Innovative Nose-to-Brain Anticancer Drug Transport Facilitated by NEO100

NEO100 促进创新的鼻到脑抗癌药物运输

• 批准号: 9465196
• 负责人: THOMAS C. CHEN
• 金额: $ 30万
• 依托单位: NEONC TECHNOLOGIES, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9465196
• 关键词: Alkylating Agents; Antineoplastic Agents; Biological; Biological Markers; Blood; Blood - brain barrier anatomy; Blood Circulation; Bortezomib; Brain; Brain Diseases; Brain Neoplasms; Brazil; Calibration; Caring; Cell Death; Cell Proliferation; Central Nervous System Diseases; Clinic; Clinical; Clinical Trials; Core Facility; Diagnosis; Disease; Drug Delivery Systems; Drug Transport; Future; Glioblastoma; Goals; Image; In Vitro; Intracranial Neoplasms; Intravenous; Intravenous infusion procedures; Lesion; Leukocytes; Luciferases; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of brain; Measurement; Measures; Medical; Metastatic malignant neoplasm to brain; Methods; Modeling; Monitor; Monoterpenes; Multiple Myeloma; Nature; Nebulizer; Nose; Organ; Patient-Focused Outcomes; Patients; Penetration; Peripheral; Pharmaceutical Preparations; Pharmacologic Substance; Primary Neoplasm; Proteasome Inhibitor; Public Health; Rattus; Recurrence; Regimen; Resistance; Rodent; Route; Self-Administered; Site; Stress; Therapeutic; Time; Treatment Efficacy; Tumor Tissue; Validation; Work; angiogenesis; anti-cancer; anticancer activity; base; brain tissue; cancer cell; drug distribution; endoplasmic reticulum stress; innovation; lipophilicity; neoplastic cell; novel; novel strategies; optical imaging; outcome forecast; perilla alcohol; portability; prevent; standard of care; temozolomide; therapy outcome; transcription factor CHOP; tumor; tumor growth; uptake

Project Summary/Abstract 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.

项目摘要/摘要 许多药物具有很高的效力，但无法发挥大量的治疗活性 大脑的疾病，因为血脑屏障（BBB）有效地阻止了它们进入该地点 脑内疾病。例如，大多数胶质母细胞瘤患者，尽管当前尽了最大的努力 医疗保健，诊断后两年内死亡。因此，对新方法有很大的医疗需求 有效的大脑药物输送，特别是针对恶性脑癌，但也是其他疾病。 作为解决这一医疗需求的解决方案，我们试图开发一种新型的二元二进制鼻内共递送方法，该方法将 规避BBB并使其他BBB不受欢迎的化学治疗药物的访问。作为 我们选择了BBB可侵入药物的模型，我们选择了硼替佐米（BZM），这是一种高度活性的抗癌化合物，是 静脉注射对多发性骨髓瘤（白细胞癌）静脉注射时非常有效。我们 已经表明，BZM也具有非常有效杀死脑癌细胞的效力，但它行不通 当通过静脉输注给予时，因为它无法越过BBB并进入大脑内部的肿瘤。 perillyly醇（POH）是源自自然的结合，当通过 恶性脑癌患者的鼻子。这种传递方法是无创的，耐受性很好，并且 患者可以使用便携式雾化器管理POH。据认为 POH至少可以通过直接的鼻子到脑运输来轻松地向大脑传递。对于我们自己的工作， 我们拥有高度纯化的POH，称为Neo100。 我们的工作假设预测，在Neo100和BZM的鼻内共递送期间，Neo100将充当 从鼻子到脑载体将BMZ运输到大脑中，从而规避BBB障碍物。这样，两者俩 代理商将到达大脑中的肿瘤部位，并在协同中展开他们杀死肿瘤的任务。我们的目标 该项目是这种鼻内药物共递送在大鼠肿瘤模型中起作用的概念证明。在 第一个具体目的，我们将测量在BZM内鼻内递送BZM后，有多少药物进入大鼠的大脑 POH的存在或不存在。我们还将寻找药物作用的生物学标志物，以表明 药物发挥活性。在第二个特定目标中，我们将使用鼻内药物输送来治疗大脑 癌症，以确定这种新颖的共递送方法是否足够有效以产生治疗 结果。 如果成功，该项目将为非侵入性的二进制二进制二进制运输奠定基础 BBB渗透活性且潜在适用于各种CNS疾病的药物。在 胶质母细胞瘤，未来临床验证和这种方法的实施的情况有可能 为具有严峻预后的患者组提供有效的治疗选择。