Abstract
An increased demand for iron is a hallmark of cancer cells and is thought necessary to promote high cell proliferation, tumor progression and metastasis. This makes iron metabolism an attractive therapeutic target. Unfortunately, current iron-based therapeutic strategies often lack effectiveness and can elicit off-target toxicities. We report here a dual-therapeutic prodrug,
DOXjade
, that allows for iron chelation chemo-photothermal cancer therapy. This prodrug takes advantage of the clinically approved iron chelator deferasirox (ExJade®) and the topoisomerase 2 inhibitor, doxorubicin (DOX). Loading
DOXjade
onto ultrathin 2D Ti
3
C
2
MXene nanosheets produces a construct,
Ti
3
C
2
-PVP@DOXjade
, that allows the iron chelation and chemotherapeutic functions of
DOXjade
to be photo-activated at the tumor sites, while potentiating a robust photothermal effect with photothermal conversion efficiencies of up to 40%. Antitumor mechanistic investigations reveal that upon activation,
Ti
3
C
2
-PVP@DOXjade
serves to promote apoptotic cell death and downregulate the iron depletion-induced iron transferrin receptor (TfR). A tumor pH-responsive iron chelation/photothermal/chemotherapy antitumor effect was achieved both
in vitro
and
in vivo
. The results of this study highlight what may constitute a promising iron chelation-based phototherapeutic approach to cancer therapy.
Image 1
•
A conceptually novel “dual-therapeutic prodrug nanomedicine” strategy was designed for synergistic cancer therapy.
•
An innovative pH responsive dual-therapeutic conjugate
DOXjade
was synthesized based on deferasirox and doxorubicin.
•
Ti
3
C
2
-PVP@DOXjade
with photoirradiation showed pH-responsive iron chelation/PTT/chemotherapy antitumor effect.
•
This study thus serves to demonstrate a promising step forward in the development of precise cancer therapies.