Journal
INTERNATIONAL JOURNAL OF PHARMACEUTICS
Volume 627, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.ijpharm.2022.122224
Keywords
Primary hyperoxaluria; h LDHA inhibitors; Polymeric micelles; Chitosan; Redox-sensitive; Hepatocytes drug delivery
Categories
Funding
- 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]
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In this study, two nanocarriers based on chitosan conjugates were designed and synthesized to selectively transport hLDHA inhibitors into hepatocytes and disrupt them once they reach the cytosol. The redox-sensitive nanocarrier showed high drug loadings and encapsulation efficiencies for the hLDHA inhibitors tested, and it disassembled under the reducing conditions present inside hepatocytes, releasing the encapsulated inhibitor.
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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