Establishment of delivery system to the brain for antilsodies, enzymes, and neurotrophic factors without breakage of blood-brain barrier

已知某种细胞在注射后可以从血流中迁移到特定的靶器官。它们包括脑迁移细胞，如神经干细胞、部分骨髓来源细胞、淋巴细胞和小胶质细胞。小胶质细胞是大脑中神经胶质细胞的一个亚群，通过其吞噬活性和产生酶、细胞因子和营养因子，在神经细胞的发育、分化和维持中发挥重要作用。小胶质细胞脑迁移的机制被认为是通过跨细胞途径，因为小胶质细胞迁移发生时没有任何血脑屏障的破坏。我发现小胶质细胞克隆细胞保留了从循环中迁移到大脑的能力，并且小胶质细胞可以通过将小胶质细胞转染的半乳糖苷酶基因表达载体注射到循环中，将感兴趣的基因传递到大脑。同时，我成功地分离了几种可以模拟和/或竞争小胶质脑迁移活动的肽。这些肽足够小，可以附着在几种化学物质和生化物质上，也可以作为脑迁移标签放在重组蛋白的序列上。我指出了肽穿透血脑屏障并分布于脑实质的能力，因此，修饰的肽对于多用途的大脑递送工具是有用的，包括体内PET成像在内的几项分析证明了其有效性。现在，我和我的同事们正试图用我们的新肽生产几种针对大脑的药物。我们的多肽可以开辟一条通往脑实质的道路，甚至是像pet配体这样穿透性差的化合物。此外，我们希望我们的多肽能够更灵活地将许多生物活性物质输送到大脑中。

It is known that a certain kind of cells can migrate into a specific target organ from blood flow when injected. They include brain-migrating cells such as neural stem cells, a part of bone marrow derived cells, lymphocytes and microglia. Microglia are subpopulation of glial cell in the brain and play important roles in the development, differentiation and maintenance of neural cells via their phagocytic activity and production of enzymes, cytokines and trophic factors. The mechanism of microglial brain migration is thought to be via a trans cellular pathway because microglial migration occur with out any breakage of the blood brain barrier. I found that microglia clone cells retain the capability to migrate into the brain from the circulation and that microglia can deliver the gene of interest to brain, by injecting microglia transfected galactosidase gene expressing vector to the circulation.Meanwhile, I have successfully isolated several peptide which can mimic and/or compete the microglial brain-migrating activity. The peptides are small enough to be attached to several chemicals and biochemical materials and also to put in the sequence franking to recombinant protein as a brain-migrating tag. I indicated the ability of the peptides to penetrate through the BBB and distribute in brain parenchyma, therefore, the modified peptides are useful for the multi-purpose delivery tool to the brain, an availability of which was proved by several analyses including in vivo PET imaging.Now I and my colleagues are trying to produce several brain-targeting drugs with our novel peptide. Our peptides may open the way of delivering into brain parenchyma even a compound as the PET-ligand with poor penetrability into brain. Further, we expect that our peptides offer the more flexibility in use for the delivery of many bio active materials into the brain.