Synergistic eradicating impact of 5-fluouracil with FeO nanoparticles-diethyldithiocarbamate in colon cancer spheroids.

Background: Cancer stem cells' (CSCs) resistance to 5-fluorouracil (Fu), which is the main obstacle in treating colon cancer (CC), can be overcome by ferroptosis. The latter, herein, can be triggered by FeO nanoparticles (inducer of iron accumulation) and diethyldithiocarbamate-inhibited glutathione system and aldehyde dehydrogenase (ALDH1A1-maintained stemness, therapeutic resistance and metastasis). Materials & methods: Nanocomplex of FeO nanoparticles and diethyldithiocarbamate (FD) was used in combination with Fu to investigate its potential synergistic anti-CSC influence using CC spheroid models. Results: In Fu + FD-treated spheroids, the strongest growth inhibition, the highest cell death percentage, and the lowest CD133+-CSCs percentage and stemness gene expressions (e.g., drug efflux transporter), and the strongest antimetastatic effect were recorded with high synergistic indexes. Conclusion: Fu + FD represents effective combination therapy for chemoresistant CC cells.

[Box: see text].

Spin Trapping of Nitric Oxide by Hemoglobin and Ferrous Diethyldithiocarbamate in Model Tumors Differing in Vascularization.

Animal tumors serve as reasonable models for human cancers. Both human and animal tumors often reveal triplet EPR signals of nitrosylhemoglobin (HbNO) as an effect of nitric oxide formation in tumor tissue, where NO is complexed by Hb. In search of factors determining the appearance of nitrosylhemoglobin (HbNO) in solid tumors, we compared the intensities of electron paramagnetic resonance (EPR) signals of various iron-nitrosyl complexes detectable in tumor tissues, in the presence and absence of excess exogenous iron(II) and diethyldithiocarbamate (DETC). Three types of murine tumors, namely, L5178Y lymphoma, amelanotic Cloudman S91 melanoma, and Ehrlich carcinoma (EC) growing in DBA/2 or Swiss mice, were used. The results were analyzed in the context of vascularization determined histochemically using antibodies to CD31. Strong HbNO EPR signals were found in melanoma, i.e., in the tumor with a vast amount of a hemorrhagic necrosis core. Strong Fe(DETC)2NO signals could be induced in poorly vascularized EC. In L5178Y, there was a correlation between both types of signals, and in addition, Fe(RS)2(NO)2 signals of non-heme iron-nitrosyl complexes could be detected. We postulate that HbNO EPR signals appear during active destruction of well-vascularized tumor tissue due to hemorrhagic necrosis. The presence of iron-nitrosyl complexes in tumor tissue is biologically meaningful and defines the evolution of complicated tumor-host interactions.

Identification, Isolation, and Characterization of a Novel Degradation Impurity of Busulfan Using Preparative Chromatography, NMR, and LC-MS.

BACKGROUND: Busulfan is the most effective medication for treating chronic myelogenous or granulocytic leukemia because it has cytotoxic properties that harm or kill hematopoietic cells. It cannot absorb light in the Ultraviolet range due to its structure. Because of this, it is very challenging to quantify using traditional HPLC coupled with UV/Photodiode Array detectors. So, using sodium diethyldithiocarbamate, a derivatization method was developed to quantify related impurities. A significant unknown impurity was identified in derivatized samples of busulfan and a noticeably high percentage level was discovered during routine drug testing. OBJECTIVE: We aimed to isolate, and characterize the unknown impurity observed in the samples and to identify its root cause. METHODS: Preparative HPLC was used to isolate the unidentified, derivatized impurity, and 1H NMR, 13C NMR, and MS were used to decipher its structural components. RESULTS: The spectral characterization data analysis showed that the unknown impurity was related to busulfan. Additionally, it was noted that the impurity developed as a result of the residual buffer used to prepare the derivatizing reagent. CONCLUSION: The isolated impurity was found to be same as comparable to that found in busulfan drug substances, according to the results of the characterization tools. An alternative method of reagent preparation was optimized and deemed satisfactory because the buffer used in reagent preparation is the only factor contributing to the formation of impurities. HIGHLIGHTS: Using cutting-edge analytical characterization tools, it was possible to explain the structural characteristics of an unknown impurity and discover that it was a novel impurity, which undoubtedly contributes to the comprehension of drug substance reaction properties.

