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

项目摘要/摘要 许多药物效力很强，但不能对人发挥实质性的治疗作用 大脑紊乱，因为血脑屏障(BBB)有效地阻止他们进入 脑部疾病。例如，大多数胶质母细胞瘤患者，尽管目前尽了最大努力 医疗，确诊后两年内死亡。因此，医学上对新方法的需求很大。 有效的脑部药物输送，特别是对恶性脑癌，但对其他疾病也是如此。 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腔联合给药方法，该方法将 绕过血脑屏障，使其他不透血脑屏障的化疗药物能够进入大脑。作为一名 对于血脑屏障不渗透药物的模型，我们选择了硼替佐米(BZM)，这是一种高效的抗癌化合物 对多发性骨髓瘤患者静脉注射非常有效，多发性骨髓瘤是一种白细胞癌。我们 已经证明BZM也有非常有效地杀死脑癌细胞的效力，但它不起作用 当通过静脉输液给药时，因为它不能穿过血脑屏障，到达大脑内部的肿瘤。 紫苏醇(POH)是一种来源于自然的化合物，通过 对恶性脑癌患者的鼻子。这种给药方法是非侵入性的，耐受性很好，而且 患者可以使用便携式雾化器给自己注射POH。据认为，它的高亲脂性 POH使其能够轻松地传输到大脑，至少在一定程度上是通过直接的鼻到脑传输。为了我们自己的工作， 我们独一无二地提供了一种高度纯化的POH版本，称为NEO100。 我们的工作假说预测，在NEO100和BZM的鼻腔联合递送过程中，NEO100将作为一个 鼻到脑的载体将BMZ运送到大脑中，从而绕过血脑屏障。这样一来，两者都 药物将到达大脑中的肿瘤部位，并协同展开他们的肿瘤杀灭任务。我们的目标是 项目是建立这种鼻腔药物共给药在大鼠肿瘤模型中起作用的原则证明。在 第一个特定目标，我们将测量BZM鼻腔给药后大鼠大脑中有多少药物进入 存在或不存在POH。我们还将寻找药物效应的生物标记物，以表明 药物发挥作用。在第二个具体目标中，我们将使用鼻腔给药来治疗大鼠脑损伤 癌症，以确定这种新的联合递送方法是否足够有效，以产生治疗 结果。 如果成功，该项目将为许多其他生物的非侵入性、二元鼻到脑传输奠定基础 低血脑屏障穿透活性和潜在的适用于各种中枢神经系统疾病的药物。在……里面 胶质母细胞瘤的病例、未来的临床验证和该方法的实施有可能 为预后不佳的患者群体提供有效的治疗选择。

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.