121048 20240319081020.0 doi 10.1016/j.ijpharm.2022.122224 sideral 131512 ART-2022-131512 eng Salido, S. Chitosan derivatives as nanocarriers for hLDHA inhibitors delivery to hepatic cells: A selective strategy for targeting primary hyperoxaluria diseases 2022 Access copy available to the general public Unrestricted Primary hyperoxalurias (PHs) are a group of inherited alterations of the hepatic glyoxylate metabolism that result in an excess of oxalate production by the oxidation of glyoxylate by the human lactate dehydrogenase A enzyme (hLDHA). The selective liver inhibition of this enzyme is one of the therapeutic strategies followed in the treatment of this disease. Even though several efforts have been recently performed using gene silencing by the RNA interference approach, small-molecule inhibitors that selectively reach hepatocytes are preferred since they present the advantages of a lower production cost and better pharmacological properties. In that sense, the design, synthesis, and physicochemical characterization by NMR, FTIR, DLS and TEM of two nanocarriers based on chitosan conjugates (1, non-redox-sensitive; 2, redox-sensitive) have been performed to (i) achieve the selective transport of hLDHA inhibitors into hepatocytes and (ii) their disruption once they reach the hepatocytes cytosol. Polymer 2 self-assembled into micelles in water and showed high drug loadings (19.8–24.5 %) and encapsulation efficiencies (31.9–40.8%) for the hLDHA inhibitors (I-III) tested. The non-redox-sensitive micelle 1 remained stable under different glutathione (GSH) concentrations (10 μM and 10 mM), and just a residual release of the inhibitor encapsulated was observed (less than 10 %). On the other hand, micelle 2 was sufficiently stable under in vitro physiological conditions (10 μM, GSH) but it quickly disassembled under the simulated reducing conditions present inside hepatocytes (10 mM GSH), achieving a 60 % release of the hLDHA inhibitor encapsulated after 24 h, confirming the responsiveness of the developed carrier to the high levels of intracellular GSH. info:eu-repo/grantAgreement/ES/MCIU/RTI2018-098560-B-C22 info:eu-repo/semantics/openAccess by-nc-nd http://creativecommons.org/licenses/by-nc-nd/3.0/es/ 5.8 2022 PHARMACOLOGY & PHARMACY 39 / 278 = 0.14 2022 Q1 T1 0.906 2022 Pharmaceutical Science 2022 Q1 10.5 2022 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Alejo-Armijo, A. Parola, A.J. Sebastián, V. Universidad de Zaragoza (orcid)0000-0002-6873-5244 Alejo, T. Universidad de Zaragoza (orcid)0000-0002-9324-0446 Irusta, S. Universidad de Zaragoza (orcid)0000-0002-2966-9088 Arruebo, M. Universidad de Zaragoza (orcid)0000-0003-3165-0156 Altarejos, J. 5005 555 Universidad de Zaragoza Dpto. Ing.Quím.Tecnol.Med.Amb. Área Ingeniería Química 5005 790 Universidad de Zaragoza Dpto. Ing.Quím.Tecnol.Med.Amb. Área Tecnologi. Medio Ambiente 627 (2022), 122224 [12 pp.] Int. j. pharm. International Journal of Pharmaceutics 0378-5173 5555350 http://zaguan.unizar.es/record/121048/files/texto_completo.pdf Versión publicada 2358417 http://zaguan.unizar.es/record/121048/files/texto_completo.jpg?subformat=icon icon Versión publicada oai:zaguan.unizar.es:121048 articulos driver 2024-03-18-16:03:22 ARTICLE