Hydroxyethyl starch stabilized copper-diethyldithiocarbamate nanocrystals for cancer therapy.

Cancer stem cells (CSCs) have been recognized as the culprit for tumor progression, treatment resistance, metastasis, and recurrence while redox homeostasis represents the Achilles' Heel of CSCs. However, few drugs or formulations that are capable of elevating oxidative stress have achieved clinical success for eliminating CSCs. Here, we report hydroxyethyl starch stabilized copper-diethyldithiocarbamate nanoparticles (CuET@HES NPs), which conspicuously suppress CSCs not only in vitro but also in numerous tumor models in vivo. Furthermore, CuET@HES NPs effectively inhibit CSCs in fresh tumor tissues surgically excised from hepatocellular carcinoma patients. Mechanistically, we uncover that hydroxyethyl starch stabilized copper-diethyldithiocarbamate nanocrystals via copper­oxygen coordination interactions, thereby promoting copper-diethyldithiocarbamate colloidal stability, cellular uptake, intracellular reactive oxygen species production, and CSCs apoptosis. As all components are widely used in clinics, CuET@HES NPs represent promising treatments for CSCs-rich solid malignancies and hold great clinical translational potentials. This study has critical implications for design of CSCs targeting nanomedicines.

Anti-metastatic breast cancer potential of novel nanocomplexes of diethyldithiocarbamate and green chemically synthesized iron oxide nanoparticles.

Mortality rate of metastatic breast cancer is linked to cancer stem cells (CSCs)' aggressive features (chemoresistance to apoptosis and redox imbalance). Therefore, unique dual therapeutic strategy compacts CSCs with inducing oxidative stress-mediated nonapoptosis (ferroptosis), confers effective malignant tumor eradication. Diethyldithiocarbamate (DDC) is a potent inhibitor of CSC aldehyde dehydrogenase and lowers glutathione (GSH) which aggravate iron-dependent ferroptosis. Herein, nanoformulations of DDC with green chemically synthesized ferrous oxide nanoparticles (FeO NPs) and ferric oxide (Fe2O3 NPs) were prepared. Due to nanoparticle characters and synergistic effect between iron oxide NPs and DDC, nanocomplexes (DFeO NPs and DFe2O3 NPs, respectively) exhibited the strongest anti-metastatic cancer potency in vitro. Because of corresponding iron oxide nature, DFeO NPs demonstrated better therapeutic efficacy than DFe4O3 NPs, in mammary tumor liver metastasis-bearing mice, in terms of tumor size, histological analysis, immunostaining % of ki-67+ and caspase 3+, and gene expression of p53 and BCl2. The potent anti-tumor effect of DFeO nanocomplex is attributed to the maximum elevation of reactive oxygen species and lipid peroxidation (ferroptosis hall marker) with severe depletion of GSH and Nrf2 selectively in both tumor tissues, causing CSC eradication with halting metastatic activity. The latters were confirmed by lowering CD44+ % and gene expression of HIF-α, ß-catenin, Notch, ABCG2-mediated chemoresistance, and MMP9 with diminishing liver tumor marker. Moreover, this nanocomplex did not cause any abnormal alterations in histological and biochemical parameters, compared to healthy group. Therefore, the selective apoptotic and ferroptotic with anti-CSC effects of DFeO NPs open new safe avenue for metastatic tumor therapy.

Disulfiram oxy-derivatives induce entosis or paraptosis-like death in breast cancer MCF-7 cells depending on the duration of treatment.

