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Anti-HIV efficacy and biodistribution of nucleoside reverse transcriptase inhibitors delivered as squalenoylated prodrug nanoassemblies

Paper ID Volume ID Publish Year Pages File Format Full-Text
6537 499 2013 8 PDF Available
Title
Anti-HIV efficacy and biodistribution of nucleoside reverse transcriptase inhibitors delivered as squalenoylated prodrug nanoassemblies
Abstract

Due to their hydrophilic nature, most nucleoside reverse transcriptase inhibitors (NRTIs) display a variable bioavailability after oral administration and a poor control over their biodistribution, thus hampering their access to HIV sanctuaries. The limited cellular uptake and activation in the triphosphate form of NRTIs further restrict their efficacy and favour the emergence of viral resistance. We have shown that the conjugation of squalene (sq) to the nucleoside analogues dideoxycytidine (ddC) and didanosine (ddI) leads to amphiphilic prodrugs (ddC-sq and ddI-sq) that spontaneously self-organize in water as stable nanoassemblies of 100–300 nm. These nanoassemblies can also be formulated with polyethylene glycol coupled to either cholesterol (Chol-PEG) or squalene (sq-PEG). When incubated with peripheral blood mononuclear cells (PBMCs) in vitro infected with HIV, the NRTI-sq prodrugs enhanced the antiviral efficacy of the parent NRTIs, with a 2- to 3-fold decrease of the 50% effective doses and a nearly 2-fold increase of the selectivity index. This was also the case with HIV-1 strains resistant to ddC and/or ddI. The enhanced antiviral activity of ddI-sq was correlated with an up to 5-fold increase in the intracellular concentration of the corresponding pharmacologically active metabolite ddA-TP. The ddI-sq prodrug was further investigated in vivo by the oral route, the preferred route of administration of NRTIs. Pharmacokinetics studies performed on rats showed that the prodrug maintained low amounts of free ddI in the plasma. Administration of 3H-ddI-sq led to radioactivity levels higher in the plasma and relevant organs in HIV infection as compared to administration of free 3H-ddI. Taken together, these results show the potential of the squalenoylated prodrugs of NRTIs to enhance their absorption and improve their biodistribution, but also to enhance their intracellular delivery and antiviral efficacy towards HIV-infected cells.

Keywords
Squalenoylation; Nanoassemblies; Prodrug; Didanosine; Zalcitabine
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Anti-HIV efficacy and biodistribution of nucleoside reverse transcriptase inhibitors delivered as squalenoylated prodrug nanoassemblies
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Publisher
Database: Elsevier - ScienceDirect
Journal: Biomaterials - Volume 34, Issue 20, July 2013, Pages 4831–4838
Authors
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Subjects
Physical Sciences and Engineering Chemical Engineering Bioengineering
Get Full-Text Now
Don't Miss Today's Special Offer
Price was $35.95
You save - $31
Price after discount Only $4.95
100% Money Back Guarantee
Full-text PDF Download
Online Support
Any Questions? feel free to contact us