title: In vitro and in vivo evaluation of novel cross-linked saccharide based polymers as bile acid sequestrants.
abstract: Bile acid sequestrants (BAS) represent a therapeutic approach for the management of hypercholesterolemia that relies on the cationic polymeric nature of BAS to selectively bind negatively charged bile acids. We hypothesized that the cross-linking of β-cyclodextrin (β-CD) and saccharides such as starch or dextrin with divinyl sulfone (DVS) yields homo- and hetero-polymeric materials with the ability to trap sterols. Our hypothesis was put to test by synthesizing a library of 22 polymers that were screened to evaluate their capability to sequester both cholesterol (CHOL) and cholic and deoxycholic acids (CA and DCA). Three polymers synthesized in high yield were identified as promising. Two were neutral hetero-polymers of β-CD and starch or dextrin and the third was a weakly cationic homo-polymer of starch, highlighting the importance of the cavity effect. They were tested in hypercholesterolemic male Wistar rats and their ability to regulate hypercholesterolemia was similar to that for the reference BAS cholestyramine, but with two additional advantages: (i) they normalized the TG level and (ii) they did not increase the creatinine level. Neither hepatotoxicity nor kidney injury was detected, further supporting them as therapeutical candidates to manage hypercholesterolemia.
authors.affiliation: Departamento de Química Orgánica, Facultad de Ciencias, Instituto de Biotecnología, Universidad de Granada, E18071 Granada, Spain. fhmateo@ugr.es.
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Lopez-Jaramillo
authors.affiliation: Departamento de Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad de Granada, E18071 Granada, Spain. mgiron@ugr.es.
authors.forename: Maria Dolores
authors.initials: MD
authors.lastname: Giron-Gonzalez
authors.affiliation: Departamento de Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad de Granada, E18071 Granada, Spain. rsalto@ugr.es.
authors.forename: Rafael
authors.initials: R
authors.lastname: Salto-Gonzalez
authors.affiliation: Departamento de Química Orgánica, Facultad de Ciencias, Instituto de Biotecnología, Universidad de Granada, E18071 Granada, Spain. fhmateo@ugr.es.
authors.forename: Fernando
authors.initials: F
authors.lastname: Hernandez-Mateo
authors.affiliation: Departamento de Química Orgánica, Facultad de Ciencias, Instituto de Biotecnología, Universidad de Granada, E18071 Granada, Spain. fhmateo@ugr.es.
authors.forename: Francisco
authors.initials: F
authors.lastname: Santoyo-Gonzalez
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000302:isolation & purification* / Q000378:metabolism; D003432:Cross-Linking Reagents; D006937:Hypercholesterolemia / Q000378:metabolism / Q000517:prevention & control*; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D008297:Male; D011108:Polymers / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar; D013213:Starch / Q000737:chemistry*; D013450:Sulfones / Q000737:chemistry*; D047392:beta-Cyclodextrins / Q000737:chemistry*
chemical_list: D001647:Bile Acids and Salts; D003432:Cross-Linking Reagents; D011108:Polymers; D013450:Sulfones; D047392:beta-Cyclodextrins; C009873:divinyl sulfone; D013213:Starch; C031215:betadex