Nanoparticle delivery of transition-metal chelators to the brain: Oxidative stress will never see it coming!
Nanoparticle delivery of transition-metal chelators to the brain: Oxidative stress will never see it coming!
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DOI：
10.2174/187152712799960709
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发表时间：
2012-02
期刊：
影响因子：
--
通讯作者：
Zhu X
中科院分区：
文献类型：
--
作者：
Bonda DJ;Liu G;Men P;Perry G;Smith MA;Zhu X
阿尔茨海默病（AD）的典型病理损害是显著和异常金属积聚的部位。因此，金属螯合疗法为AD的神经元退化提供了非常有吸引力的治疗措施，尽管其机构存在根本性缺陷。也就是说，结合并从体内除去过量过渡金属的螯合剂必须穿透血脑屏障（BBB），以对脑中金属的存在引起的氧化损伤灌输任何真实的效果。尽管在螯合给药方面取得了许多进展，但是，这种重要的要求在治疗上仍然遥不可及：最有效的螯合剂-即，对过渡金属如铁和铜具有高亲和力和特异性的那些是庞大的和亲水的，使得难以到达它们的生理作用位置。此外，小的亲脂性螯合剂，可以穿过大脑的防御墙，基本上遭受他们的过度有效。也就是说，它们通过从重要的RNA酶中去除过渡金属来诱导对增殖细胞的毒性。幸运的是，研究提供了一个漏洞。纳米颗粒，微小的，人造或天然的有机聚合物，能够运输金属螯合剂穿过血脑屏障，无论其大小和亲水性如何。因此，所述化合物可以充分改善AD脑中过量金属的氧化毒性，而本身不诱导任何此类毒性。我们在这里讨论了目前的状况，纳米粒输送系统，因为它们涉及到AD螯合治疗，并阐述其作用机制。一个令人兴奋的AD治疗的未来就在前方。
The pathological lesions typical of Alzheimer disease (AD) are sites of significant and abnormal metal accumulation. Metal chelation therapy, therefore, provides a very attractive therapeutic measure for the neuronal deterioration of AD, though its institution suffers fundamental deficiencies. Namely, chelating agents, which bind to and remove excess transition metals from the body, must penetrate the blood-brain barrier (BBB) to instill any real effect on the oxidative damages caused by the presence of the metals in the brain. Despite many advances in chelation administration, however, this vital requirement remains therapeutically out of reach: the most effective chelators—i.e., those that have high affinity and specificity for transition metals like iron and copper—are bulky and hydrophilic, making it difficult to reach their physiological place of action. Moreover, small, lipophilic chelators, which can pass through the brain’s defensive wall, essentially suffer from their over-effectiveness. That is, they induce toxicity on proliferating cells by removing transition metals from vital RNA enzymes. Fortunately, research has provided a loophole. Nanoparticles, tiny, artificial or natural organic polymers, are capable of transporting metal chelating agents across the BBB regardless of their size and hydrophilicity. The compounds can thereby sufficiently ameliorate the oxidative toxicity of excess metals in an AD brain without inducing any such toxicity themselves. We here discuss the current status of nanoparticle delivery systems as they relate to AD chelation therapy and elaborate on their mechanism of action. An exciting future for AD treatment lies ahead.
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DOI：
10.1111/j.1600-0773.1997.tb00390.x
发表时间：
1997-04-01
期刊：
PHARMACOLOGY & TOXICOLOGY
影响因子：
--
作者：
Gassen, M;Youdim, MBH
通讯作者：
Youdim, MBH
影响因子：
3.9
作者：
Alyautdin, RN;Tezikov, EB;Kreuter, J
通讯作者：
Kreuter, J
影响因子：
4.5
作者：
Kreuter, J;Shamenkov, D;Alyautdin, R
通讯作者：
Alyautdin, R
影响因子：
4
作者：
Castellani, Rudy J.;Lee, Hyoung-gon;Smith, Mark A.
通讯作者：
Smith, Mark A.
影响因子：
5.8
作者：
BORCHARD, G;AUDUS, KL;KREUTER, J
通讯作者：
KREUTER, J