Primary hyperoxalurias (PHs) represent rare diseases
associated
with disruptions in glyoxylate metabolism within hepatocytes. Impaired
glyoxylate detoxification in PH patients results in its accumulation
and subsequent conversion into oxalate, a process catalyzed by the
hepatic lactate dehydrogenase A enzyme (
h
LDHA). Targeting
this enzyme selectively in the liver using small organic molecules
emerges as a potential therapeutic strategy for PH. However, achieving
selective hepatic inhibition of
h
LDHA poses challenges,
requiring precise delivery of potential inhibitors into hepatocytes
to mitigate adverse effects in other tissues. Our recent efforts focused
on the design of polymeric micelle nanocarriers tailored for the selective
transport and release of
h
LDHA inhibitors into liver
tissues. In this study, we synthesized and assessed the internalization
and disaggregation dynamics of chitosan-based polymeric micelles in
both hepatic and nonhepatic cell models using live-cell imaging. Our
findings indicate that lactonolactone residues confer internalization
capacity to the micelles upon exposure to cells. Moreover, we demonstrated
the intracellular disaggregation capacity of these nanocarriers facilitated
by the cystamine redox-sensitive linker attached to the polymer. Importantly,
no cytotoxic effects were observed throughout the experimental time
frame. Finally, our results underscore the higher selectivity of these
nanocarriers for hepatic HepG2 cells compared to other nonhepatic
cell models.