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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要许多药剂非常有效，但无法发挥显着的治疗活性大脑疾病，因为血脑屏障（BBB）有效地阻止他们进入脑内疾病。例如，尽管目前尽最大努力，大多数胶质母细胞瘤患者医疗护理，诊断后两年内死亡。因此，医学界非常需要新的方法有效的脑部药物输送，特别是针对恶性脑癌，但也适用于其他疾病。作为这一医疗需求的解决方案，我们寻求开发一种新颖的二元鼻内联合给药方法，该方法将绕过血脑屏障，使血脑屏障无法渗透的化疗药物能够进入大脑。作为一个在血脑屏障不渗透药物模型中，我们选择了硼替佐米 (BZM)，这是一种高活性抗癌化合物，对患有多发性骨髓瘤（一种白细胞癌症）的患者进行静脉注射非常有效。我们已表明 BZM 也具有非常有效地杀死脑癌细胞的效力，但它不起作用当通过静脉输注给药时，因为它不能穿过血脑屏障到达脑内的肿瘤。紫苏醇 (POH) 是一种源自自然界的化合物，通过途径给予时显示出抗癌活性。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，并且患者可以使用便携式雾化器自行施用 POH。据认为，其高亲脂性 POH 能够轻松地将其输送到大脑，至少部分是通过直接从鼻子到大脑的运输。为了我们自己的工作，我们拥有独特的高度纯化版本的 POH，称为 NEO100。我们的工作假设预测，在 NEO100 和 BZM 鼻内共同给药期间，NEO100 将充当鼻子到大脑的载体将 BMZ 运输到大脑中，从而绕过 BBB 障碍。这样一来，双方药物将到达大脑中的肿瘤部位并协同完成其肿瘤杀死任务。我们的目标该项目旨在验证这种鼻内药物共同递送在大鼠肿瘤模型中的作用。在第一个具体目标，我们将测量鼻内递送 BZM 后有多少药物进入大鼠大脑存在或不存在 POH。我们还将寻找药物作用的生物标记，作为药物作用的迹象药物发挥活性。在第二个具体目标中，我们将采用鼻内给药的方式来治疗患有脑损伤的大鼠。癌症，以确定这种新颖的共同递送方法是否足够有效以产生治疗效果结果。如果成功，该项目将为许多其他非侵入性、二元鼻子到大脑的运输奠定基础具有低血脑屏障渗透活性和潜在适用于多种中枢神经系统疾病的药剂。在就胶质母细胞瘤而言，这种方法的未来临床验证和实施有可能为预后严峻的患者群体提供有效的治疗选择。