Vector-mediated delivery of a polyamide ("peptide") nucleic acid analogue through the blood-brain barrier in vivo.
Vector-mediated delivery of a polyamide ("peptide") nucleic acid analogue through the blood-brain barrier in vivo.
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DOI：
10.1073/pnas.92.12.5592
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发表时间：
1995-06
影响因子：
11.1
通讯作者：
W. Pardridge;R. Boado;Young-Sook Kang
中科院分区：
文献类型：
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作者：
W. Pardridge;R. Boado;Young-Sook Kang
聚酰胺（“肽”）核酸（PNAs）是具有抗原和反义作用的分子，如果这些分子能够通过构成血脑屏障的脑毛细血管内皮壁进行运输，可能被证明是有效的神经药物。本研究中使用的模型PNA是一种18-mer，与人类免疫缺陷病毒1型rev基因反义，在氨基端被生物素化，在羧基端附近的酪氨酸残基上被碘化。生物素化的PNA连接到链霉亲和素（SA）和OX26小鼠转铁蛋白受体单克隆抗体的偶联物。血脑屏障具有高的转铁蛋白受体浓度，使OX26-SA偶联物能够将生物素化的PNA传递到大脑。尽管静脉注射后游离PNA的脑摄取可以忽略不计，但当PNA与OX26-SA载体结合时，PNA的脑摄取至少增加了28倍。在静脉注射后60分钟，与OX26-SA载体结合的PNA的脑吸收量为每克脑注射剂量的0.1%，接近静脉注射吗啡的脑吸收量。RNase保护实验表明，结合到OX26-SA载体上的PNA保留了与合成rev mRNA结合的能力。综上所述，目前的研究表明，尽管PNAs通过血脑屏障的运输可以忽略不计，但通过将这些潜在的神经药物与载体介导的肽-药物传递系统偶联，可以将这些潜在的神经药物传递到大脑。
Polyamide ("peptide") nucleic acids (PNAs) are molecules with antigene and antisense effects that may prove to be effective neuropharmaceuticals if these molecules are enabled to undergo transport through the brain capillary endothelial wall, which makes up the blood-brain barrier in vivo. The model PNA used in the present studies is an 18-mer that is antisense to the rev gene of human immunodeficiency virus type 1 and is biotinylated at the amino terminus and iodinated at a tyrosine residue near the carboxyl terminus. The biotinylated PNA was linked to a conjugate of streptavidin (SA) and the OX26 murine monoclonal antibody to the rat transferrin receptor. The blood-brain barrier is endowed with high transferrin receptor concentrations, enabling the OX26-SA conjugate to deliver the biotinylated PNA to the brain. Although the brain uptake of the free PNA was negligible following intravenous administration, the brain uptake of the PNA was increased at least 28-fold when the PNA was bound to the OX26-SA vector. The brain uptake of the PNA bound to the OX26-SA vector was 0.1% of the injected dose per gram of brain at 60 min after an intravenous injection, approximating the brain uptake of intravenously injected morphine. The PNA bound to the OX26-SA vector retained the ability to bind to synthetic rev mRNA as shown by RNase protection assays. In summary, the present studies show that while the transport of PNAs across the blood-brain barrier is negligible, delivery of these potential neuropharmaceutical drugs to the brain may be achieved by coupling them to vector-mediated peptide-drug delivery systems.