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. 2016 Mar 20:9:21-32.
doi: 10.4137/IDRT.S38108. eCollection 2016.

Antiretroviral Drugs-Loaded Nanoparticles Fabricated by Dispersion Polymerization with Potential for HIV/AIDS Treatment

Oluwaseun Ogunwuyi  1 , Namita Kumari  2 , Kahli A Smith  3 , Oleg Bolshakov  1 , Simeon Adesina  1 , Ayele Gugssa  4 , Winston A Anderson  4 , Sergei Nekhai  5 , Emmanuel O Akala  1
Affiliations

Antiretroviral Drugs-Loaded Nanoparticles Fabricated by Dispersion Polymerization with Potential for HIV/AIDS Treatment

Oluwaseun Ogunwuyi et al. Infect Dis (Auckl). .

Abstract

Highly active antiretroviral (ARV) therapy (HAART) for chronic suppression of HIV replication has revolutionized the treatment of HIV/AIDS. HAART is no panacea; treatments must be maintained for life. Although great progress has been made in ARV therapy, HIV continues to replicate in anatomical and intracellular sites where ARV drugs have restricted access. Nanotechnology has been considered a platform to circumvent some of the challenges in HIV/AIDS treatment. Dispersion polymerization was used to fabricate two types (PMM and ECA) of polymeric nanoparticles, and each was successfully loaded with four ARV drugs (zidovudine, lamivudine, nevirapine, and raltegravir), followed by physicochemical characterization: scanning electron microscope, particle size, zeta potential, drug loading, and in vitro availability. These nanoparticles efficiently inhibited HIV-1 infection in CEM T cells and peripheral blood mononuclear cells; they hold promise for the treatment of HIV/AIDS. The ARV-loaded nanoparticles with polyethylene glycol on the corona may facilitate tethering ligands for targeting specific receptors expressed on the cells of HIV reservoirs.

Keywords: ARV drugs; CEM T cells; GALT; PBMCs; dispersion polymerization; nanoparticles.

