Journal
BIOMATERIALS
Volume 29, Issue 33, Pages 4429-4438Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2008.08.004
Keywords
Trans-activating transcriptor; Nanoparticles; Blood-brain-barrier; P-glycoprotein; Transport; Anti-HIV drugs
Funding
- National Institutes of Health, Mental Health [R21 MH06 7525]
- Cleveland Clinic
- American Heart Association, Heartland Affiliate [0710119Z]
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We have shown that nanoparticles (NPs) conjugated to trans-activating transcriptor (TAT) peptide bypass the efflux action of P-glycoprotein and increase 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 over 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 enhanced the CNS bioavailability of the encapsulated PI and maintained therapeutic drug levels 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 the replicating HIV-1 virus. (C) 2008 Elsevier Ltd. All rights reserved.
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