Disulfiram-loaded hollow copper sulfide nanoparticles show anti-tumor effects in preclinical models of colorectal cancer.

Colorectal cancer is one of the most common malignancies causing the majority of cancer-related deaths. There is an urgent need to develop new anticancer modalities. Recently, efforts have been made to turn clinically approved drugs into anticancer agents in specific tumor microenvironments via NPs. Disulfiram (DSF) as an effective copper (Cu2+)-dependent anti-tumour drug, which has been more widely used in antitumor research. Here, we constructed a novel therapeutic nanoplatforms, DSF@CuS, by encapsulating DSF in hollow CuS NPs to enable in situ chemoselective activation of DSF and hyperthermal amplified chemotherapy. The anticancer effect of DSF was enhanced by the thermal energy generated under NIR irradiation through the intrinsic photothermal conversion of CuS. As a result, significant apoptosis was induced in vitro, and tumor elimination was achieved in vivo. Collectively, DSF@CuS combined with photothermal therapy can significantly promote the apoptosis of CT26 colorectal cancer cells both in vitro and in vivo, providing a potential theoretical agent for the treatment of colorectal cancer.

Five-FU@CuS/NH2 -UiO-66 as a drug delivery system for 5-fluorouracil to colorectal cancer cells.

In this study, copper sulfide nanoparticles (CuS-NPs), which can improve the antiproliferative properties of conventional anticancer drugs such as 5-fluorouracil (5-FU), were incorporated into the pores of amine-functionalized UiO-66 (CuS/NH2 -UiO-66). The introduced nano-drug delivery system was exerted to perform an in vitro treatment on CT-26 mouse colorectal cancer cells. The synthesized final product was labeled as 5-FU@CuS/NH2 -UiO-66 and characterized through conventional methods including X-ray diffraction (XRD), Fourier transformation infrared spectroscopy (FT-IR), Brunauer-Emmett-Teller (BET) analysis, Ultraviolet-Visible (UV-Vis) analysis, Inductively coupled plasma mass spectrometry (ICP-MS), and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. In contrast to 5-FU, the outcomes of the cytotoxicity assay lacked any comparable results for 5-FU@CuS/NH2 -UiO-66.

Partitioned Microneedle Patch Based on NO Release and HSP Inhibition for mPTT/GT Combination Treatment of Melanoma.

Photothermal therapy (PTT) shows promise in cancer treatments due to its good spatiotemporal selectivity and minimal invasiveness. However, PTT has some problems such as excessive heat damage to normal tissues, tumor thermo-resistance caused by heat shock proteins (HSPs), and limited efficacy of monotherapy. Here, we construct a patch named "partitioned microneedles" (PMN-SNAP/CuS), which separates the "catalyst" bovine serum albumin-based copper sulfide nanoparticles (CuS@BSA NPs) and the "reactant" S-nitroso-N-acetylpenicillamine (SNAP) into different regions of microneedles, for enhancing mild PTT (mPTT) of melanoma. PMN-SNAP/CuS showed an excellent photothermal effect, Fenton-like catalytic activity, and nitric oxide (NO) generation ability. The combination of NO and reactive oxygen species (ROS) produced by PMN-SNAP/CuS effectively blocked the synthesis of HSPs at the source and enhanced the efficacy of mPTT. Both in vitro and in vivo results proved that PMN-SNAP/CuS significantly enhanced the inhibition of melanoma under 808 nm laser irradiation. In conclusion, our partitioned microneedle strategy based on the combination of enhanced mPTT and gas therapy (GT) provides a promising approach to enhance the therapeutic effect on melanoma.

Codelivery of CuS and DOX into Deep Tumors with Size and Charge-Switchable PAMAM Dendrimers for Chemo-photothermal Therapy.