BACKGROUND: Dithiocarbamates and derivatives (including disulfiram, DSF) are currently investigated as antineoplastic agents. We have revealed earlier the ability of hydroxocobalamin (vitamin В12b) combined with diethyldithiocarbamate (DDC) to catalyze the formation of highly cytotoxic oxidized derivatives of DSF (DSFoxy, sulfones and sulfoxides). METHODS: Electron and fluorescent confocal microscopy, molecular biology and conventional biochemical techniques were used to study the morphological and functional responses of MCF-7 human breast cancer cells to treatment with DDC and B12b alone or in combination. RESULTS: DDC induces unfolded protein response in MCF-7 cells. The combined use of DDC and B12b causes MCF-7 cell death. Electron microscopy revealed the separation of ER and nuclear membranes, leading to the formation of both cytoplasmic and perinuclear vacuoles, with many fibers inside. The process of vacuolization coincided with the appearance of ER stress markers, a marked damage to mitochondria, a significant inhibition of 20S proteasome, and actin depolimerization at later stages. Specific inhibitors of apoptosis, necroptosis, autophagy, and ferroptosis did not prevent cell death. A short- time (6-h) exposure to DSFoxy caused a significant increase in the number of entotic cells. CONCLUSIONS: These observations indicate that MCF-7 cells treated with a mixture of DDC and B12b die by the mechanism of paraptosis. A short- time exposure to DSFoxy caused, along with paraptosis, a significant activation of the entosis and its final stage, lysosomal cell death. GENERAL SIGNIFICANCE: The results obtained open up opportunities for the development of new approaches to induce non-apoptotic death of cancer cells by dithiocarbamates.

Sphingomyelin-based PEGylation Cu (DDC)2 liposomes prepared via the dual function of Cu2+ for cancer therapy: Facilitating DDC loading and exerting synergistic antitumor effects.

The old alcohol-aversion drug disulfiram (DSF) has aroused wide attention as a drug repurposing strategy in terms of cancer therapy because of the high antitumor efficacy in combination with copper ion. However, numerous defects of DSF (e.g., the short half-life and acid instability) have limited the application in cancer treatment. Cu (DDC)2, the complex of diethyldithiocarbamate (DDC, DSF metabolite) and Cu2+, have been proven as the vital active component on cancer, which have aroused the attention of researchers from DSF to Cu (DDC)2. However, the poor water solubility of Cu (DDC)2 increase more difficulties to the treatment and in-depth investigations of Cu (DDC)2. In this study, sphingomyelin (SM)-based PEGylated liposomes (SM/Chol/DSPE-mPEG2000 (55:40:5, mole%)) were produced as the carriers for Cu (DDC)2 delivery to enhance the water solubility. DDC was added to Cu-containing liposomes with a higher encapsulation efficiency of more than 90%, and it reacted with Cu2+ to synthesize Cu (DDC)2. Due to the high phase transition temperature of SM and strong intermolecular hydrogen bonds with cholesterol, SM-based liposomes would be conducive to enhancing the stability of Cu (DDC)2 and preventing drug leakage during delivery. As proven by pharmacokinetic studies, loading Cu (DDC)2 into liposomes improve bioavailability, and the area under the curve (AUC0-t) and the mean elimination half-life (t1/2) increased 1.9-time and 1.3-time to those of free Cu (DDC)2, respectively. Furthermore, the anticancer effect of Cu (DDC)2 was enhanced by the liposomal encapsulation, thus resulting in remarkable cell apoptosis in vitro and a tumor-inhibiting rate of 77.88% in vivo. Thus, it was concluded that Cu (DDC)2 liposomes could be promising in cancer treatment.

Diethyldithiocarbamate/silk fibroin/polyethylene oxide nanofibrous for cancer therapy: Fabrication, characterization and in vitro evaluation.

Cancer has become a serious disease threatening human health. To tackle this issue, developing the existing potent anticancer drugs is critical to reducing the time and cost associated with creating a new drug from scratch. Diethyldithiocarbamate (DDC) - an anticancer drug- has received considerable attention due to its selectivity and reactivity. In this study, we prepared a nanofibrous matrix from silk fibroin/polyethylene oxide loaded with diethyldithiocarbamate (DDC@SF/PEO) from an aqueous solution via an electrospinning process. Upon DDC incorporation, the nanofiber's diameter has increased from 450 nm (SF/PEO) to 1202 nm (DDC@SF/PEO) confirming the successful incorporation of DDC. Furthermore, the hydrophobicity of DDC@SF/PEO nanofibrous matrix was improved by turning SF structure from random coil (silk I) to ß-sheet (silk II) through ethanol vapor treatment. Biocompatibility of DDC@SF/PEO nanofibrous matrix on human normal cells (Wi-38) showed it was safe and the apoptosis-mediated anticancer activity of DDC was enhanced. Thus, loading DDC on SF/PEO nanofibrous matrix is the key descriptor for enhanced anticancer efficacy of DDC. Considering the all-aqueous and simplistic process, the DDC@SF/PEO nanofibrous matrix could be a promising candidate for cancer treatment applications.

