Targeted delivery of pharmacological chaperones for Gaucher disease to macrophages by a mannosylated cyclodextrin carrier
| العنوان: | Targeted delivery of pharmacological chaperones for Gaucher disease to macrophages by a mannosylated cyclodextrin carrier |
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| المؤلفون: | Antonio Díaz-Quintana, Yoshiyuki Suzuki, Kousaku Ohno, José M. García Fernández, Julio Rodríguez-Lavado, Katsumi Higaki, Juan M. Benito, José Antonio Sánchez-Alcázar, Carmen Ortiz Mellet, M. Isabel García-Moreno, José L. Jiménez-Blanco, Mario de la Mata, Eiji Nanba |
| المساهمون: | Ministerio de Economía y Competitividad (España), Fundación Ramón Areces, European Commission |
| المصدر: | Digital.CSIC. Repositorio Institucional del CSIC instname |
| سنة النشر: | 2014 |
| مصطلحات موضوعية: | chemistry.chemical_classification, Biodistribution, Drug Carriers, Gaucher Disease, biology, Cyclodextrin, Endoplasmic reticulum, Macrophages, Organic Chemistry, beta-Cyclodextrins, Active site, Biochemistry, Enzyme, Drug Delivery Systems, chemistry, Microscopy, Fluorescence, biology.protein, Fluorescence microscope, Carbohydrate Conformation, Humans, Carbohydrate conformation, Physical and Theoretical Chemistry, Conjugate, Molecular Chaperones |
| الوصف: | et al. Gaucher 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. This 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. |
| تدمد: | 1477-0539 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8079ace436ee9d8a4c2847c4239e2f7bTest https://pubmed.ncbi.nlm.nih.gov/24589885Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....8079ace436ee9d8a4c2847c4239e2f7b |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14770539 |
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