Sparse-View Photoacoustic Reconstruction Method for Diabetic Retinopathy Using Feature Fusion Network.

Diabetic retinopathy is one of the most prevalent microvascular complications of diabetes mellitus, and photoacoustic imaging is an effective method for imaging diabetic retinal vessels. Photoacoustic imaging is an emerging noninvasive imaging method based on the photoacoustic effect, which offers advantages of contrast, resolution, and depth imaging. Appropriate photoacoustic reconstruction methods are essential for obtaining high-quality photoacoustic images. In this study, a multi-input self-attention multiscale feature fusion network (SAMF-Net) is proposed for photoacoustic reconstruction. The algorithm accepts two inputs, namely the original photoacoustic signal and the traditional reconstructed image. Furthermore, a global feature extraction module based on the self-attention mechanism is employed to focus on the global information. The results demonstrate that the proposed method exhibits superior reconstruction capability under different sparse detection views. The method has instructive value for photoacoustic image reconstruction and has the potential for further application in the diagnosis of diabetic retinopathy.

Non-contact photoacoustic imaging with a silicon photonics-based Laser Doppler Vibrometer.

Photoacoustic imaging has emerged as a powerful, non-invasive modality for various biomedical applications. Conventional photoacoustic systems require contact-based ultrasound detection and expensive, bulky high-power lasers for the excitation. The use of contact-based detectors involves the risk of contamination, which is undesirable for most biomedical applications. While other non-contact detection methods can be bulky, in this paper, we demonstrate a proof-of-concept experiment for compact and contactless detection of photoacoustic signals on silicone samples embedded with ink-filled channels. A silicon photonics-based Laser Doppler Vibrometer (LDV) detects the acoustic waves excited by a compact pulsed laser diode. By scanning the LDV beam over the surface of the sample, 2D photoacoustic images were reconstructed of the sample.

Clinical application of photoacoustic imaging for cervical precursor lesion detection.

PURPOSE: Early diagnosis of a precursor lesion in the uterine cervix is an essential factor in uterine cervical cancer prevention. Although colposcopy is an established procedure for detecting high-risk patients, its accuracy and reproducibility are relatively low. Some supportive or alternative techniques to improve the early diagnosis of a precursor lesion have been studied, and correct diagnosis with high reliability using a minimally invasive, cost-effective technique has been pursued. This study aimed to examine the possibility of using photoacoustic (PA) imaging as a supportive technique to improve the accuracy of early diagnosis of cervical precursor lesions. METHODS: A PA imaging system for microvessels was used to detect angiogenesis in severe lesions. A total of 21 patients who underwent surgical treatment and 114 outpatients who visited our colposcopy clinic were examined. A retrospective evaluation of PA images was performed as follows: (i) pathological assessment of the specific PA findings and (ii) retrospective evaluation of the severe lesion detection rate through PA. RESULTS: PA image evaluation and pathological findings showed dense angiogenesis in a severe precursor lesion appearing as a "hot spot" in the PA image. A comparison with colposcopy findings was performed for accuracy evaluation, and the detection rate of severe lesions using PA was relatively high (positive predictive value, 84.5%; negative predictive value, 82.1%). CONCLUSION: Our results indicate the possibility of using PA imaging for early diagnosis of severe cervical precursor lesions. With its ability to yield quantitative information, PA imaging can improve ultrasound diagnosis.

In vivo spatiotemporal characterizing diverse body transportation of optical labeled high immunity aluminium adjuvants with photoacoustic tomography.

Vaccine development requires high-resolution, in situ, and visual adjuvant technology. To address this need, this work proposed a novel adjuvant labeling that involved indocyanine green (ICG) and bovine serum albumin (BSA) with self-assembled aluminium adjuvant (Alum), which was called BSA@ICG@Alum. This compound exhibited excellent photoacoustic properties and has been confirmed its safety, biocompatibility, high antigen binding efficiency, and superior induction of immune response. Photoacoustic tomography (PAT) tracked the distribution of Alum in lymph nodes (LNs) and lymphatic vessels in real time after diverse injection modalities. The non-invasive imaging approach revealed that BSA@ICG@Alum was transported to the draining LNs 60 min after intramuscular injection and to distal LNs within 30 min after lymph node injection. In conclusion, PAT enabled real-time three-dimensional and quantitative visualization, thus offering a powerful tool for advancing vaccine design by providing critical insights into adjuvant transport and immune system activation.

