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Enhanced anti-HIV efficacy of indinavir after inclusion in CD4-targeted lipid nanoparticles.
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ABSTRACT: Background
Combination drug therapy has reduced plasma HIV to undetectable levels; however, drug-sensitive virus persists in patients' lymphoid tissue. We have reported significant lymphoid tissue drug localization with indinavir-associated lipid nanoparticles (LNPs). Our current objective is to evaluate whether additional enhancement is achievable by targeting these particles to CD4-HIV host cells.Methods
We characterized 2 peptide-coated (CD4-BP2 and CD4-BP4) drug-associated LNPs and demonstrated CD4-cell specificity. Drug-associated LNPs expressing polyethyleneglycol were exposed on HIV-2-infected cells under dynamic conditions that emulated lymph node physiology for 15, 30, and 60 minutes at concentrations from 0 to 25 μM and evaluated for antiviral activity and cell-associated drug concentrations. The specificity of CD4-mediated enhancement of indinavir LNPs antiviral activity was evaluated by blocking with anti-CD4 antibody.Results
Inclusion of CD4-binding peptides on LNPs enhanced antiviral activity for all incubation conditions, compared with control particles or soluble drug (eg, 60 minutes exposure, EC50 = 0.12-0.13 vs. 0.46 μM for targeted nanoparticles vs. soluble drug). The CD4-BP4 peptide exhibited higher efficiency in eliciting antiviral activity than CD4-BP2-coated particles (EC50 = 7.5 μM vs. >25 μM at 15 minutes drug exposure). This enhancement seems to be driven by CD4 availability and cell-associated indinavir concentrations, as blocking of CD4 significantly ablated indinavir efficacy in targeted particles and indinavir concentrations reflected the observed anti-HIV activity.Conclusions
We constructed CD4-targeted LNPs that provide selective binding and efficient delivery of indinavir to CD4-HIV host cells. Inclusion of polyethyleneglycol in LNPs would minimize immune recognition of peptides. The enhancement of anti-HIV effects is effective even under limited time exposure.
SUBMITTER: Endsley AN
PROVIDER: S-EPMC3551348 | biostudies-literature | 2012 Dec
REPOSITORIES: biostudies-literature
Publications
Enhanced anti-HIV efficacy of indinavir after inclusion in CD4-targeted lipid nanoparticles.
Journal of acquired immune deficiency syndromes (1999) 20121201 4
<h4>Background</h4>Combination drug therapy has reduced plasma HIV to undetectable levels; however, drug-sensitive virus persists in patients' lymphoid tissue. We have reported significant lymphoid tissue drug localization with indinavir-associated lipid nanoparticles (LNPs). Our current objective is to evaluate whether additional enhancement is achievable by targeting these particles to CD4-HIV host cells.<h4>Methods</h4>We characterized 2 peptide-coated (CD4-BP2 and CD4-BP4) drug-associated LN ...[more]