Bile acids modulation of nanoparticle macrophage uptake

Nanoparticulate systems are widely studied to obtain selective targeting of encapsulated drugs in specific body sites. The uptake modulation of nanoparticles by macro-phages appears of relevant importance in this regard. An efficacious macrophage uptake is necessary in order to eradicate intracellular pathogens, such us HIV in brain macrophages, considered as a sanctuary for this virus. The lack of penetration of anti-HIV drugs in the macrophages is attributed to the expression of active efflux transporters (AET) on their membranes. The nanoparticulate systems, able to elude AET, can constitute an excellent vehicle able to target their encapsulated drugs in macrophages, being known their ability to ingest and disrupt the foreign material in the body. On the other hand, when the uptake activity is exerted by the macrophages of the reticuloendothelial system (RES), the nanoparticles are easily removed from the bloodstream before they can perform designed therapeutic function, such as a selective targeting of anticancer drugs in tumoral tissues or cells, by passive or active mechanisms. In order to obtain nanocarriers with stealth properties against the RES, PEG is currently used as coating material to the surface of nanoparticles . Here we propose the use of bile acids in order to formulate nanoparticulate systems able to modulate their uptake in macrophages. As model drug we chosen zidovudine (AZT). We have previously demonstrated that AZT conjugation with ursodeoxycholic acid, allows to obtain a lipophilic prodrug (UDCA-AZT) able to elude the AET systems whose AZT is substrate, with a consequent increase of the uptake in murine macrophages. Here we demonstrate that nanoparticles obtained by nanoprecipitation of UDCA-AZT in the presence of taurocholate (nano-tauro) or ursodeoxycholate (nano-UDCA) are strongly or weakly uptaken by murine macrophages, respectively. Finally, we have evaluated the UDCA-AZT uptake in the central nervous system (CNS) following nasal administration of nano-tauro formulation