Enhanced Anti-HIV Efficacy of Indinavir After Inclusion in CD4-Targeted Lipid Nanoparticles
| Autor: | Aaron N. Endsley, Rodney J. Y. Ho |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
CD4-Positive T-Lymphocytes
Drug Anti-HIV Agents media_common.quotation_subject Indinavir Peptide Microbial Sensitivity Tests Pharmacology Article medicine Humans Pharmacology (medical) media_common EC50 chemistry.chemical_classification Drug Carriers Liposome biology Infectious Diseases Targeted drug delivery chemistry HIV-2 Liposomes biology.protein Nanoparticles Antibody Drug carrier medicine.drug |
| Zdroj: | JAIDS Journal of Acquired Immune Deficiency Syndromes. 61:417-424 |
| ISSN: | 1525-4135 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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