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Figures

Figure 1
Figure 1
Scanning electron micrographs of ARV drugs-loaded hydrolyzable crosslinked PEG-poly caprolactone (ECA) nanoparticles (A and B) and ARV drugs-loaded hydrolyzable crosslinked PEG-poly methylmethacrylate (PMM) nanoparticles (C).
Figure 2
Figure 2
Typical particle size distribution for PEG-polycarpolactone (A) and PEG-polymethymethacrylate (B). ARV drugs-loaded hydrolyzable crosslinked nanoparticles.
Figure 3
Figure 3
Typical particle zeta potential distribution for PEG-polycarpolactone (A) and PEG-polymethymethacrylate (B). ARV drugs-loaded hydrolyzable crosslinked nanoparticles.
Figure 4
Figure 4
Cumulative amount released versus time for ARV drugs-loaded PEG-polymethylmethacrylate based nanoparticles (Raltegravir: ε = 8.15–31.28 μg; Niverapine: ε = 7.5–36.84 μg; Lamivudine: ε = 1.20–3.59 μg; and Zidovudine: ε = 2.06–16.74 μg).
Figure 5
Figure 5
Cumulative amount released versus time for ARV drugs-loaded PEG-polycaprolactone based nanoparticles (Raltegravir: ε = 6.31–30.2 μg); Niverapine: ε = 6.7–57 μg; Lamivudine: ε = 0.14–4.71 μg; and Zidovudine: ε = 0.56–37.46 μg).
Figure 6
Figure 6
Inhibition of HIV-1 one round infection by PMM nanoparticles. (A) Inhibition of HIV-1 in CEM T cells by ARV combination PMM nanoparticles. CEM T cells were seeded in 96 wells plates, infected with VSVG HIV-Luc and allowed to incubate overnight. The following day, the cells were treated with different concentrations of combination anti-retroviral nanoparticles containing lamivudine, zidovudine, nevirapine, and raltegravir. After incubating overnight, a luciferase activity was measured. The half maximal effective concentration (EC50) was determined with GraphPad Prizm 6 Software. (B) Inhibition of HIV-1 in peripheral blood mononuclear cells (PBMCs) by ARV combination PMM nanoparticles. Activated PBMCs were seeded in 96 wells plates, infected with VSVG HIV-Luc and allowed to incubate overnight. The following day, the cells were treated with different concentrations of combination anti-retroviral nanoparticles containing lamivudine, zidovudine, nevirapine, and raltegravir. After incubating overnight, a luciferase activity was measured. Results were analyzed in Prism. (C) Inhibition of HIV-1 reverse transcriptase (RT) in PBMCs. Activated PBMCs were infected with HIV-1 Luc and then treated with DMSO, zidovudine, blank PMM nanoparticles or combo (ARV) PMM nanoparticles for 6 hours. DNA was extracted and analyzed by real-time PCR on Roche 480 II using primers for early HIV-1 LTR and β-globin gene as a reference. The asterisk indicates p = 0.005. Unpaired t-test was used to determine statistical significance. (D) Effect of ARV combination PMM nanoparticles on PBMCs viability. PBMCs were seeded in 96 well plates, treated with combination anti-retroviral nanoparticles containing lamivudine, zidovudine, nevirapine, and raltegravir and incubated overnight. Cell viability was determined with trypan blue exclusion assay. The half maximal cytotoxicity concentration (CC50) was determined with GraphPad Prizm 6 Software.
Figure 7
Figure 7
Inhibition of HIV-1 one round infection by ECA nanoparticles. (A) Inhibition of HIV-1 in CEM T cells by ARV combination ECA nanoparticles. CEM T cells were seeded in 96 wells plates, infected with VSVG HIV-Luc and allowed to incubate overnight. The following day, the cells were treated with different concentrations of combination anti-retroviral nanoparticles containing lamivudine, zidovudine, nevirapine, and raltegravir. After incubating overnight, a luciferase activity was measured. EC50 was determined in GraphPad Prizm 6. (B) Effect of ARV combination ECA nanoparticles on cell viability in CEM cells. CEM cells were seeded in 96 well plates, treated with combo (ARV) ECA nanoparticles for 6 hours and incubated overnight. Cell viability was determined with trypan blue exclusion assay. CC50 was determined with GraphPad Prizm 6 Software. (C) Inhibition of HIV-1 RT in PBMCs by ECA nanoparticles. Activated PBMCs were infected with HIV-1 Luc and treated with combo (ARV) ECA nanoparticles or zidovudine for 6 hours or left untreated. DNA was extracted and analyzed by real-time PCR on Roche 480 II using primers for early HIV-1 LTR and β-globin gene as a reference. The asterisk indicates p = 0.01. Unpaired t-test was used to determine statistical significance. (D) Effect of ARV combination ECA nanoparticles on cell viability in PBMCs. PBMCs were seeded in 96 well plates and treated with combo (ARV) ECA nanoparticles for 6 hours and then incubated overnight. Cell viability was determined with trypan blue exclusion assay. CC50 was determined with GraphPad Prizm 6 Software.
Scheme 1
Scheme 1
Surface-modified nanoparticles capable of crossing the intestinal epithelium via β1-integrin receptors on M cells.
Scheme 2
Scheme 2
Synthesis and structure of stealth hydrolyzable crosslinked PEG-PMMA (PMM) nanoparticles (A = N,O-dimethacryloylhydroxylamine (crosslinker); B = methyl methacrylate (MMA); C = poly(ethylene glycol)n monomethyl ether monomethacrylate (PEG-MA; n = 1000); D = crosslinked polymer).
Scheme 3
Scheme 3
Synthesis and structure of stealth crosslinked poly-ε-Caprolactone-HEMA Nanoparticle (ECA).
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