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

Abstract

Long-acting nanoformulated antiretroviral therapy (nanoART) that target monocyte-macrophage 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 affected several therapeutic factors: drug bioavailability increased as much as 5 times and PD activity improved as much as 100 times. Drug particles administered to human peripheral blood lymphocyte reconstituted NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ mice and infected with HIV-1ADA at a tissue culture infective dose50 of 104 infectious viral particles/ml 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 facilitate drug carriage and facilitate antiretroviral responses.

An Enhanced Emtricitabine-Loaded Long-Acting Nanoformulation for Prevention or Treatment of HIV Infection

“…There are various combination nanoformulations that have been reported (7,8,12,(25)(26)(27)(28)(29). Freeling et al produced solid lipid nanoparticles containing boosted lopinavir (L/r) and TFV.…”

“…Using macaque model, the investigators demonstrated enhanced penetration of the ARV drugs into lymph nodes compared to that of free drugs (10,27). Other investigators have used wet-milled technique to develop FTC crystals that boosted protease inhibitor efficacy in humanized mice when linked with folic acid (28,29). Recently, the LATTE-2 study, administering long-acting cabotegravir and rilpivirine intramuscularly every 2 months or every month, has announced positive results (30).…”

Pharmacodynamics of folic acid receptor targeted antiretroviral nanotherapy in HIV-1-infected humanized mice

“…The present study on FA-nanoATV/r treated NSG mice builds on prior PK and PD studies. The promising results lay a foundation to further develop nanoformulations for clinical use(Puligujja et al, 2015). …”

Magnetic resonance imaging of folic acid-coated magnetite nanoparticles reflects tissue biodistribution of long-acting antiretroviral therapy

“…18,19 This, taken together, makes FA conjugation suitable for MP targeting of ARV nanoparticles (nanoformulated antiretroviral therapy [nanoART]) for treatment of HIV-1 infection. 18,19 In particular, PK and pharmacodynamics (PD) studies have demonstrated that such targeting strategies improve drug biodistribution. However, efficacy determinations have entailed intensive tissue drug chemical analyses.…”

“…However, efficacy determinations have entailed intensive tissue drug chemical analyses. 18,20 We posit that testing of targeting ligands can be sped by MRI evaluation of magnetite-labeled ARV particle tissue distributions.…”