Accurate targeting of therapeutic agents to specific tumor tissues, especially via deep tumor penetration, has been an effective strategy in cancer treatments. Here, we described a flexible nanoplatform, pH-responsive zwitterionic acylsulfonamide betaine-functionalized fourth-generation PAMAM dendrimers (G4-AB), which presented multiple advantages for chemo-photothermal therapy, including template synthesis of ultrasmall copper sulfide (CuS) nanoparticles and further encapsulation of doxorubicin (DOX) (G4-AB-DOX/CuS), long-circulating performance by a relatively large size and zwitterionic surface in a physiological environment, combined size shrinkage, and charge conversions via pH-responsive behavior in an acidic tumor microenvironment (TME). Accordingly, high tumor penetration and positive cell uptake for CuS and DOX have been determined, which triggered an excellent combination treatment under near-infrared irradiation in comparison to the monochemotherapy system and irresponsive chemo-photothermal system. Our study represented great promise in constructing multifunctional carriers for the effective delivery of photothermal nanoparticles and drugs in chemo-photothermal therapy.

Photothermal and Acid-Responsive Fucoidan-CuS Bubble Pump Microneedles for Combined CDT/PTT/CT Treatment of Melanoma.

Transdermal cancer therapy faces great challenges in clinical practice due to the low drug transdermal efficiency and the unsatisfactory effect of monotherapy. Herein, we develop a novel bubble pump microneedle system (BPMN-CuS/DOX) by embedding sodium bicarbonate (NaHCO3) into hyaluronic acid microneedles (MNs) loaded with fucoidan-based copper sulfide nanoparticles (Fuc-CuS NPs) and doxorubicin (DOX). BPMN-CuS/DOX can generate CO2 bubbles triggered by an acidic tumor microenvironment for deep and rapid intradermal drug delivery. Fuc-CuS NPs exhibit excellent photothermal effect and Fenton-like catalytic activity, producing more reactive oxygen species (ROS) by photothermal therapy (PTT) and chemodynamic therapy (CDT), which enhances the antitumor efficacy of DOX and reduces the dosage of its chemotherapy (CT). Simultaneously, DOX increases intracellular hydrogen peroxide (H2O2) supplementation and promotes the sustained production of ROS. BPMN-CuS/DOX significantly inhibits melanoma both in vitro and in vivo by the combination of CDT, PTT, and CT. In short, our study significantly enhances the effectiveness of transdermal drug delivery by constructing BPMNs and provides a promising novel strategy for transdermal cancer treatment with multiple therapies.

Synthesis, antibacterial evaluation, and safety assessment of CuS NPs against Pectobacterium carotovorum subsp. carotovorum.

BACKGROUND: Copper agents have been widely used in crop protection because of their unique mechanism against resistant pathogenic bacteria; however, their application brings environmental pollution and biosafety problems. Therefore, environmentally friendly copper agents have attracted attention. In this study, copper sulfide nanoparticles (CuS NPs) were prepared, characterized, analyzed for antibacterial activity and safety. RESULTS: Characterization results showed that the prepared pure CuS NPs have flake nanostructures, hexagonal crystal system, and size range from 40 to 60 nm. These CuS NPs exerted excellent antibacterial effects [median effective concentration (EC50 ) = 17 mg L-1 ] against Pectobacterium carotovorum subsp. carotovorum (Pcc) in vitro and can effectively delay and reduce bacterial infection in vivo. Antibacterial mechanism analysis revealed that CuS NPs can increase the levels of reactive oxygen species (ROS) and lipid peroxidation and destroy the structure of bacterial cells as observed through scanning electron microscopy (SEM) and Fourier-transform infrared (FTIR) spectroscopy. These NPs can also inhibit the motility of Pcc. At 7 and 14 days, the 50% lethal concentrations (LC50 ) of CuS NPs against earthworms were 1136 and 783 mg kg-1 , respectively, indicating their low acute toxicity to earthworms and environmental friendliness. Furthermore, the cells (L02) treated by CuS NPs showed relatively high cell viability (> 96%) and low apoptosis rate (only 5.2%), proving that CuS NPs had low cytotoxicity. CONCLUSION: Compared with commercial dicopper chloride trihydroxide (Cu2 (OH)3 Cl), CuS NPs could be used as a highly effective, lowly toxic, and environmentally friendly antibacterial agent. © 2021 Society of Chemical Industry.

