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

    Year: 2022

    Journal: Int. J. Pharm., Volume 627, NOV 5

    Authors: Salido, S.; Alejo-Armijo, A.; Parola, A. J.; Sebastian, V; Alejo, T.; Irusta, S.; Arruebo, M.; Altarejos, J.

    Organizations: Spanish Ministerio de Ciencia, Innovacion y Universidades [RTI2018-098560-BC22]; Andalusian Consejeria de Economia y Conocimiento (FEDER program 2014-2020) [1380682]; Associate Laboratory for Green ChemistryLAQV - FCT/MCTES [UIDB/50006/2020]

    Keywords: Primary hyperoxaluria; h LDHA inhibitors; Polymeric micelles; Chitosan; Redox-sensitive; Hepatocytes drug delivery

    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 se-lective 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 mu M 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 mu M, GSH) but it quickly disassembled under the simulated reducing conditions present inside hepatocytes (10 mM GSH), achieving a 60 % release of the hLDHA inhibitor encap-sulated after 24 h, confirming the responsiveness of the developed carrier to the high levels of intracellular GSH.
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