Surface Decoration via Physical Interaction of Cupric Diethyldithiocarbamate Nanocrystals and Its Impact on Biodistribution and Tumor Targeting.

The vascular wall is the first physiologic barrier that circulating nanoparticles (NPs) encounter, which also is a key biological barrier to cancer drug delivery. NPs can continually scavenge the endothelium for biomarkers of cancer, and the chance of NPs' extravasation into the tumors can be enhanced. Here, we envision P-selectin as a target for specific delivery of drug nanocrystals to tumors. The cupric diethyldithiocarbamate nanocrystals (CuET NCs) were first prepared by an antisolvent method, and then nanocrystals were coated with fucoidan via physical interaction. The fucoidan-coated CuET nanocrystals (CuET@Fuc) possess high drug loading and have the ability to interact with human umbilical vein endothelial cells expressing P-selectin, which transiently enhances the endothelial permeability and facilitates CuET@Fuc extravasation from the peritumoral vascular to achieve higher tumor accumulation of drugs than bare CuET NCs. The CuET NC shows poorer anticancer efficacy than CuET@Fuc at the same dose of CuET. Upon repeated dosing of CuET@Fuc for 2 weeks, no mortality was observed in treated melanoma-bearing mice, while the mortality in the control group and excipient-treated groups reached 23%. The growth rate of melanoma in the CuET@Fuc-treated group was significantly lower than those in other groups. Furthermore, an acute toxicity study revealed that CuET@Fuc is a safe formulation for cancer treatment.

A PDA-DTC/Cu-MnO2 nanoplatform for MR imaging and multi-therapy for triple-negative breast cancer treatment.

Herein, a multi-functional nanoplatform (PDA-DTC/Cu-MnO2) was established, which has been employed for MR imaging-guided multi-therapy (CDT, PTT and chemotherapy) for cancer treatment. The in vitro and in vivo results confirmed that the biocompatible nanoplatform could significantly induce tumor cell death and inhibit tumor growth.

A bismuth diethyldithiocarbamate compound induced apoptosis via mitochondria-dependent pathway and suppressed invasion in MCF-7 breast cancer cells.

Interest in bismuth(III) dithiocarbamate complexes as potential drug candidates is increasing due to their low toxicity compared to other group 15 elements (pnictogen) of the periodic table. Bismuth dithiocarbamate compounds have been reported to induce greater cytotoxicity in various human carcinoma cancer cell lines. Using various in vitro cancer-related assays, we investigated the antiproliferative activity of bismuth diethyldithiocarbamate, denoted as 1, against the MCF-7 human breast adenocarcinoma cell line and the effect on genes that may be involved in antiproliferation, apoptosis, DNA fragmentation, invasion and polyubiquitination functions. In general, 1 exhibited high cytotoxicity in MCF-7 cells, with an IC50 of 1.26 ± 0.02 µM, by inducing the intrinsic apoptotic pathway, as ascertained by measurements of intracellular reactive oxygen species (ROS), caspase activity, the amount of cytochrome c released and the extent of DNA fragmentation and by staining assays that reveal apoptotic cells. In addition, 1 significantly attenuated cell invasion and modulated several cancer-related genes, including PLK2, FIGF, FLT4, PARP4, and HDAC11, as determined via gene expression analysis. The NF-κB signaling pathway was inhibited by 1 upon the activation of Lys48- and Lys63-linked polyubiquitination, thus leading to its degradation via the proteasome. Overall, 1 has the potential to act as an antiproliferative agent and a proteasome inhibitor in estrogen-positive breast cancer.

