A unique carrier for delivery of therapeutic compounds beyond the blood-brain barrier.
A unique carrier for delivery of therapeutic compounds beyond the blood-brain barrier.
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一个独特的载体，用于在血脑屏障之外提供治疗化合物。
DOI：
10.1371/journal.pone.0002469
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发表时间：
2008-06-25
期刊：
影响因子：
3.7
通讯作者：
Jefferies, Wilfred A.
中科院分区：
文献类型：
--
作者：
Karkan, Delara;Pfeifer, Cheryl;Vitalis, Timothy Z.;Arthur, Gavin;Ujiie, Maki;Chen, Qingqi;Tsai, Sam;Koliatis, Gerrasimo;Gabathuler, Reinhard;Jefferies, Wilfred A.
许多神经系统疾病的治疗干预都受到血脑屏障 (BBB) 形成的物理障碍的阻碍，血脑屏障阻止大多数药物从血液进入大脑。因此，确定向大脑输送药物的有效模式仍然是分子医学和纳米生物技术的“圣杯”。构成 BBB 的脑毛细血管拥有一种内源性受体，可将铁转运蛋白（称为 p97（黑转铁蛋白））运送穿过 BBB。在这里，我们探讨了这样一个假设：作为 p97 缀合物“搭载”的治疗药物可以穿过血脑屏障来治疗无法手术的脑肿瘤。人 p97 与化疗药物紫杉醇 (PTAX) 或阿霉素 (ADR) 共价连接，静脉注射后，使用药物的放射性标记和荧光衍生物测量它们对脑组织和其他器官的渗透。为了确定缀合物的功效，我们使用裸鼠模型来评估p97-药物缀合物对皮下生长的神经胶质瘤和乳腺肿瘤与颅内生长的肿瘤和乳腺肿瘤的活性。推注注射的 p97 药物缀合物和未缀合的 p97 在几分钟内穿过脑毛细血管内皮，并在 24 小时内累积至注射量的 1-2%。 p97-药物缀合物的脑递送在数量上比游离药物对照高 10 倍。此外，游离 ADR 和 p97-ADR 缀合物同样抑制脑外神经胶质瘤的皮下生长。值得一提的是，与相似累积剂量的游离 ADR 相比，只有 p97-ADR 缀合物能够显着延长患有颅内神经胶质瘤或乳腺肿瘤的动物的存活时间。这项研究为 p97 作为载体提供了初步的概念证明，该载体能够将治疗水平的药物从血液运送到大脑，用于治疗神经系统疾病，包括各类常驻和转移性脑肿瘤。因此，考虑在各种临床环境中实施这种新颖的递送平台以治疗急性和慢性神经系统疾病可能是谨慎的。
Therapeutic intervention in many neurological diseases is thwarted by the physical obstacle formed by the blood-brain barrier (BBB) that excludes most drugs from entering the brain from the blood. Thus, identifying efficacious modes of drug delivery to the brain remains a “holy grail” in molecular medicine and nanobiotechnology. Brain capillaries, that comprise the BBB, possess an endogenous receptor that ferries an iron-transport protein, termed p97 (melanotransferrin), across the BBB. Here, we explored the hypothesis that therapeutic drugs “piggybacked” as conjugates of p97 can be shuttled across the BBB for treatment of otherwise inoperable brain tumors. Human p97 was covalently linked with the chemotherapeutic agents paclitaxel (PTAX) or adriamycin (ADR) and following intravenous injection, measured their penetration into brain tissue and other organs using radiolabeled and fluorescent derivatives of the drugs. In order to establish efficacy of the conjugates, we used nude mouse models to assess p97-drug conjugate activity towards glioma and mammary tumors growing subcutaneously compared to those growing intracranially. Bolus-injected p97-drug conjugates and unconjugated p97 traversed brain capillary endothelium within a few minutes and accumulated to 1–2% of the injected by 24 hours. Brain delivery with p97-drug conjugates was quantitatively 10 fold higher than with free drug controls. Furthermore, both free-ADR and p97-ADR conjugates equally inhibited the subcutaneous growth of gliomas growing outside the brain. Evocatively, only p97-ADR conjugates significantly prolonged the survival of animals bearing intracranial gliomas or mammary tumors when compared to similar cumulated doses of free-ADR. This study provides the initial proof of concept for p97 as a carrier capable of shuttling therapeutic levels of drugs from the blood to the brain for the treatment of neurological disorders, including classes of resident and metastatic brain tumors. It may be prudent, therefore, to consider implementation of this novel delivery platform in various clinical settings for therapeutic intervention in acute and chronic neurological diseases.
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影响因子：
3.7
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