| Popis: |
Despite tremendous improvement in the development of antiretroviral therapy (ART) for treatment of human immunodeficiency virus‐1 (HIV‐1), a cure is currently missing. One of the main challenges in HIV-1 treatment is postulated to be due to the accumulation of HIV-1 particles in the latent tissue reservoirs, where they are protected from both antiretrovirals (ARVs) and immune surveillance mechanisms. Interestingly, it has been shown that binding of the monosialodihexosylgangliosid (GM3) to CD169 (Siglec‐1) plays an important role in the glycoprotein‐independent sequestration of HIV‐1 particles in non-lysosomal virus‐containing compartments (VCCs) in CD169+ myeloid cells. Therefore, VCCs represent potential virus latent tissue reservoirs and provide protection for virus from immunological surveillance. In this dissertation, GM3‐functionalized lipid-coated polymer nanoparticles (NPs) referred to as HIV-1 mimicking lipid-coated polymer NPs were designed to target the VCCs and deliver ARVs to achieve full virus eradication. HIV-1 mimicking lipid-coated polymer NPs were assembled using poly(lactic‐co‐glycolic) acid (PLGA) as well as polylactic acid (PLA) polymer cores. After a systematic characterization of HIV-1 mimicking lipid-coated polymer NPs, the NPs were applied as a virus mimicking model to investigate the effect of core stiffness on NP binding, uptake, and intracellular fate mediated by GM3‐CD169 binding in CD169+ macrophages. Our results suggest that GM3‐CD169‐mediated sequestration of NPs in non-lysosomal VCC-like compartments is not only regulated by ligand–receptor interactions but also determined by the core stiffness of polymer NPs. Subsequently, ARV-loaded HIV-1 mimicking polymer NPs were developed as long-acting nanocarriers for delivery of a combination of Rilpivirine (RPV) and Cabotegravir (CAB) to VVCs in CD169+ primary human monocyte-derived macrophages (MDMs) for a duration of at least 28 days. Cellular drug concentrations and inhibitory effects obtained for GM3- or phosphatidylserine (PS) -mediated binding to CD169+ MDMs were quantified, and GM3-presenting PLA NPs were found to provide the most efficient and longest lasting inhibition of viral infection. Our findings pave the path towards designing a new class of polymer NPs aimed to target VCCs in CD169+ macrophages and to utilize CD169+ tissue resident macrophages as cellular drug depots for eradicating viral latent tissue reservoirs or as long-acting prevention and treatment strategies against HIV-1 infection. |