CuS nanoparticles and camptothecin co-loaded thermosensitive injectable hydrogel with self-supplied H2O2 for enhanced chemodynamic therapy.

Chemodynamic therapy (CDT) is a kind of anti-tumor strategy emerging in recent years, but the concentration of hydrogen peroxide (H2O2) in the tumor microenvironment is insufficient, and it is difficult for a single CDT to completely inhibit tumor growth. Here, we designed a CuS nanoparticles (NPs) and camptothecin (CPT) co-loaded thermosensitive injectable hydrogel (SCH) with self-supplied H2O2 for enhanced CDT. SCH is composed of CuS NPs and CPT loaded into agarose hydrogel according to a certain ratio. We injected SCH into the tumor tissue of mice, and under the irradiation of near-infrared region (NIR) laser at 808 nm, CuS NPs converted the NIR laser into heat to realize photothermal therapy (PTT), and at the same time, the agarose hydrogel was changed into a sol state and CPT was released. CPT activates nicotinamide adenine dinucleotide phosphate oxidase, increases the level of H2O2 inside the tumor, and realizes the self-supply of H2O2. At the same time, CuS can accelerate the release of Cu2+ in an acidic environment and light, combined with H2O2 generated by CPT for CDT treatment, and consume glutathione in tumor and generate hydroxyl radical, thus inducing tumor cell apoptosis. The SCH system we constructed achieved an extremely high tumor inhibition rate in vitro and in vivo, presenting a new idea for designing future chemical kinetic systems.

Light-induced shape-memory polyurethane composite film containing copper sulfide nanoparticles and modified cellulose nanocrystals.

Light-induced shape-memory polymer (LSMP) materials have advantages of remote control and precise stimulation under suitable photoactive factors. The excellent performance, stability, and low cost are significant for LSMP materials. Herein, a novel stable and cheap LSMP was prepared with polyurethane (PU) and copper sulfide nanoparticles (CuS NPs) supported on modified cellulose nanocrystals (MCNC) (CuS NPs@MCNC). For the photosensitivity, CuS NPs were formed and assembled on MCNC without other additives. These prepared LSMP films exhibited good light-induced shape memory, which was ascribed to the highly photothermal effect of CuS NPs. We found that the shape recovery ratio was 97.4 % when the PU nanocomposite film containing 0.2 wt.% CuS NPs@MCNC was irradiated by near-infrared (NIR) for 21 s. The ratio was still over 85.7 % after five times of repeat test. These LSMPs contained CuS NPs@MCNC have potential to be applied as a prospective material for medical devices and new packaging.

Homogeneous assay based on the pre-reduction and selective cation exchange for detection of multiple targets by atomic spectrometry.

In view of the high sensitivity and good selectivity, chemical vapor generation atomic spectrometry (CVG-AS) and inductively coupled plasma mass spectrometer (ICP-MS), especially low-cost atomic fluorescence spectrometry (AFS) have been widely used in bioassay. However, the existing AS method is mostly based on heterogeneous strategies, and can't detect multiple targets in one system. In this study, we present the discovery and mechanism study of a phenomenon of Hg2+ pre-reduction that the concentration of Hg2+ decreased when it was mixed with the reductants (ascorbic acid (AA), SnCl2, or NaBH4/KBH4) over long-time reaction (hours) by CVG-AFS and ICP-MS. A homogeneous Cu2+ assay method was developed based on the competition reaction of Cu2+ and Hg2+ for consuming AA, and its application in the detection of pyrophosphate (PPi) and alkaline phosphatase (ALP) was investigated based on the PPi complexation with Cu2+, and ALP hydrolyzation of PPi using CVG-AFS as a representative detector. Subsequently, in order to further verify the applicability of the system, cation exchange reaction (CER) was utilized here based on the selectively recognize Ag+ and C-Ag+-C by CuS nanoparticles (NPs). As the exchanged Cu2+ from CuS NPs can be sensitively and selectively detected via above-mentioned Cu2+ assay method, this strategy can be extended for the Ag+, DNA and prostate specific antigen (PSA) detection based on base complementary pairing and the specific recognition of aptamer. Under the optimal experimental conditions, the system showed high sensitivity for the detection of Cu2+, PPi, ALP, Ag+, DNA, and PSA, with limit of detections (LODs) of 0.12 nmol L-1, 25 µmol L-1, 0.025 U/L, 0.2 nmol L-1, 0.05 nmol L-1, and 0.03 ng/mL, respectively. The method was successfully used to determination Cu2+, ALP, and PSA in human serums, showing similar results with those of ICP-MS and kits methods.