Seesaw conformations of Npl4 in the human p97 complex and the inhibitory mechanism of a disulfiram derivative.

p97, also known as valosin-containing protein (VCP) or Cdc48, plays a central role in cellular protein homeostasis. Human p97 mutations are associated with several neurodegenerative diseases. Targeting p97 and its cofactors is a strategy for cancer drug development. Despite significant structural insights into the fungal homolog Cdc48, little is known about how human p97 interacts with its cofactors. Recently, the anti-alcohol abuse drug disulfiram was found to target cancer through Npl4, a cofactor of p97, but the molecular mechanism remains elusive. Here, using single-particle cryo-electron microscopy (cryo-EM), we uncovered three Npl4 conformational states in complex with human p97 before ATP hydrolysis. The motion of Npl4 results from its zinc finger motifs interacting with the N domain of p97, which is essential for the unfolding activity of p97. In vitro and cell-based assays showed that the disulfiram derivative bis-(diethyldithiocarbamate)-copper (CuET) can bypass the copper transporter system and inhibit the function of p97 in the cytoplasm by releasing cupric ions under oxidative conditions, which disrupt the zinc finger motifs of Npl4, locking the essential conformational switch of the complex.

Copper(II)-disulfiram loaded melanin-dots for cancer theranostics.

Copper(II) diethyldithiocarbamate complex (CuET), the metabolite of disulfiram complexed with copper, is the component responsible for cancer treatment efficacy of disulfiram. But the hydrophobic property of CuET limits its use in vivo, and an appropriate drug delivery system needs to be developed. Ultrasmall melanin nanoparticle (M-Dot) with excellent biosafety and biocompatibility properties has been synthesized in our previous studies. Herein we prepared CuET loaded with M-Dots through hydrophobic interaction, which could enhance the water solubility significantly. After the administration of M-Dots-CuET in mice tumor models, the nanoparticles showed good tumor accumulation as evidenced by the enhanced photoacoustic signal in tumor regions. M-Dots-CuET also displayed excellent tumor inhibition capability, and the tumor growth inhibition value (TGI) was 45.1%. When combined with photothermal therapy, the TGI reached up to 78.6%. In summary, M-Dots-CuET provide a new potential strategy for cancer theranostics.

Biodegradable Quantum Composites for Synergistic Photothermal Therapy and Copper-Enhanced Chemotherapy.

In recent times, the combination therapy has garnered enormous interest owing to its great potential in clinical research. It has been reported that disulfiram, a clinical antialcoholism drug, could be degraded to diethyldithiocarbamate (DDTC) in vivo and subsequently result in the copper-DDTC complex (Cu(DDTC)2) toward ablating cancer cells. In addition, the ultrasmall copper sulfide nanodots (CuS NDs) have shown great potential in cancer treatment because of their excellent photothermal and photodynamic therapeutic efficiencies. Herein, by taking advantage of the interactions between CuS and DDTC, a new multifunctional nanoplatform based on DDTC-loaded CuS (CuS-DDTC) NDs is successfully fabricated, leading to the achievement of the synergistic effect of photothermal and copper enhanced chemotherapy. All experimental results verified promising synergistic therapeutic effects. Moreover, in vivo biocompatibility and metabolism experiments displayed that the CuS-DDTC NDs could be quickly excreted from the body with no apparent toxicity signs. Together, our findings indicated the superior synergistic therapeutic effect of photothermal and copper-enhanced chemotherapy, providing a promising anticancer strategy based on the CuS-DDTC NDs drug delivery system.

Transcriptional Induction of Cystathionine γ-Lyase, a Reactive Sulfur-Producing Enzyme, by Copper Diethyldithiocarbamate in Cultured Vascular Endothelial Cells.

