Nasal chitosan microparticles target a zidovudine prodrug to brain HIV sanctuaries

• We evidence for the first time that the uptake of prodrug UDCA–AZT in murine macrophages is higher than that of zidovudine.
• Intravenous administration of zidovudine (AZT) and UDCA–AZT is not efficient in brain targeting.
• Nasal administration of physical mixture/microparticles produces detectable amounts of UDCA−AZT in the cerebrospinal fluid.
• Chitosan nasal microspheres show the best performance in UDCA–AZT uptake in cerebrospinal fluid.
• This formulation can induce the AZT transport in macrophages located in the subarachnoid spaces of cerebrospinal fluid.

Zidovudine (AZT) is an antiretroviral drug that is a substrate of active efflux transporters (AETs) that extrude the drug from the central nervous system (CNS) and macrophages, which are considered to be sanctuaries of HIV. The conjugation of AZT to ursodeoxycholic acid is known to produce a prodrug (UDCA–AZT) that is able to elude the AET systems, indicating the potential ability of this prodrug to act as a carrier of AZT in the CNS and in macrophages. Here, we demonstrate that UDCA–AZT is able to permeate and remain in murine macrophages with an efficiency twenty times higher than that of AZT. Moreover, we propose the nasal administration of this prodrug in order to induce its uptake into the CNS. Chitosan chloride-based microparticles (CP) were prepared by spray-drying and were characterized with respect to size, morphology, density, water uptake and the dissolution profile of UDCA–AZT. The CP sample was then nasally administered to rats. All in vitro and in vivo measurements were also performed for a CP parent physical mixture. The CP sample was able to increase the dissolution rate of UDCA–AZT and to reduce water uptake with respect to its parent physical mixture, inducing better uptake of UDCA–AZT into the cerebrospinal fluid of rats, where the prodrug can act as an AZT carrier in macrophages.

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