A Fluorescence Strategy for Silver Ion Assay via Cation Exchange Reaction and Formation of Poly(thymine)-templated Copper Nanoclusters.

The detection of Ag+ ions in the environment and biological systems is important to both environmental monitoring and modern medicine. Herein, a novel and label-free method was developed for Ag+ detection, which utilizes a florescence strategy combining DNA-templated copper nanoclusters (Cu NCs) with cation exchange reactions. The method is primarily based on the effective detection of an Ag+-triggered cation exchange reaction and the release of free Cu2+ from CuS nanoparticles (CuS NPs), while the probe T30 serves as an effective template for the formation of fluorescence-inducing Cu NCs. Under optimal conditions, this sensing system displays high sensitivity with a 50 nM limit of detection and a range from 0 - 100 µM. In addition, the proposed method exhibits high selectivity and, therefore, was successfully applied to the analysis of real samples. Overall, these results demonstrate that our established method has advantages of design and operation simplicity, as well as cost-effectiveness.

Surface-Functionalized Modified Copper Sulfide Nanoparticles Enhance Checkpoint Blockade Tumor Immunotherapy by Photothermal Therapy and Antigen Capturing.

Nanomaterial-based tumor photothermal therapy (PTT) has attracted increasing attention and been a promising method for cancer treatment because of its low level of adverse effects and noninvasiveness. However, thermotherapy alone still cannot control tumor metastasis and recurrence. Here, we developed surface-functionalized modified copper sulfide nanoparticles (CuS NPs). CuS NPs can not only be used as photothermal mediators for tumor hyperthermia but can adsorb tumor antigens released during hyperthermia as an antigen-capturing agent to induce antitumor immune response. We selected maleimide polyethylene glycol-modified CuS NPs (CuS NPs-PEG-Mal) with stronger antigen adsorption capacity, in combination with an immune checkpoint blocker (anti-PD-L1) to evaluate the effect of hyperthermia, improving immunotherapy in a 4T1 breast cancer tumor model. The results showed that hyperthermia based on CuS NPs-PEG-Mal distinctly increased the levels of inflammatory cytokines in the serum, leading to a tumor immunogenic microenvironment. In cooperation with anti-PD-L1, PTT mediated by CuS NPs-PEG-Mal enhanced the number of tumor-infiltrating CD8+ T cells and inhibited the growth in primary and distant tumor sites of the 4T1 tumor model. The therapeutic strategies provide a simple and effective treatment option for metastatic and recurrent tumors.

Cetuximab-modified CuS nanoparticles integrating near-infrared-II-responsive photothermal therapy and anti-vessel treatment.

BACKGROUND: Photothermal therapy (PTT) has received extensive attention owing to its non-invasive nature and highly therapeutic outcomes. PTT agents and near-infrared (NIR) laser are essential elements in PTT. However, most PTT agents are composed of heavy metals, characterized by serious cytotoxicity and side effects, and NIR irradiation often damages normal tissue owing to the high dose, thus limiting the clinical application of PTT. PURPOSE: In this regard, exploring new perspectives enabling more PTT agents to be enriched into the tumor and NIR laser irradiation decay in PTT is vital. METHODS: In this study, cetuximab (Ab), an anti-angiogenic antibody which targets the EGFR, was modified on CuS NPs (CuS-Ab NPs) to improve the aggregation of CuS NPs in the tumor. RESULTS: The cellular uptake data and the biodistribution results showed comparable accumulation of CuS-Ab NPs in tumor, thus decreasing the cytotoxicity and side effects in normal tissues. More importantly, the modification of Ab in CuS-Ab NPs impressively inhibited the formation and progression of tumor vessels, as demonstrated by immunohistochemistry staining. The introduction of anti-vessel treatment requires CuS-Ab NPs to provide weak PTT, which means that a small amount of laser energy is required, inevitably causing negligible damage to normal tissue. CONCLUSION: Therefore, our tailor-made CuS-Ab NPs have promising potential in clinical applications.