As toxic substances can enter the circulating blood and cross endothelial monolayers to reach parenchymal cells in organs, vascular endothelial cells are an important target compartment for such substances. Reactive sulfur species protect cells against oxidative stress and toxic substances, including heavy metals. Reactive sulfur species are produced by enzymes, such as cystathionine γ-lyase (CSE), cystathionine ß-synthase, 3-mercaptopyruvate sulfurtransferase, and cysteinyl-tRNA synthetase. However, little is known about the regulatory mechanisms underlying the expression of these enzymes in vascular endothelial cells. Bio-organometallics is a research field that analyzes biological systems using organic-inorganic hybrid molecules (organometallic compounds and metal coordinating compounds) as molecular probes. In the present study, we analyzed intracellular signaling pathways that mediate the expression of reactive sulfur species-producing enzymes in cultured bovine aortic endothelial cells, using copper diethyldithiocarbamate (Cu10). Cu10 selectively upregulated CSE gene expression in vascular endothelial cells independent of cell density. This transcriptional induction of endothelial CSE required both the diethyldithiocarbamate scaffold and the coordinated copper ion. Additionally, the present study revealed that ERK1/2, p38 MAPK, and hypoxia-inducible factor (HIF)-1α/HIF-1ß pathways mediate transcriptional induction of endothelial CSE by Cu10. The transcription factors NF-κB, Sp1, and ATF4 were suggested to act in constitutive CSE expression, although the possibility that they are involved in the CSE induction by Cu10 cannot be excluded. The present study used a copper complex as a molecular probe to reveal that the transcription of CSE is regulated by multiple pathways in vascular endothelial cells, including ERK1/2, p38 MAPK, and HIF-1α/HIF-1ß. Bio-organometallics appears to be an effective strategy for analyzing the functions of intracellular signaling pathways in vascular endothelial cells.

Diethyldithiocarbamate-copper nanocomplex reinforces disulfiram chemotherapeutic efficacy through light-triggered nuclear targeting.

To circumvent the huge cost, long R&D time and the difficulty to identify the targets of new drugs, repurposing the ones that have been clinically approved has been considered as a viable strategy to treat different diseases. In the current study, we outlined the rationale for repurposing disulfiram (DSF, an old alcohol-aversion drug) to treat primary breast cancer and its metastases. Methods: To overcome a few shortcomings of the individual administration of DSF, such as the dependence on copper ions (Cu2+) and limited capability in selective targeting, we here artificially synthesized the active form of DSF, diethyldithiocarbamate (DTC)-Cu complex (CuET) for cancer therapeutics. To achieve a greater efficacy in vivo, smart nanomedicines were devised through a one-step self-assembly of three functional components including a chemically stable and biocompatible phase-change material (PCM), the robust anticancer drug (CuET) and a near-infrared (NIR) dye (DIR), namely CuET/DIR NPs. A number of in vitro assays were performed including the photothermal efficacy, light-triggered drug release behavior, nuclear localization, DNA damage and induction of apoptosis of CuET/DIR NPs and molecular mechanisms underlying CuET-induced repression on cancer metastatic behaviors. Meanwhile, the mice bearing 4T1-LG12-drived orthotopic tumors were employed to evaluate in vivo biodistribution and anti-tumor effect of CuET/DIR NPs. The intravenous injection model was employed to reflect the changes of the intrinsic metastatic propensity of 4T1-LG12 cells responding to CuET/DIR NPs. Results: The rationally designed nanomedicines have self-traceability for bioimaging, long blood circulation time for enhanced drug accumulation in the tumor site and photo-responsive release of the anticancer drugs. Moreover, our data unearthed that CuET/DIR nanomedicines behave like "Trojan horse" to transport CuET into the cytoplasm, realizing substantial intracellular accumulation. Upon NIR laser irradiation, massive CuET would be triggered to release from the nanomedicines and reach a high local concentration towards the nucleus, where the pro-apoptotic effects were conducted. Importantly, our CuET/DIR nanomedicines revealed a pronounced capability to leash breast cancer metastases through inhibition on EMT. Additionally, these nanomedicines showed great biocompatibility in animals. Conclusion: These combined data unearthed a remarkably enhanced tumor-killing efficacy of our CuET nanomedicines through nuclear targeting. This work may open a new research area of repurposing DSF as innovative therapeutic agents to treat breast cancer and its metastases.

Picomolar-level detection of mercury within non-biological/biological aqueous media using ultra-sensitive polyaniline-Fe3O4-silver diethyldithiocarbamate nanostructure.

