Enhanced anti-HIV efficacy of indinavir after inclusion in CD4-targeted lipid nanoparticles.
J Acquir Immune Defic Syndr
; 61(4): 417-24, 2012 Dec 01.
Article
en En
| MEDLINE
| ID: mdl-22743598
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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Portadores de Fármacos
/
Linfocitos T CD4-Positivos
/
VIH-2
/
Indinavir
/
Fármacos Anti-VIH
/
Nanopartículas
/
Liposomas
Límite:
Humans
Idioma:
En
Revista:
J Acquir Immune Defic Syndr
Asunto de la revista:
SINDROME DA IMUNODEFICIENCIA ADQUIRIDA (AIDS)
Año:
2012
Tipo del documento:
Article
País de afiliación:
Estados Unidos