In vivo targeted-imaging of mitochondrial acidification in an aristolochic acid I-induced nephrotoxicity mouse model by a fluorescent/photoacoustic bimodal probe.

Aristolochic acid I (AAI), a natural compound in aristolochia type Chinese medicinal herb, is generally acknowledged to have nephrotoxicity, which may be associated with mitophagy. Mitophagy is a cellular process with important functions that drive AAI-induced renal injury. Mitochondrial pH is currently measured by fluorescent probes in cell culture, but existing probes do not allow for in situ imaging of AAI-induced mitophagy in vivo. We developed a ratiometric fluorescent/PA dual-modal probe with a silicon rhodamine fluorophore and a pH-sensitive hemicyanine dye covalently linked via a short chain to obtain a FRET type probe. The probe was used to measure AAI-mediated mitochondrial acidification in live cells and in vivo. The Förster resonance energy transfer (FRET)-mediated ratiometric and bimodal method can efficiently eliminate signal variability associated with the commonly used one-emission and single detection mode by ratiometric two channels of the donor and acceptor. The probe has good water-solubility and low molecular weight with two positively charged, facilitating its precise targeting into renal mitochondria, where the fluorescent/PA changes in response to mitochondrial acidification, enabling dynamic and semi-quantitative mapping of subtle changes in mitochondrial pH in AAI-induced nephrotoxicity mouse model for the first time. Also, the joint use of L-carnitine could mitigate the mitophagy in AAI-induced nephrotoxicity.

Performance evaluation of image co-registration methods in photoacoustic mesoscopy of the vasculature.

Objective:The formation of functional vasculature in solid tumours enables delivery of oxygen and nutrients, and is vital for effective treatment with chemotherapeutic agents. Longitudinal characterisation of vascular networks can be enabled using mesoscopic photoacoustic imaging, but requires accurate image co-registration to precisely assess local changes across disease development or in response to therapy. Co-registration in photoacoustic imaging is challenging due to the complex nature of the generated signal, including the sparsity of data, artefacts related to the illumination/detection geometry, scan-to-scan technical variability, and biological variability, such as transient changes in perfusion. To better inform the choice of co-registration algorithms, we compared five open-source methods, in physiological and pathological tissues, with the aim of aligning evolving vascular networks in tumours imaged over growth at different time-points.Approach:Co-registration techniques were applied to 3D vascular images acquired with photoacoustic mesoscopy from murine ears and breast cancer patient-derived xenografts, at a fixed time-point and longitudinally. Images were pre-processed and segmented using an unsupervised generative adversarial network. To compare co-registration quality in different settings, pairs of fixed and moving intensity images and/or segmentations were fed into five methods split into the following categories: affine intensity-based using 1)mutual information (MI) or 2)normalised cross-correlation (NCC) as optimisation metrics, affine shape-based using 3)NCC applied to distance-transformed segmentations or 4)iterative closest point algorithm, and deformable weakly supervised deep learning-based using 5)LocalNet co-registration. Percent-changes in Dice coefficients, surface distances, MI, structural similarity index measure and target registration errors were evaluated.Main results:Co-registration using MI or NCC provided similar alignment performance, better than shape-based methods. LocalNet provided accurate co-registration of substructures by optimising subfield deformation throughout the volumes, outperforming other methods, especially in the longitudinal breast cancer xenograft dataset by minimising target registration errors.Significance:We showed the feasibility of co-registering repeatedly or longitudinally imaged vascular networks in photoacoustic mesoscopy, taking a step towards longitudinal quantitative characterisation of these complex structures. These tools open new outlooks for monitoring tumour angiogenesis at the meso-scale and for quantifying treatment-induced co-localised alterations in the vasculature.

Enhancing photoacoustic imaging for lung diagnostics and BCI communication: simulation of cavity structures artifact generation and evaluation of noise reduction techniques.