Mercury as the 3rd most toxic, non-biodegradable, and carcinogenic pollutant can adversely affect the ecosystem and health of living species through its bioaccumulation within the nature that can affect the top consumer in the food chain; therefore, it is vital to sense/remove Hg2+ within/from aqueous media using practical approaches. To address this matter, we modified the glassy carbon electrode (GCE) with ultra-sensitive, interconnected, sulfurized, and porous nanostructure consisted of polyaniline-Fe3O4-silver diethyldithiocarbamate (PANi-F-S) to enhance the sensitivity, selectivity, and limit of detection (LOD) of the sensor. Obtained results showed that at optimum conditions (i.e., pH value of 7, deposition potential of - 0.8 V, and accumulation time of 120 s), for Hg2+ concentration ranging from 0.4 to 60 nM, the modified electrode showing linear relative coefficient of 0.9983, LOD of 0.051 nM, LOQ of 0.14 nM, and sensitivity of 1618.86 µA µM-1 cm-2 highlights superior sensitivity of the developed platform until picomolar level. Additionally, the modified electrode showed ideal repeatability, stability, reproducibility, and selectivity (by considering Zn2+, Cd2+ Pb2+, Cu2+, Ni2+, and Co2+ as metal interferences) and recovered more than 99% of the Hg2+ ions within non-biological (mineral, tap, and industrial waters) and biological (blood plasma sample) fluids. Graphical abstract.

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

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.

Evaluation of the accumulation of disulfiram and its copper complex in A549 cells using mass spectrometry.

The famous alcohol-aversion drug disulfiram (DSF) is a promising candidate for repurposing in cancer therapy, as indicated by many ongoing and completed clinical trials. Existing researches focus on demonstrating that the anti-cancer activity of DSF is enhanced by copper ions, or solving the problem that DSF is easily decomposed in the body to lose its activity. However, the metabolic kinetics of its ultimate anti-cancer metabolite DDC-Cu (bis-diethyldithiocarbamate-copper) in cells and how it exerts anti-cancer mechanisms remain unclear. In this work, mass spectrometric evaluation of the intracellular and extracellular accumulation of DSF and its copper complex DDC-Cu was performed. Combined with cytotoxicity assay, staining analysis and flow cytometry, we found that DDC-Cu could easily pass through the cell membrane of A549 cells, and accumulate intracellularly for a long time. This process can lead to cellular morphological changes, an increase in ROS content, cell cycle arrest in the G0/G1 phase and apoptosis. Besides, molecular cancer-relevant targets of DDC-Cu in cancer cells were further discussed. This work investigated the cytotoxic mechanism of DDC-Cu, which has important clinical significance for its application in cancer therapy.

Doxorubicin intercalated copper diethyldithiocarbamate functionalized layered double hydroxide hybrid nanoparticles for targeted therapy of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the deadliest cancers due to its long incubation period and low cure rate. Layered double hydroxide (LDH) nanoparticles have attracted considerable research interest in the field of nanomedicine owing to their surface effects and good biocompatibility. In this research, we synthesized a hexagonal nanoparticle by the co-precipitation method, referred to as Cu-Al LDH. As an alternative to traditional drug-loading methods, sodium diethyldithiocarbamate (DDC) was introduced and combined with Cu2+ in LDHs to form a diethyldithiocarbamate-copper complex (Cu(DDC)2), which was not only the composition of carrier materials but also an effective component for cancer therapy. Doxorubicin (DOX) was also encapsulated into LDHs due to the clinical relevance of DOX treatment for HCC. Formulations of the Cu(DDC)2 and DOX co-loaded nanoparticles were optimized to precisely control the Cu(DDC)2/DOX ratio. The nanoparticles were coated with polyethylene glycol-graft-polyglutamic acid (PEG-PLG) through electrostatic adsorption to improve the stability of the nanoparticles. The outer layer was decorated with hyaluronic acid (HA) to achieve specific targeting of tumors. Compared with non-HA coated nanoparticles, HA coated nanoparticles showed greater cellular uptake in Hep G2 cells, which could cause higher cytotoxicity. In addition, targeted nanoparticles effectively inhibited tumor growth in mouse models of ectopic hepatocellular carcinoma. It can be concluded that there is a great potential for synergistic cancer therapy using the novel DOX intercalated Cu(DDC)2 functionalized layered double hydroxide hybrid nanoparticles.