Towner Rheal A, Saunders Debra, Lerner Megan, Silasi Mansat Robert, Yuan Tian, Barber Dylan, Faakye Janet, Nyul-Toth Adam, Csiszar Anna, Greenwood-Van Meerveld Beverley, Smith Nataliya
Advanced Magnetic Resonance Center, Oklahoma Medical Research Foundation Oklahoma, OK, USA.
Department of Neuroscience Program, University of Oklahoma Health Sciences Center Oklahoma, OK, USA.
Am J Nucl Med Mol Imaging. 2021 Oct 15;11(5):363-373. eCollection 2021.
The blood-brain barrier (BBB) is usually impermeable to several drugs, which hampers treatment of various brain-related diseases/disorders. There have been several approaches to open the BBB, including intracarotid infusion of hyperosmotic concentrations of arabinose, mannitol, oleic or linoleic acids, or alkylglycerols, intravenous infusion of bradykinin B2, administration of a fragment of the ZO toxin from , targeting specific components of the tight junctions (e.g. claudin-5) with siRNA or novel peptidomimetic drugs, or the use of ultrasound with microbubbles. We propose the use of a low molecular weight (MW), nitrone-type compound, OKN-007, which can temporarily open up the BBB for 1-2 hours. Gadolinium (Gd)-based compounds assessed ranged in MW from 546 (Gd-DTPA) to 465 kDa (β-galactosidase-Gd-DOTA). We also included an albumin-based CA (albumin-Gd-DTPA-biotin) for assessment, as well as an antibody (Ab) against a neuron-specific biomarker conjugated to Gd-DOTA (anti-EphB2-Gd-DOTA). For the anti-EphB2 (goat Ab)-Gd-DOTA assessment, we utilized an anti-goat Ab conjugated with horse radish peroxidase (HRP) for confirmation of the presence of the anti-EphB2-Gd-DOTA probe. In addition, a Cy5 labeled anti-EphB2 Ab was co-administered with the anti-EphB2-Gd-DOTA probe, and assessed . This study demonstrates that OKN-007 may be able to temporarily open up the BBB to augment the delivery of various compounds ranging in MW from as small as ~550 to as large as ~470 kDa. This compound is an investigational new drug for glioblastoma (GBM) therapy in clinical trials. The translational capability for human use to augment the delivery of non-BBB-permeable drugs is extremely high.
血脑屏障（BBB）通常对多种药物具有不透性，这阻碍了各种脑部相关疾病/病症的治疗。已经有多种打开血脑屏障的方法，包括颈内动脉输注高渗浓度的阿拉伯糖、甘露醇、油酸或亚油酸，或烷基甘油；静脉输注缓激肽B2；给予来自[未提及具体来源]的ZO毒素片段；用小干扰RNA（siRNA）或新型拟肽药物靶向紧密连接的特定成分（如claudin-5）；或使用微泡超声。我们提议使用一种低分子量（MW）的硝酮类化合物OKN-007，它可以使血脑屏障暂时开放1至2小时。所评估的基于钆（Gd）的化合物分子量范围从546（Gd-DTPA）到465 kDa（β-半乳糖苷酶-Gd-DOTA）。我们还纳入了一种基于白蛋白的造影剂（白蛋白-Gd-DTPA-生物素）进行评估，以及一种与Gd-DOTA偶联的针对神经元特异性生物标志物的抗体（Ab）（抗-EphB2-Gd-DOTA）。对于抗-EphB2（山羊Ab）-Gd-DOTA评估，我们使用与辣根过氧化物酶（HRP）偶联的抗山羊Ab来确认抗-EphB2-Gd-DOTA探针的存在。此外，将Cy5标记的抗-EphB2 Ab与抗-EphB2-Gd-DOTA探针共同给药并进行评估[此处原文assessed后缺少内容]。本研究表明，OKN-007可能能够暂时打开血脑屏障，以增强分子量范围从小至约550到大致约470 kDa的各种化合物的递送。这种化合物是一种用于胶质母细胞瘤（GBM）治疗的临床试验中的研究性新药。其用于人类增强非血脑屏障可渗透药物递送的转化能力极高。
