Pharmacodynamics of long-acting folic acid-receptor targeted ritonavir-boosted atazanavir nanoformulations

Pavan Puligujja, Shantanu S. Balkundi, Lindsey M. Kendrick, Hannah M. Baldridge, James R. Hilaire, Aditya N. Bade, Prasanta K. Dash, Gang Zhang, Larisa Y. Poluektova, Santhi Gorantla, Xin Ming Liu, Tianlei Ying, Yang Feng, Yanping Wang, Dimiter S. Dimitrov, Jo Ellyn M. McMillan, Howard E. Gendelman

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

Long-acting nanoformulated antiretroviral therapy (nanoART) that targets monocyte-macrophages could improve the drug's half-life and protein-binding capacities while facilitating cell and tissue depots. To this end, ART nanoparticles that target the folic acid (FA) receptor and permit cell-based drug depots were examined using pharmacokinetic and pharmacodynamic (PD) tests. FA receptor-targeted poloxamer 407 nanocrystals, containing ritonavir-boosted atazanavir (ATV/r), significantly increased drug bioavailability and PD by five and 100 times, respectively. Drug particles administered to human peripheral blood lymphocyte reconstituted NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ mice and infected with HIV-1ADA led to ATV/r drug concentrations that paralleled FA receptor beta staining in both the macrophage-rich parafollicular areas of spleen and lymph nodes. Drug levels were higher in these tissues than what could be achieved by either native drug or untargeted nanoART particles. The data also mirrored potent reductions in viral loads, tissue viral RNA and numbers of HIV-1p24+ cells in infected and treated animals. We conclude that FA-P407 coating of ART nanoparticles readily facilitates drug carriage and antiretroviral responses.

Original languageEnglish (US)
Pages (from-to)141-150
Number of pages10
JournalBiomaterials
Volume41
DOIs
StatePublished - Feb 1 2015

Keywords

  • Folic acid receptor
  • Human immunodeficiency virus type one
  • Long-acting nanoformulated antiretroviral therapy
  • Non-obese diabetic severe combined immunodeficient mice
  • Pharmacodynamics
  • Pharmacokinetics

ASJC Scopus subject areas

  • Bioengineering
  • Ceramics and Composites
  • Biophysics
  • Biomaterials
  • Mechanics of Materials

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  • Cite this

    Puligujja, P., Balkundi, S. S., Kendrick, L. M., Baldridge, H. M., Hilaire, J. R., Bade, A. N., Dash, P. K., Zhang, G., Poluektova, L. Y., Gorantla, S., Liu, X. M., Ying, T., Feng, Y., Wang, Y., Dimitrov, D. S., McMillan, J. E. M., & Gendelman, H. E. (2015). Pharmacodynamics of long-acting folic acid-receptor targeted ritonavir-boosted atazanavir nanoformulations. Biomaterials, 41, 141-150. https://doi.org/10.1016/j.biomaterials.2014.11.012