Pandemics like COVID-19 have highlighted the potential of Photoacoustic imaging (PAI) for Brain-Computer Interface (BCI) communication and lung diagnostics. However, PAI struggles with the clear imaging of blood vessels in areas like the lungs and brain due to their cavity structures. This paper presents a simulation model to analyze the generation and propagation mechanism within phantom tissues of PAI artifacts, focusing on the evaluation of both Anisotropic diffusion filtering (ADF) and Non-local mean (NLM) filtering, which significantly reduce noise and eliminate artifacts and signify a pivotal point for selecting artifact-removal algorithms under varying conditions of light distribution. Experimental validation demonstrated the efficacy of our technique, elucidating the effect of light source uniformity on artifact-removal performance. The NLM filtering simulation and ADF experimental validation increased the peak signal-to-noise ratio by 11.33% and 18.1%, respectively. The proposed technique adds a promising dimension for BCI and is an accurate imaging solution for diagnosing lung diseases.

Glutathione-responsive biodegradable nanohybrid for cancer photoacoustic imaging and gas-assisted photothermal therapy.

Photothermal therapy (PTT), particularly in the near-infrared-II (NIR-II) range, has attracted widespread attention over the past years. However, the accompanied inflammatory responses can result in undesirable side effects and contribute to treatment ineffectiveness. Herein, we introduced a novel biodegradable nanoplatform (CuS/HMON-PEG) capable of PTT and hydrogen sulfide (H2S) generation, aimed at modulating inflammation for improved cancer treatment outcomes. The embedded ultrasmall copper sulphide (CuS) nanodots (1-2 nm) possessed favorable photoacoustic imaging (PAI) and NIR-II photothermal capabilities, rendering CuS/HMON-PEG an ideal phototheranostic agent. Upon internalization by 4T1 cancer cells, the hollow mesoporous organosilica nanoparticle (HMON) component could react with the overproduced glutathione (GSH) to produce H2S. In addition to the anticipated photothermal tumor ablation and H2S-induced mitochondrial dysfunction, the anti-inflammatory regulation was also been demonstrated by the downregulation of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1beta (IL-1ß). More importantly, the modulation of inflammation also promoted wound healing mediated by PTT. This work not only presents a H2S-based nanomodulator to boost NIR-II PTT but also provides insights into the construction of novel organic/inorganic hybrid nanosystems.

Optical Transmission in Single-Layer Brain Tissues under Different Optical Source Types: Modelling and Simulation.

The human brain is a complex organ controlling daily activity. Present technique models have mostly focused on multi-layer brain tissues, which lack understanding of the propagation characteristics of various single brain tissues. To better understand the influence of different optical source types on individual brain tissues, we constructed single-layer brain models and simulated optical propagation using the Monte Carlo method. Based on the optical simulation results, sixteen optical source types had different optical energy distributions, and the distribution in cerebrospinal fluid had obvious characteristics. Five brain tissues (scalp, skull, cerebrospinal fluid, gray matter, and blood vessel) had the same set of the first three optical source types with maximum depth, while white matter had a different set of the first three optical source types with maximum depth. Each brain tissue had different optical source types with the maximum and minimum full width at half maximum. The study on single-layer brain tissues under different optical source types lays the foundation for constructing complex brain models with multiple tissue layers. It provides a theoretical reference for optimizing the selection of optical source devices for brain imaging.

Tailoring Plasmonic Nanoheaters Size for Enhanced Theranostic Agent Performance.

The introduction of optimized nanoheaters, which function as theranostic agents integrating both diagnostic and therapeutic processes, holds significant promise in the medical field. Therefore, developing strategies for selecting and utilizing optimized plasmonic nanoheaters is crucial for the effective use of nanostructured biomedical agents. This work elucidates the use of the Joule number (Jo) as a figure of merit to identify high-performance plasmonic theranostic agents. A framework for optimizing metallic nanoparticles for heat generation was established, uncovering the size dependence of plasmonic nanoparticles optical heating. Gold nanospheres (AuNSs) with a diameter of 50 nm and gold nanorods (AuNRs) with dimensions of 41×10 nm were identified as effective nanoheaters for visible (530 nm) and infrared (808 nm) excitation. Notably, AuNRs achieve higher Jo values than AuNSs, even when accounting for the possible orientations of the nanorods. Theoretical results estimate that 41×10 nm gold nanorods have an average Joule number of 80, which is significantly higher compared to larger rods. The photothermal performance of optimal and suboptimal nanostructures was evaluated using photoacoustic imaging and photothermal therapy procedures. The photoacoustic images indicate that, despite having larger absorption cross-sections, the large nanoparticle volume of bigger particles leads to less efficient conversion of light into heat, which suggests that the use of optimized nanoparticles promotes higher contrast, benefiting photoacoustic-based procedures in diagnostic applications. The photothermal therapy procedure was performed on S180-bearing mice inoculated with 41×10 nm and 90×25 nm PEGylated AuNRs. Five minutes of laser irradiation of tumor tissue with 41×10 nm produced an approximately 9.5% greater temperature rise than using 90×25 AuNRs in the therapy trials. Optimizing metallic nanoparticles for heat generation may reduce the concentration of the nanoheaters used or decrease the light fluence for bioscience applications, paving the way for the development of more economical theranostic agents.

