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.

项目总结/摘要 许多药剂是高度有效的，但不能对抗肿瘤药物发挥实质性的治疗活性。 由于血脑屏障（BBB）有效地阻止了它们进入大脑的部位， 脑内疾病例如，大多数胶质母细胞瘤患者，尽管目前的最大努力， 在诊断后两年内死亡。因此，对于新的方法存在巨大的医学需求 有效的脑部药物输送，特别是对于恶性脑癌，但也适用于其他疾病。 作为这种医疗需求的解决方案，我们寻求开发一种新的二元鼻内共递送方法， 绕过血脑屏障，并使血脑屏障不可渗透的化疗药物能够进入大脑。作为 作为血脑屏障不渗透药物的模型，我们选择了硼替佐米（BZM），一种高活性的抗癌化合物， 当静脉注射给多发性骨髓瘤（一种白色血细胞癌症）患者时非常有效。我们 已经证明BZM也有非常有效地杀死脑癌细胞的潜力，但它不起作用 当通过静脉输注给药时，因为它不能穿过BBB并到达脑内的肿瘤。 紫苏醇（POH）是一种天然化合物，通过给药显示出抗癌活性。 恶性脑癌患者的鼻子。这种递送方法是非侵入性的，并且耐受性非常好， 患者可以用便携式喷雾器自己施用POH。据认为， POH使其能够容易地递送到大脑，至少部分地通过直接的鼻-脑运输。为了我们自己的工作， 我们有一种高纯度的POH，称为NEO 100。 我们的工作假设预测，在鼻内共递送NEO 100和BZM期间，NEO 100将充当鼻内共递送的载体。 鼻-脑载体将BMZ转运到大脑中，从而绕过BBB障碍。这样，两个 药剂将到达脑中的肿瘤部位并协同展开它们的肿瘤杀伤任务。我们的目标 项目是建立鼻内药物共输送在大鼠肿瘤模型中起作用的原理验证。在 第一个具体的目标，我们将测量在鼻内递送BZM后有多少药物进入大鼠的脑。 有无POH。我们还将寻找药物作用的生物标志物，作为药物作用的指示。 药物发挥作用。在第二个具体目标中，我们将使用鼻内给药来治疗脑损伤大鼠， 癌症，以确定这种新的共同递送方法是否足够有效， 结果。 如果成功的话，这个项目将为许多其他非侵入性的二元鼻脑运输奠定基础。 具有低BBB穿透活性和对多种CNS病症的潜在适用性的药物制剂。在 胶质母细胞瘤的情况下，未来的临床验证和实施这种方法有可能 为预后不良的患者群体提供了有效的治疗选择。