Nanoscale Copper(II)–Diethyldithiocarbamate Coordination Polymer as a Drug Self-Delivery System for Highly Robust and Specific Cancer Therapy

Abstract

Disulfiram (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.

Targeting Ubiquitin–Proteasome System With Copper Complexes for Cancer Therapy

“…In addition to inducing apoptosis, CuET also triggers non-apoptotic cell death, such as paraptosis in drug-resistant prostate cancer cells ( Chen et al, 2018b ). The anti-cancer activity of CuET or CuIET has been proven in multiple xenograft mouse models (including, but not limited to SW 1990, MDA-MB-231, and AMO-1 cancer cells) and has good tolerance ( Han et al, 2013 ; Skrott et al, 2017 ; Peng et al, 2020 ). Moreover, some clinical trials of the combination of DSF and copper have been completed (NCT00742911 and NCT03034135) or are in progress (NCT04265274, NCT03714555, NCT03363659, and NCT02715609), providing a potential strategy for tumor therapy.…”

Copper Dithiocarbamates: Coordination Chemistry and Applications in Materials Science, Biosciences and Beyond

“…As hinted above [270], another potential route to circumvent the low water solubility is the so-called Trojan horse approach, whereby the pre-formed copper complex is encapsulated into a vestibule. Approaches here include encapsulation in a polymer matrix [270], the aqueous core of liposomes [273], within hyaluronic acid nanoparticles [274,275] or apoferritin [276]. Related to this approach is an interesting report of stabilised metal ion ligand complex (SMILE) technology, whereby [Cu(S 2 CNEt 2 ) 2 ] is embedded into nanoparticles comprised of various stabilising agents that are already approved as safe excipients by the UD Food and Drug Administration [277].…”

Nanoparticle-Hydrogel Systems Containing Platensimycin for Local Treatment of Methicillin-Resistant Staphylococcus aureus Infection

“…Fluorescent dyes Ce6, DiD, etc. are widely used as drug models to investigate the tissue separation or drug retention rate of the drug delivery system in vivo. , After subcutaneous injection of fluorescent dye Ce6-loaded NP-gel (NP-gel­(Ce6)), free Ce6, and PAMAM/Ce6 nanoparticles, their fluorescence intensity within 24 h was observed by live whole-body imaging (Figure ). The fluorescence intensity of both free Ce6 and PAMAM/Ce6 nanoparticle groups decreased at 6 h, and almost no fluorescence was observed at 24 h. However, the fluorescence of the NP-gel­(Ce6) treated group remained at a high level within 24 h. This result indicates that the NP-gel would extend the residence time of the encapsulated drug in the subcutaneous area, thereby improving its therapeutic index against bacterial infections.…”