Mannose-Anchored Nano-Selenium Loaded Nanostructured Lipid Carriers of Etravirine for Delivery to HIV Reservoirs.

The present investigation aims to develop and explore mannosylated lipid-based carriers to deliver an anti-HIV drug, Etravirine (TMC) and Selenium nanoparticles (SeNPs), to the HIV reservoirs via the mannose receptor. The successful mannosylation was evaluated by the change in zeta potential and lectin binding assay using fluorescence microscopy. Electron microscopy and scattering studies were employed to study the structure and surface of the nanocarrier system. The presence of selenium at the core-shell of the nanocarrier system was confirmed by X-ray photoelectron spectroscopy and energy dispersive X-ray analysis. Further, the in vitro anti-HIV1 efficacy was assessed using HIV1 infected TZM-bl cells followed by in vivo biodistribution studies to evaluate distribution to various reservoirs of HIV. The results exhibited higher effectiveness and a significant increase in the therapeutic index as against the plain drug. The confocal microscopy and flow cytometry studies exhibited the efficient uptake of the coumarin-6 tagged respective formulations. The protective effect of nano selenium toward oxidative stress was evaluated in rats, demonstrating the potential of the lipidic nanoparticle-containing selenium in mitigating oxidative stress in all the major organs. The in vivo biodistribution assessment in rats showed a 12.44, 8.05 and 9.83-fold improvement in the brain, ovary, and lymph node biodistribution, respectively as compared with plain TMC. Delivery of such a combination via mannosylated nanostructured lipid carriers could be an efficient approach for delivering drugs to reservoirs of HIV while simultaneously reducing the oxidative stress induced by such long-term therapies by co-loading Nano-Selenium.

Dual loaded nanostructured lipid carrier of nano-selenium and Etravirine as a potential anti-HIV therapy.

There is a dire need for dual-long-acting therapy that could simultaneously target different stages of the HIV life cycle and providing a dual-prolonged strategy for improved anti-HIV therapy while reducing oxidative stress associated with the prolonged treatment. Thus, in the present work, nanostructured lipid carriers of Etravirine were developed and modified with nano-selenium. The dual-loaded nanocarrier system was fabricated using the double emulsion solvent evaporation method, further screened and optimized using the design of experiments methodology. The spherical core-shell type of a system was confirmed with an electron microscope and small-angle neutron scattering, while XPS confirmed the presence of selenium at the core-shell of the nanocarrier. In vitro assessment against HIV1 (R5 and X4 strains) infected TZM-bl cells exhibited higher efficacy for the dual-loaded nanocarrier system than the plain drug, which could be attributed to the synergistic effect of the nano-selenium. Confocal microscopy and flow cytometry results exhibited enhanced uptake in TZM-bl cells compared to plain drug. A significant increase of GSH, SOD, CAT was observed in animals administered with the dual-loaded nanocarrier system containing nano-selenium, suggesting the protective potential of the lipidic nanoparticle containing the nano-selenium. Improvement in the in vivo pharmacokinetic parameters was also observed, along with a higher accumulation of the dual-loaded nanocarrier in remote HIV reservoir organs like the brain, ovary, and lymph node. The results suggest the potential of a dual-loaded formulation for synergistically targeting the HIV1 infection while simultaneously improving the intracellular anti-oxidant balance for improving a prolonged anti-HIV therapy.

Synthesis and in-vitro anti-HIV-1 evaluation of novel pyrazolo[4,3-c]pyridin-4-one derivatives.

In our continuing efforts to find novel anti-HIV compounds, we have synthesized sixteen novel pyrazolo[4,3-c]pyridin-4-one derivatives. All the synthesized compounds were screened for anti-HIV activity against HIV-1VB59 (R5, subtype C). Compounds 12a-12c and 12e were also tested against HIV-1UG070 (X4, subtype D) in TZM-bl cell line. Compound 12c was found to be the most active against HIV-1VB59 and HIV-1UG070 with IC50 value 3.67 µM and 2.79 µM, and therapeutic indices 185 and 243, respectively. The lead compound 12c inhibited the HIV-192/BR/018 (R5, subtype B) and drug resistant isolates, NIH-119 (X4/R5, subtype B) and NARI-DR (R5, subtype C) effectively. The activity of the lead compound was further confirmed by PBMC assays. The molecular docking data showed that the most active compound 12c binds in the non-nucleoside binding pocket of HIV-1 reverse transcriptase, which was confirmed by the ToA assay. Thus the study indicated that 12c may be considered as a NNRTI and further explored as a lead for anti-HIV drug development.