CuS-Based Theranostic Micelles for NIR-Controlled Combination Chemotherapy and Photothermal Therapy and Photoacoustic Imaging.

Cancer remains a major threat to human health due to low therapeutic efficacies of currently available cancer treatment options. Nanotheranostics, capable of simultaneous therapy and diagnosis/monitoring of diseases, has attracted increasing amounts of attention, particularly for cancer treatment. In this study, CuS-based theranostic micelles capable of simultaneous combination chemotherapy and photothermal therapy (PTT), as well as photoacoustic imaging, were developed for targeted cancer therapy. The micelle was formed by a CuS nanoparticle (NP) functionalized by thermosensitive amphiphilic poly(acrylamide-acrylonitrile)-poly(ethylene glycol) block copolymers. CuS NPs under near-infrared (NIR) irradiation induced a significant temperature elevation, thereby enabling NIR-triggered PTT. Moreover, the hydrophobic core formed by poly(acrylamide-acrylonitrile) segments used for drug encapsulation exhibited an upper critical solution temperature (UCST; ∼38 °C), which underwent a hydrophobic-to-hydrophilic transition once the temperature rose above the UCST induced by NIR-irradiated CuS NPs, thereby triggering a rapid drug release and enabling NIR-controlled chemotherapy. The CuS-based micelles conjugated with GE11 peptides were tested in an epidermal growth factor receptor-overexpressing triple-negative breast cancer model. In both two-dimensional monolayer cell and three-dimensional multicellular tumor spheroid models, GE11-tagged CuS-based micelles under NIR irradiation, enabling the combination chemotherapy and PTT, exhibited the best therapeutic outcome due to a synergistic effect. These CuS-based micelles also displayed a good photoacoustic imaging ability under NIR illumination. Taken together, this multifunctional CuS-based micelle could be a promising nanoplatform for targeted cancer nanotheranostics.

64 CuS-labeled nanoparticles: a new sentinel-lymph-node-mapping agent for PET-CT and photoacoustic tomography.

Determining sentinel lymph node (SLN) status is critical to cancer staging and treatment decisions. Currently, in clinical practice, 99m Tc-radiocolloid-mediated planar scintigraphy and single-photon emission computed tomography (SPECT) are used to guide the biopsy and resection of SLNs. Recently, an emerging technique that combines positron emission tomography (PET) and photoacoustic tomography (PAT; PET-PAT) may offer accurate information in detecting SLNs. Herein, we report a kind of 64 CuS-labeled nanoparticle (64 CuS-NP) for the detection of SLNs with PET-PAT. We subcutaneously injected 64 CuS-NPs into the rats' forepaw pads. After 24 h, the rats' first draining axillary lymph nodes (i.e. the SLNs) could be clearly visualized with micro-PET (µPET)-CT. Rats were sacrificed after µPET-CT imaging, their axillary lymph nodes were surgically identified, and then PAT was employed to discover 64 CuS-NP-avid SLNs, which were embedded inside tissues. Biodistribution, autoradiography, and copper staining analyses confirmed the SLNs' high uptake of 64 CuS-NPs. Our study indicates that 64 CuS-NPs are a promising dual-function agent for both PET-CT and PAT and could be used with multi-modal imaging strategies such as PET-PAT to identify SLNs in a clinical setting. Copyright © 2016 John Wiley & Sons, Ltd.