title: Oral particle uptake and organ targeting drives the activity of amphotericin B nanoparticles.
abstract: There are very few drug delivery systems that target key organs via the oral route, as oral delivery advances normally address gastrointestinal drug dissolution, permeation, and stability. Here we introduce a nanomedicine in which nanoparticles, while also protecting the drug from gastric degradation, are taken up by the gastrointestinal epithelia and transported to the lung, liver, and spleen, thus selectively enhancing drug bioavailability in these target organs and diminishing kidney exposure (relevant to nephrotoxic drugs). Our work demonstrates, for the first time, that oral particle uptake and translocation to specific organs may be used to achieve a beneficial therapeutic response. We have illustrated this using amphotericin B, a nephrotoxic drug encapsulated within N-palmitoyl-N-methyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycol chitosan (GCPQ) nanoparticles, and have evidenced our approach in three separate disease states (visceral leishmaniasis, candidiasis, and aspergillosis) using industry standard models of the disease in small animals. The oral bioavailability of AmB-GCPQ nanoparticles is 24%. In all disease models, AmB-GCPQ nanoparticles show comparable efficacy to parenteral liposomal AmB (AmBisome). Our work thus paves the way for others to use nanoparticles to achieve a specific targeted delivery of drug to key organs via the oral route. This is especially important for drugs with a narrow therapeutic index.
authors.affiliation: Departamento de Farmacia y Tecnologia Farmaceutica, Facultad de Farmacia, Universidad Complutense de Madrid , Plaza Ramon y Cajal s/n, Madrid, 28040, Spain.
authors.forename: Dolores R
authors.initials: DR
authors.lastname: Serrano
authors.forename: Aikaterini
authors.initials: A
authors.lastname: Lalatsa
authors.forename: M Auxiliadora
authors.initials: MA
authors.lastname: Dea-Ayuela
authors.forename: Pablo E
authors.initials: PE
authors.lastname: Bilbao-Ramos
authors.forename: Natalie L
authors.initials: NL
authors.lastname: Garrett
authors.forename: Julian
authors.initials: J
authors.lastname: Moger
authors.forename: Josep
authors.initials: J
authors.lastname: Guarro
authors.forename: Javier
authors.initials: J
authors.lastname: Capilla
authors.forename: M Paloma
authors.initials: MP
authors.lastname: Ballesteros
authors.forename: Andreas G
authors.initials: AG
authors.lastname: Schätzlein
authors.forename: Francisco
authors.initials: F
authors.lastname: Bolás
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Torrado
authors.forename: Ijeoma F
authors.initials: IF
authors.lastname: Uchegbu
mesh_terms: D000284:Administration, Oral; D000666:Amphotericin B / Q000493:pharmacokinetics*; D000818:Animals; D000935:Antifungal Agents / Q000493:pharmacokinetics; D000981:Antiprotozoal Agents / Q000493:pharmacokinetics; D016503:Drug Delivery Systems / Q000379:methods*; D004355:Drug Stability; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D050997:Nanomedicine; D053758:Nanoparticles / Q000737:chemistry*
chemical_list: D000935:Antifungal Agents; D000981:Antiprotozoal Agents; D000666:Amphotericin B
keywords: N-palmitoyl,N-methyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycol chitosan; amphotericin B; nanomedicine; nanoparticles; oral delivery