TAT-conjugated nanoparticles for the CNS delivery of anti-HIV drugs.
TAT-conjugated nanoparticles for the CNS delivery of anti-HIV drugs.
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DOI：
10.1016/j.biomaterials.2008.08.004
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发表时间：
2008-11
期刊：
影响因子：
14
通讯作者：
Labhasetwar V
中科院分区：
文献类型：
--
作者：
Rao KS;Reddy MK;Horning JL;Labhasetwar V
我们已经证明，纳米颗粒（NPs）结合反式激活转录（TAT）肽绕过p -糖蛋白的外排作用，并增加了包裹利托那韦（一种蛋白酶抑制剂（PI））穿过血脑屏障（BBB）到中枢神经系统（CNS）的运输。随着时间的推移，药物实质/毛细血管比稳定增加，而不破坏血脑屏障的完整性，这表明tat结合的NPs在运输到实质之前首先在脑血管系统中固定。脑切片的组织学分析进一步证实了NPs在脑实质中的定位。在2周时，结合NPs的脑药物水平比溶液药物高800倍。药物在四周内清除。综上所述，tat偶联的NPs提高了包封PI的中枢神经系统生物利用度，并在大脑中维持了一段时间的治疗药物水平，这可能有效地降低了中枢神经系统中的病毒载量，而中枢神经系统是复制HIV-1病毒的储存库。
We have shown that nanoparticles (NPs) conjugated to trans-activating transcriptor (TAT) peptide bypass the efflux action of P-glycoprotein and increases the transport of the encapsulated ritonavir, a protease inhibitor (PI), across the blood-brain-barrier (BBB) to the central nervous system (CNS). A steady increase in the drug parenchyma/capillary ratio with time without disrupting the BBB integrity suggests that TAT-conjugated NPs are first immobilized in the brain vasculature prior to their transport into parenchyma. Localization of NPs in the brain parenchyma was further confirmed with histological analysis of the brain sections. The brain drug level with conjugated NPs was 800-fold higher than that with drug in solution at two weeks. Drug clearance was seen within four weeks. In conclusion, TAT-conjugated NPs enhance the CNS bioavailability of the encapsulated PI and maintained therapeutic drug level in the brain for a sustained period that could be effective in reducing the viral load in the CNS which acts as a reservoir for replicating HIV-1 virus.
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