Nanoprobe Based on Novel NIR-II Quinolinium Cyanine for Multimodal Imaging.

NIR-II imaging has the advantages of high sensitivity, spatiotemporal resolution, and high penetration depth, thereby serving as a potential alternative to conventional imaging methods. Herein, a novel NIR-II dye IR-1010 (λex/λem = 1010/1058 nm) is reported with high quantum yield (3.08%) and good stability, by incorporating p-methoxyphenyl groups into a quinolinium cyanine dye. Then a multifunctional nanoprobe, termed IUFP NPs, is developed by the incorporation of upconversion (UC) nanoparticles (NPs), perfluoro-15-crown-5-ether (PFCE), and IR-1010, to display the novel performance of multimodal imaging. Under the single-wavelength excitation (980 nm), IUFP NPs simultaneously emit the NIR-II fluorescence of IR-1010 and visible UC luminescence of UCNPs, and thus realize the UC imaging for cells, and NIR-II fluorescence/photoacoustic/19F magnetic resonance imaging for blood vessels, lymph nodes and tumor in mice. This work affords a novel approach to NIR-II dyes and a general strategy for the design of multimodal imaging probes.

Advancements in photoacoustic imaging for cancer diagnosis and treatment.

Photoacoustic imaging provides in vivo morphological and functional information about tumors within surrounding tissue. By integrating ultrasound guidance, this technique enables precise localization and characterization of tumors. Moreover, the introduction of targeted contrast agents has further expanded the capabilities of photoacoustic imaging in the realm of in vivo molecular imaging. These contrast agents facilitate enhanced molecular and cellular characterization of cancer, enabling detailed insights into the disease. This review aims to provide a concise summary of the extensive research conducted in the field of Photoacoustic imaging for cancer management. It encompasses the development of the technology, its applications in clinical settings, and the advancements made in molecular imaging. By consolidating and synthesizing the existing knowledge, this review contributes to a better understanding of the potential of photoacoustic imaging in cancer care. In conclusion, photoacoustic imaging has emerged as a non-ionizing and noninvasive modality with the ability to visualize tissue's optical absorption properties while maintaining ultrasound's spatial resolution. Its integration with targeted contrast agents has enhanced molecular and cellular characterization of cancer. This review serves as a succinct overview of the extensive research conducted in the field, shedding light on the potential of photoacoustic imaging in the management of cancer.

Molecular imaging nanoprobes and their applications in atherosclerosis diagnosis.

Molecular imaging has undergone significant development in recent years for its excellent ability to image and quantify biologic processes at cellular and molecular levels. Its application is of significance in cardiovascular diseases, particularly in diagnosing them at early stages. Atherosclerosis is a complex, chronic, and progressive disease that can lead to serious consequences such as heart strokes or infarctions. Attempts have been made to detect atherosclerosis with molecular imaging modalities. Not only do imaging modalities develop rapidly, but research of relevant nanomaterials as imaging probes has also been increasingly studied in recent years. This review focuses on the latest developments in the design and synthesis of probes that can be utilized in computed tomography, positron emission tomography, magnetic resonance imaging, ultrasound imaging, photoacoustic imaging and combined modalities. The challenges and future developments of nanomaterials for molecular imaging modalities are also discussed.

Multi-parametric Photoacoustic Imaging Combined with Acoustic Radiation Force Impulse Imaging for Applications in Tissue Engineering.

