need, we seek to develop a novel binary intranasal co-delivery method that will circumvent the BBB and enable brain access of otherwise BBB-impermeable chemotherapeutic drugs. As a model for a BBB-impermeable drug, we chose bortezomib (BZM), a highly active anticancer compound that is very effective when given intravenously to patients with multiple myeloma, a cancer of white blood cells. We have shown that BZM has the potency to very effectively kill brain cancer cells as well, but it does not work when given via intravenous infusion, because it cannot cross the BBB and reach tumors inside the brain. Perillyl alcohol (POH) is acompound derived from nature that has shown anticancer activity when given via the nose to patients with malignant brain cancer. This delivery method is non-invasive and very well tolerated, and patients can administer POH themselves with a portable nebulizer. It is thought that the high lipophilicity of POH enables its easy delivery to the brain, at least in part via direct nose-to-brain transport. For our own work, we have uniquely available a highly purified version of POH, called NEO100. Our working hypothesis predicts that during intranasal co-delivery of NEO100 and BZM, NEO100 will act as a nose-to-brain carrier to transport BMZ into the brain, thereby circumventing the BBB obstacle. This way, both agents will reach the tumor site in the brain and unfold their tumor-killing task in concert. The goal of our project is toestablish proof-of-principle that this intranasal drug co-delivery works in a rat tumor model. In the first specific aim, we will measure how much drug enters the brain of rats after intranasal delivery of BZM in the presence or absence of POH. We will also look for biological markers of drug effects, as an indication that the drugs exerted activity. In the second specific aim, we will use intranasal drug delivery to treat rats with brain cancers, in order to determine whether this novel co-delivery approach is effective enough to yield therapeutic outcomes. If successful, this project will set the stage for non-invasive, binary nose-to-brain transport of many other pharmaceutical agents with low BBB penetration activity and potential applicability to diverse CNS disorders. In the case of glioblastoma, future clinical validation and implementation of this approach has the potential to provide an effective therapeutic option to a patient group with otherwise grim prognosis.
Public Health Relevance Statement: Project Narrative Unlike systemic cancers, brain neoplasms have not benefited from substantial improvements in cancer therapeutic regimens that have occurred over the past decades. Many potent pharmaceutical agents are unable to exert their substantial activities due to the limitation of blood brain barrier (BBB). As a solution to this unmet medical need, we seek to develop a novel binary intranasal co-delivery (NEO100 and BZM) method that will circumvent the BBB and enable brain access of otherwise BBB-impermeable chemotherapeutic drug, bortezomib (BZM). Since NEO100 itself harbors anticancer activity (ER stress inducer), both agents will reach the tumor foci inside the brain and unfold their tumor-killing task in concert. If successful, our project will contribute to the improvement of public health by providing better treatment options for brain tumors.
Project Terms: Alkylating Agents; angiogenesis; anti-cancer; anticancer activity; Antineoplastic Agents; base; Biological; Biological Markers; Blood; Blood - brain barrier anatomy; Blood Circulation; Bortezomib; Brain; Brain Diseases; Brain Neoplasms; brain tissue; Brazil; Calibration; cancer cell; Caring; Cell Death; Cell Proliferation; Central Nervous System Diseases; Clinic; Clinical; Clinical Trials; Core Facility; Diagnosis; Disease; Drug Delivery Systems; drug distribution; Drug Transport; endoplasmic reticulum stress; Future; Glioblastoma; Goals; Image; In Vitro; innovation; Intracranial Neoplasms; Intravenous; Intravenous infusion procedures; Lesion; Leukocytes; lipophilicity; Luciferases; Malignant - descriptor; Malignant neoplasm of brain; Malignant Neoplasms; Measurement; Measures; Medical; Metastatic malignant neoplasm to brain; Methods; Modeling; Monitor; Monoterpenes; Multiple Myeloma; Nature; Nebulizer; neoplastic cell; Nose; novel; novel strategies; optical imaging; Organ; outcome forecast; Patient-Focused Outcomes; Patients; Penetration; perilla alcohol; Peripheral; Pharmaceutical Preparations; Pharmacologic Substance; portability; prevent; Primary Neoplasm; Proteasome Inhibitor; Public Health; Rattus; Recurrence; Regimen; Resistance; Rodent; Route; Self-Administered; Site; standard of care; Stress; temozolomide; Therapeutic; therapy outcome; Time; transcription factor CHOP; Treatment Efficacy; tumor; tumor growth; Tumor Tissue; uptake; Validation; Work
