Galactose-based
Thermosensitive Nanogels for Targeted
Drug Delivery of Iodoazomycin Arabinofuranoside (IAZA) for Theranostic
Management of Hypoxic Hepatocellular Carcinoma
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Abstract
In
this study, galactose-based nanogels were prepared by reversible
addition–fragmentation chain transfer process to facilitate
the targeted delivery of iodoazomycin arabinofuranoside (IAZA), a
clinical drug for imaging solid hypoxic tumors, and evaluate its role
in hypoxia-selective (radio)theranostic (therapy + diagnostic) management
of therapy-resistant cancer cells. The nanogels have a cross-linked
temperature-responsive core and a dense carbohydrate shell. Their
thermoresponsive nature allowed the controlled encapsulation of IAZA
drug for targeted delivery and release in hypoxic hepatocellular carcinoma
via asialoglycoprotein receptor-mediated uptake. The synthesized nanogel-IAZA
delivery systems demonstrated a stable, nonburst release of IAZA over
10 h with up to 0.6 mM loading capacity of IAZA within the nanogel.
The cytotoxicity evaluations of the nanogels demonstrated that they
are relatively nontoxic in multiple cell lines. The radiosensitization
studies indicated that IAZA in encapsulated form offers a superior
radiosensitization of hypoxic cells (sensitizer enhancement ratio
for IAZA alone, 1.33; 1.62 for nanogel encapsulated IAZA). These studies
suggest that galactose-based nanogels may serve as a versatile drug
delivery system for IAZA (and other azomycin-based agents) and enable
its hypoxia-selective multimodal theranostic applications to manage
hypoxic solid (hepatocellular) tumors by facilitating position/single
photon emission tomography-based imaging, external beam radiation
therapy, and <i>in situ</i> molecular radiotherapy