title: Hydrolyzed galactomannan-modified nanoparticles and flower-like polymeric micelles for the active targeting of rifampicin to macrophages.
abstract: Inhalable nanocarriers that are uptaken by macrophages represent an appealing approach for the targeting of antibiotics to the tuberculosis reservoir. In the present work, we report on the development of rifampicin (RIF)-loaded nanoparticles and flower-like polymeric micelles surface-modified with hydrolyzed galatomannan (GalM-h), a polysaccharide of mannose and galactose, two sugars that are recognized by lectin-like receptors. Initially, pure or GalM-h-associated chitosan nanoparticles (NPs) were produced by ionotropic gelation. Despite the composition, NPs displayed positive zeta potential values between +18.0 and +24.5 mV and a size ranging between 263 and 340 nm. In addition, RIF payloads were approximately 1.0% w/w. To increase the encapsulation efficiency, a more complex nanocarrier based on poly(epsilon-caprolactone)-b-poly(ethylene-glycol)-b-poly(epsilon-caprolactone) flower-like polymeric micelles (PMs) coated with chitosan or GalM-h/chitosan were engineered. These polymeric micelles displayed a bimodal size distribution with a positive zeta potential between +6.7 and +8.1 mV. More importantly, the drug encapsulation capacity was increased 12.9-fold with respect to the NPs. An agglutination assay with concanavalin A confirmed the presence of GalM-h on the surface. Qualitative uptake studies by fluorescence microscopy revealed that GalM-h-modified systems were taken-up by RAW 264.7 murine macrophages. Finally, the intracellular/cell associated levels of RIF following the incubation of cells with free or encapsulated drug indicated that while chitosan hinders the uptake, GalM-h leads to a significant increase of the intracellular concentration.
authors.affiliation: Department of Pharmaceutical Technology, The Group of Biomaterials and Nanotechnology for Improved Medicines (BIONIMED), University of Buenos Aires, 956 Junin St., Buenos Aires CP 113, Argentina.
authors.forename: Marcela A
authors.initials: MA
authors.lastname: Moretton
authors.forename: Diego A
authors.initials: DA
authors.lastname: Chiappetta
authors.forename: Fernanda
authors.initials: F
authors.lastname: Andrade
authors.forename: José
authors.initials: J
authors.lastname: das Neves
authors.forename: Domingos
authors.initials: D
authors.lastname: Ferreira
authors.forename: Bruno
authors.initials: B
authors.lastname: Sarmento
authors.forename: Alejandro
authors.initials: A
authors.lastname: Sosnik
mesh_terms: D000818:Animals; D002460:Cell Line; D005690:Galactose / Q000031:analogs & derivatives; D006868:Hydrolysis; D008264:Macrophages / Q000737:chemistry* / Q000378:metabolism*; D008351:Mannans / Q000737:chemistry* / Q000493:pharmacokinetics*; D008422:Materials Testing; D051379:Mice; D008823:Micelles; D058990:Molecular Targeted Therapy / Q000379:methods*; D053769:Nanocapsules / Q000008:administration & dosage / Q000737:chemistry* / Q000648:ultrastructure; D011108:Polymers / Q000737:chemistry; D012293:Rifampin / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: D008351:Mannans; D008823:Micelles; D053769:Nanocapsules; D011108:Polymers; C012990:galactomannan; D012293:Rifampin; D005690:Galactose