Tissue engineering is a dynamic field focusing on the creation of advanced scaffolds for tissue and organ regeneration. These scaffolds are customized to their specific applications and are often designed to be complex, large structures to mimic tissues and organs. This study addresses the critical challenge of effectively characterizing these thick, optically opaque scaffolds that traditional imaging methods fail to fully image due to their optical limitations. We introduce a novel multi-modal imaging approach combining ultrasound, photoacoustic, and acoustic radiation force impulse imaging. This combination leverages its acoustic-based detection to overcome the limitations posed by optical imaging techniques. Ultrasound imaging is employed to monitor the scaffold structure, photoacoustic imaging is employed to monitor cell proliferation, and acoustic radiation force impulse imaging is employed to evaluate the homogeneity of scaffold stiffness. We applied this integrated imaging system to analyze melanoma cell growth within silk fibroin protein scaffolds with varying pore sizes and therefore stiffness over different cell incubation periods. Among various materials, silk fibroin was chosen for its unique combination of features including biocompatibility, tunable mechanical properties, and structural porosity which supports extensive cell proliferation. The results provide a detailed mesoscale view of the scaffolds' internal structure, including cell penetration depth and biomechanical properties. Our findings demonstrate that the developed multimodal imaging technique offers comprehensive insights into the physical and biological dynamics of tissue-engineered scaffolds. As the field of tissue engineering continues to advance, the importance of non-ionizing and non-invasive imaging systems becomes increasingly evident, and by facilitating a deeper understanding and better characterization of scaffold architectures, such imaging systems are pivotal in driving the success of future tissue-engineering solutions.

Novel Metal-Free Nanozyme for Targeted Imaging and Inhibition of Atherosclerosis via Macrophage Autophagy Activation to Prevent Vulnerable Plaque Formation and Rupture.

Atherosclerosis is a primary cause of cardiovascular and cerebrovascular diseases, with the unpredictable rupture of vulnerable atherosclerotic plaques enriched with lipid-laden macrophages being able to lead to heart attacks and strokes. Activating macrophage autophagy presents itself as a promising strategy for preventing vulnerable plaque formation and reducing the risk of rupture. In this study, we have developed a novel metal-free nanozyme (HCN@DS) that integrates the functions of multimodal imaging-guided therapy for atherosclerosis. HCN@DS has demonstrated high macrophage-targeting abilities due to its affinity toward scavenger receptor A (SR-A), along with excellent photoacoustic and photothermal imaging capabilities for guiding the precise treatment. It combines mild photothermal effects with moderate reactive oxygen species (ROS) generation to treat atherosclerosis. This controlled approach activates autophagy in atherosclerotic macrophages, inhibiting foam cell formation by reducing the uptake of oxidized low-density lipoproteins (oxLDL) and promoting efferocytosis and cholesterol efflux in macrophages. Additionally, it prevents plaque rupture by inhibiting apoptosis and inflammation within the plaque. Therefore, this metal-free nanozyme holds great potential for reducing the risk of atherosclerosis due to its high biosafety, excellent targeting ability, dual-modality imaging capability, and appropriate modulation of autophagy.

Joint segmentation and image reconstruction with error prediction in photoacoustic imaging using deep learning.

Deep learning has been used to improve photoacoustic (PA) image reconstruction. One major challenge is that errors cannot be quantified to validate predictions when ground truth is unknown. Validation is key to quantitative applications, especially using limited-bandwidth ultrasonic linear detector arrays. Here, we propose a hybrid Bayesian convolutional neural network (Hybrid-BCNN) to jointly predict PA image and segmentation with error (uncertainty) predictions. Each output pixel represents a probability distribution where error can be quantified. The Hybrid-BCNN was trained with simulated PA data and applied to both simulations and experiments. Due to the sparsity of PA images, segmentation focuses Hybrid-BCNN on minimizing the loss function in regions with PA signals for better predictions. The results show that accurate PA segmentations and images are obtained, and error predictions are highly statistically correlated to actual errors. To leverage error predictions, confidence processing created PA images above a specific confidence level.

Gold nanorod-assisted theranostic solution for nonvisible residual disease in bladder cancer.

