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Nanoscale Copper(II)–Diethyldithiocarbamate Coordination Polymer as a Drug Self-Delivery System for Highly Robust and Specific Cancer Therapy
journal contribution
posted on 2020-07-01, 13:39 authored by Ying Peng, Peng Liu, Yingcai Meng, Shuo Hu, Jinsong Ding, Wenhu ZhouDisulfiram
(DSF), an old alcohol-aversion drug, has been repurposed
for cancer therapy, and mechanistic studies reveal that it needs to
be metabolized to diethyldithiocarbamate (DTC) and subsequently coordinates
with copper(II) to form the DTC–copper complex (CuET) for anticancer
activation. Here, we utilized this mechanism to construct a CuET self-delivery
nanosystem based on the metal coordination polymer for highly robust
and selective cancer therapy. In our design, the nanoparticles were
facilely prepared under mild conditions by virtue of the strong coordination
between Cu2+ and DTC, yielding 100% CuET loading capacity
and allowing for further hyaluronic acid (HA) modification (CuET@HA
NPs). The CuET@HA NPs could selectively deliver into cancer cells
and release the active component of CuET in response to both endo/lysosome
acidic pH and intracellular abundant GSH, which induces strong cytotoxicity
toward cancer cells over normal cells taking advantage of the p97
pathway interference mechanism. Upon intravenous injection, the self-assembled
system could passively accumulate into a tumor and elicit potent tumor
growth inhibition at a dose of 1 mg/kg without any noticeable side
effects. Given the cost-effective and easily scaled-up preparation,
our designed nanosystem provides a promising strategy to pave the
way for clinical translation of DSF-based cancer chemotherapy.