Hydrogels have drawn considerable attention in the field of
drug delivery, yet their poor mechanical strength and uncontrollable drug release behavior have hindered further applications in clinical practice. Taking utility of
metal-
ligand coordination for structurally reinforcing the
hydrogel network, we report design and synthesis of magnetic
nanocomposite hydrogels (HA-DOPA·MNPs) that are crosslinked by
DOPA-Fe(III) coordination existing between
dopamine-conjugated
hyaluronan (HA-
DOPA) and
iron oxide magnetic nanoparticles (MNPs). The MNPs in the
nanocomposite hydrogel not only serve as structural crosslinkers, but also facilitate magnetic
hyperthermia and on-demand release of
doxorubicin (DOX) in HA-DOPA·MNPs/DOX
hydrogels, for release rate of DOX accelerates when external alternating magnetic field (AMF) is ON, and it restores to a slow pace when AMF is OFF. Importantly, HA-DOPA·MNPs/DOX
hydrogel shows a longer retention time than HA-
DOPA/DOX gel or DOX
solution in vivo. Further experiments confirm the efficacious anticancer potency of HA-DOPA·MNPs/DOX in vitro and in vivo, that is mediated by a combination
therapy consisting of
chemotherapy (DOX) and
hyperthermia (MNPs). In contrast, single-modality treatment (DOX or
hyperthermia only) fails to show an equivalent efficacy at the same dose. STATEMENT OF SIGNIFICANCE: This study reports the design of a class of magnetic
nanocomposite hydrogel (HA-DOPA·MNPs) that was structurally reinforced by
DOPA-Fe (III) coordination between HA-
DOPA and
iron oxide MNPs. On one hand, MNPs served as crosslinking centers for structurally reinforcing the
nanocomposite hydrogel; on the other hand, MNPs facilitated temperature rise under an external MNPs, which prompted on-demand drug release as well as a combination
therapy. Comparing to single modality treatment (
chemotherapy or
hyperthermia alone), the HA-DOPA·MNPs/DOX formulation with AMF demonstrated better efficacy against proliferation of
tumor cells (A375) both in vitro and in vivo. We believe that design of HA-DOPA·MNPs/DOX
hydrogel in this report provides a general approach to fabricate structurally-reinforced
nanocomposite hydrogels for on-demand
drug delivery and efficacious combination
therapy.