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Por favor, use este identificador para citar o enlazar a este item: http://hdl.handle.net/10261/99774
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dc.contributor.authorRodríguez-Lavado, Julioes_ES
dc.contributor.authorMata, Mario de laes_ES
dc.contributor.authorJiménez Blanco, José L.es_ES
dc.contributor.authorGarcía Moreno, María Isabeles_ES
dc.contributor.authorBenito, Juan M.es_ES
dc.contributor.authorDíaz-Quintana, Antonioes_ES
dc.contributor.authorSánchez-Alcázar, José Antonioes_ES
dc.contributor.authorOrtiz-Mellet, Carmenes_ES
dc.contributor.authorGarcía Fernández, José Manueles_ES
dc.date.accessioned2014-07-14T09:36:41Z-
dc.date.available2014-07-14T09:36:41Z-
dc.date.issued2014-
dc.identifierdoi: 10.1039/c3ob42530d-
dc.identifierissn: 1477-0520-
dc.identifier.citationOrganic and Biomolecular Chemistry 12(14): 2289-2301 (2014)es_ES
dc.identifier.urihttp://hdl.handle.net/10261/99774-
dc.descriptionet al.-
dc.description.abstractGaucher disease (GD) is a rare monogenetic disorder leading to dysfunction of acid β-glucosidase (β-glucocerebrosidase; GCase) and accumulation of glucosylceramide in lysosomes, especially in macrophages (Gaucher cells). Many of the mutations at the origin of GD do not impair the catalytic activity of GCase, but cause misfolding and subsequent degradation by the quality control system at the endoplasmic reticulum. Pharmacological chaperones (PCs) capable of restoring the correct folding and trafficking of the endogenous mutant enzyme represent promising alternatives to the currently available enzyme replacement and substrate reduction therapies (ERT and SRT, respectively), but unfavorable biodistribution and potential side-effects remain important issues. We have now designed a strategy to enhance the controlled delivery of PCs to macrophages that exploit the formation of ternary complexes between the PC, a trivalent mannosylated β-cyclodextrin (βCD) conjugate and the macrophage mannose receptor (MMR). First, PC candidates with appropriate relative avidities towards the βCD cavity and the GCase active site were selected to ensure efficient transfer of the PC cargo from the host to the GCase active site. Control experiments confirmed that the βCD carrier was selectively recognized by mannose-specific lectins and that the corresponding PC:mannosylated βCD supramolecular complex retained both the chaperoning activity, as confirmed in human GD fibroblasts, and the MMR binding ability. Finally, fluorescence microscopy techniques proved targeting and cellular uptake of the PC-loaded system in macrophages. Altogether, the results support that combined cyclodextrin encapsulation and glycotargeting may improve the efficacy of PCs for GD. This journal is © 2014 the Partner Organisations.-
dc.description.sponsorshipThis work was supported by the Spanish Ministerio de Economía y Competitividad (MINECO), contract numbers SAF2010-15670 and CTQ2010-15848, the Fondo Europeo de Desarrollo Regional (FEDER), and the Fundación Ramón Areces. JRL is grateful to the Spanish Ministerio de Economía y Competitividad for a pre-doctoral FPI fellowship.-
dc.publisherRoyal Society of Chemistry (UK)es_ES
dc.rightsclosedAccess-
dc.titleTargeted delivery of pharmacological chaperones for Gaucher disease to macrophages by a mannosylated cyclodextrin carrieres_ES
dc.typeartículoes_ES
dc.identifier.doi10.1039/c3ob42530d-
dc.embargo.terms2015-02-01-
dc.date.updated2014-07-14T09:36:42Z-
dc.description.versionPeer Reviewed-
dc.language.rfc3066eng-
dc.contributor.funderMinisterio de Economía y Competitividad (España)-
dc.contributor.funderFundación Ramón Areces-
dc.contributor.funderEuropean Commission-
dc.relation.csicSíes_ES
dc.identifier.funderhttp://dx.doi.org/10.13039/501100003329es_ES
dc.identifier.funderhttp://dx.doi.org/10.13039/100008054es_ES
dc.identifier.funderhttp://dx.doi.org/10.13039/501100000780es_ES
dc.type.coarhttp://purl.org/coar/resource_type/c_6501es_ES
item.openairetypeartículo-
item.cerifentitytypePublications-
item.grantfulltextnone-
item.fulltextNo Fulltext-
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
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