Residual nonvisible bladder cancer after proper treatment caused by technological and therapeutic limitations is responsible for tumor relapse and progression. This study aimed to demonstrate the feasibility of a solution for simultaneous detection and treatment of bladder cancer lesions smaller than one millimeter. The α5ß1 integrin was identified as a specific marker in 81% of human high-grade nonmuscle invasive bladder cancers and used as a target for the delivery of targeted gold nanorods (GNRs). In a preclinical model of orthotopic bladder cancer expressing the α5ß1 integrin, the photoacoustic imaging of targeted GNRs visualized lesions smaller than one millimeter, and their irradiation with continuous laser was used to induce GNR-assisted hyperthermia. Necrosis of the tumor mass, improved survival, and computational modeling were applied to demonstrate the efficacy and safety of this solution. Our study highlights the potential of the GNR-assisted theranostic strategy as a complementary solution in clinical practice to reduce the risk of nonvisible residual bladder cancer after current treatment. Further validation through clinical studies will support the findings of the present study.

From Morphology to Therapeutic Strategies: Exploring New Applications of Ultrasound for Diabetic Peripheral Neuropathy Diagnosis and Management.

Diabetic peripheral neuropathy (DPN) is a common complication of diabetes that can result in severe lower limb pain and amputation. Early detection and treatment of DPN are vital, but this condition is often missed due to a lack of symptoms and the insensitivity of testing methods. This article reviews various ultrasound imaging modalities in the direct and indirect evaluation of peripheral neuropathy. Moreover, how ultrasound-related therapeutic strategies are playing a role in clinical treatment is discussed. Finally, the application of innovative methodologies in the diagnosis of DPN, including ultrasound attenuation, photoacoustic imaging, and artificial intelligence, is described.

Development of a Controllable Intelligent Drug Delivery System for Efficient Treatment of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a complex inflammatory disease of the joints, which is often accompanied by degeneration of articular cartilage and bone erosion, seriously affecting the quality of life and psychological state of patients. RA is difficult to be cured completely, and currently the main purpose of relief is through the use of anti-inflammatory and antirheumatic drugs, hormones, and biological agents. Tofacitib is a new type of small molecule inhibitor, which has a good effect in the treatment of RA. The current direct drug delivery method has serious side effects caused by the systemic distribution of the drug, so there is a need to develop an intelligent drug delivery system to realize precise treatment. In this work, tofacitib, gallic acid, targeted molecule folic acid, and Fe(III) were selected to assemble a novel type of artificial controllable nanodrug GF-TF. The self-photoacoustic/magnetic resonance imaging (self-PA/MRI) monitored the enrichment of GF-TF in the lesion in real-time, and artificially regulated the addition of deferoxamine (DFO) at the optimal enrichment. DFO strongly chelates Fe(III) in GF-TF and causes its structure to disintegrate gradually, and the self-PA/MRI signal of GF-TF became weaker while tofacitib began to be released, thus realizing the precise and artificially controlled release of the drug under the guidance of imaging. This nanodrug not only achieves efficient aggregation of drugs in inflamed joints, but also achieves real-time monitoring and precise control of drug release through self-PA/MRI, providing a new strategy for the precise treatment of RA.

Mitochondrial Sulfenated-Protein-Targeted Covalent Immobilization Boosting Efficient Copper(II) Depletion for Enhanced Cancer Treatment.

Copper plays a vital role in cellular metabolism and oxidative stress regulation. Visualizing and controlling the copper level in mitochondrion have been proven to be promising and efficient strategies for the diagnosis and treatment of triple-negative breast cancer (TNBC). However, developing an advanced probe for simultaneous visualization and depletion of mitochondrial copper remains a huge challenge. Herein, we for the first time report a mitochondria-anchorable, copper-responsive, and depleting probe d-IR-DPA and evaluate its potential for quantitative visualization of intratumoral copper(II) and anti-TNBC in vivo. Taking advantage of the mitochondrion-targeting and sulfenated-protein-mediated covalent immobilization characteristics, this probe not only enables the quantitative detection of Cu2+ levels in various types of tumors through ratiometric photoacoustic (PA680 nm/PA800 nm) imaging but also scavenges the mitochondrial Cu2+, simultaneously igniting increased oxidative stress and mitochondrial membrane damage and eventually leading to severe TNBC cell apoptosis. More notably, the depletion of Cu2+ by d-IR-DPA can alter the cellular metabolic pathway from oxidative phosphorylation to glycolysis, inducing energy deprivation and significant suppression of TNBC tumor in living mice. Our probe may provide a valuable and powerful means for the effective treatment of TNBC as well as other copper-associated diseases.