Chitosan derivatives as nanocarriers for hLDHA inhibitors delivery to hepatic cells: A selective strategy for targeting primary hyperoxaluria diseases

Salido, S. ; Alejo-Armijo, A. ; Parola, A.J. ; Sebastián, V. (Universidad de Zaragoza) ; Alejo, T. (Universidad de Zaragoza) ; Irusta, S. (Universidad de Zaragoza) ; Arruebo, M. (Universidad de Zaragoza) ; Altarejos, J.

Resumen: 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.

Idioma: Inglés

DOI: 10.1016/j.ijpharm.2022.122224

Año: 2022

Publicado en: International Journal of Pharmaceutics 627 (2022), 122224 [12 pp.]
ISSN: 0378-5173

Factor impacto JCR: 5.8 (2022)

Categ. JCR: PHARMACOLOGY & PHARMACY rank: 39 / 278 = 0.14 (2022) - Q1 - T1

Factor impacto CITESCORE: 10.5 - Pharmacology, Toxicology and Pharmaceutics (Q1)

Factor impacto SCIMAGO: 0.906 - Pharmaceutical Science (Q1)

Financiación: info:eu-repo/grantAgreement/ES/MCIU/RTI2018-098560-B-C22

Tipo y forma: Article (Published version)

Área (Departamento): Área Ingeniería Química (Dpto. Ing.Quím.Tecnol.Med.Amb.)
Área (Departamento): Área Tecnologi. Medio Ambiente (Dpto. Ing.Quím.Tecnol.Med.Amb.)