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.

Nasal chitosan microparticles target a zidovudine prodrug to brain HIV sanctuaries

DALPIAZ, Alessandro
Primo
;
FOGAGNOLO, Marco;FERRARO, Luca Nicola;CAPUZZO, Antonio;PAVAN, Barbara;
2015

Abstract

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.
2015
Dalpiaz, Alessandro; Fogagnolo, Marco; Ferraro, Luca Nicola; Capuzzo, Antonio; Pavan, Barbara; Rassu, Giovanna; Salis, Andrea; Giunchedi, Paolo; Gavin...espandi
File in questo prodotto:
File Dimensione Formato  
Ativiral Res UDCA_AZT.pdf

solo gestori archivio

Descrizione: versione editoriale
Tipologia: Full text (versione editoriale)
Licenza: NON PUBBLICO - Accesso privato/ristretto
Dimensione 2.06 MB
Formato Adobe PDF
2.06 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
Preprint11392-2336116.pdf

accesso aperto

Descrizione: pre print
Tipologia: Pre-print
Licenza: PUBBLICO - Pubblico con Copyright
Dimensione 997.81 kB
Formato Adobe PDF
997.81 kB Adobe PDF Visualizza/Apri
11392_2336116_postprint_Dalpiaz_Alessandro.pdf

accesso aperto

Descrizione: post print
Tipologia: Post-print
Licenza: Creative commons
Dimensione 1.88 MB
Formato Adobe PDF
1.88 MB Adobe PDF Visualizza/Apri

I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/2336116
Citazioni
  • ???jsp.display-item.citation.pmc??? 19
  • Scopus 56
  • ???jsp.display-item.citation.isi??? 51
social impact