Sustained-release nanoART formulation for the treatment of neuroAIDS

Abstract

A novel approach was developed for the coencapsulation of an anti-HIV drug (tenofovir) and a latency-breaking agent (vorinostat), using magnetically guided layer-by-layer (LbL) assembled nanocarriers for the treatment of neuroAIDS. Ultrasmall iron oxide (Fe₃O₄) nanoparticles (10±3 nm) were synthesized and characterized. The LbL technique was used to achieve a sustained release profile, and application of 2 bilayers ([tenofovir+dextran sulphate]₂+vorinostat) to magnetic nanoparticles resulted in a 2.8 times increase in drug (tenofovir) loading and also resulted in an increase in the drug release period by 30-fold, with 100% drug release in sustained manner over a period of 5 days with the simultaneous stimulation of latent HIV expression. Nanoformulation showed a good blood–brain barrier transmigration ability (37.95%±1.5%) with good in vitro antiviral efficacy (~33% reduction of p24 level) over a period of 5 days after HIV infection in primary human astrocytes, with good cell viability (>90%). Hence, LbL arrangements of drugs on magnetic nanoparticles provides sustained release and, therefore, may improve the patient’s adherence to therapy and lead to better compliance.

Keywords:

• layer-by-layer
• magnetic nanocarriers
• blood–brain barriers
• neuroAIDS
• sustained release
• anti-HIV drug
• latency

Supplementary materials

Figure S1 DLS measurement of hydrodynamic diameter with respect to drug loading and layer-by-layer assembly deposition.

Abbreviations: DLS, dynamic light scattering; MNP, magnetic nanoparticle.

Figure S2 Mass spectrometry analysis.

Note: Mass spectrometry instrumental parameters used for the LC/MSD analyses (General Screening Method).

Abbreviations: LC/MSD, liquid chromatography–mass spectrometry data; temp, temperature; Vcap, capillary voltage; min, minute.

Figure S3 Mass spectroscopy analysis.

Notes: The number of counts versus the mass-to-charge ratio (standard peak of 288) for (A) the standard free tenofovir (1:10 water dilution); (B) released tenofovir from 1 bilayer formulation (MNP+tenefovir+dextran sulphate); and (C) released tenofovir from 2 bilayers formulation ([tenofovir+dextran sulphate]₂+vorinostat). [M+H]⁺ indicates protonated molecular ions of the formula in positive ionisation mode.

Figure S4 Cell viability of neuronal cells (SK-N-MC cells) with MNP nanoformulation.

Note: Results show the percentage of cells viable after treatment with different concentrations of (50–200 μg/mL) for 24 hours.

Abbreviation: MNP, magnetic nanoparticles.

Figure S5 p24 study to show effect of standard (free drug) vorinostat on HIV replication in human astrocytes.

Note: Different ranges of vorinostat (0.5–5 μm) were used; results show maximum p24 value at 1μM concentration, which is used for the nanoformulation development.

Acknowledgments

We acknowledge receiving financial support from National Institutes of Health (grants 1R01MH085259 and R01DA034547-01) and the NIH-AIDS Research Program for the antiretroviral drug.

Disclosure

The authors report no conflicts of interest in this work.