Dual-Targeted Zeolitic Imidazolate Frameworks Drug Delivery System Reversing Cisplatin Resistance to Treat Resistant Ovarian Cancer.

Objective: Ovarian cancer cells are prone to acquire tolerance to chemotherapeutic agents, which seriously affects clinical outcomes. The development of novel strategies to enhance the targeting of chemotherapeutic agents to overcome drug resistance and minimize side effects is significant for improving the clinical outcomes of ovarian cancer patients. Methods: We employed folic acid (FA)-modified ZIF-90 nanomaterials (FA-ZIF-90) to deliver the chemotherapeutic drug, cisplatin (DDP), via dual targeting to improve its targeting to circumvent cisplatin resistance in ovarian cancer cells, especially by targeting mitochondria. FA-ZIF-90/DDP could rapidly release DDP in response to dual stimulation of acidity and ATP in tumor cells. Results: FA-ZIF-90/DDP showed good blood compatibility. It was efficiently taken up by human ovarian cancer cisplatin-resistant cells A2780/DDP and aggregated in the mitochondrial region. FA-ZIF-90/DDP significantly inhibited the mitochondrial activity and metastatic ability of A2780/DDP cells. In addition, it effectively induced apoptosis in A2780/DDP cells and overcame cisplatin resistance. In vivo experiments showed that FA-ZIF-90/DDP increased the accumulation of DDP in tumor tissues and significantly inhibited tumor growth. Conclusion: FA-modified ZIF-90 nanocarriers can improve the tumor targeting and anti-tumor effects of chemotherapeutic drugs, reduce toxic side effects, and are expected to be a novel therapeutic strategy to reverse drug resistance in ovarian cancer.

Evolving brain network dynamics in early childhood: Insights from modular graph metrics.

Modular dynamic graph theory metrics effectively capture the patterns of dynamic information interaction during human brain development. While existing research has employed modular algorithms to examine the overall impact of dynamic changes in community structure throughout development, there is a notable gap in understanding the cross-community dynamic changes within different functional networks during early childhood and their potential contributions to the efficiency of brain information transmission. This study seeks to address this gap by tracing the trajectories of cross-community structural changes within early childhood functional networks and modeling their contributions to information transmission efficiency. We analyzed 194 functional imaging scans from 83 children aged 2 to 8 years, who participated in passive viewing functional magnetic resonance imaging sessions. Utilizing sliding windows and modular algorithms, we evaluated three spatiotemporal metrics-temporal flexibility, spatiotemporal diversity, and within-community spatiotemporal diversity-and four centrality metrics: within-community degree centrality, eigenvector centrality, between-community degree centrality, and between-community eigenvector centrality. Mixed-effects linear models revealed significant age-related increases in the temporal flexibility of the default mode network (DMN), executive control network (ECN), and salience network (SN), indicating frequent adjustments in community structure within these networks during early childhood. Additionally, the spatiotemporal diversity of the SN also displayed significant age-related increases, highlighting its broad pattern of cross-community dynamic interactions. Conversely, within-community spatiotemporal diversity in the language network exhibited significant age-related decreases, reflecting the network's gradual functional specialization. Furthermore, our findings indicated significant age-related increases in between-community degree centrality across the DMN, ECN, SN, language network, and dorsal attention network, while between-community eigenvector centrality also increased significantly for the DMN, ECN, and SN. However, within-community eigenvector centrality remained stable across all functional networks during early childhood. These results suggest that while centrality of cross-community interactions in early childhood functional networks increases, centrality within communities remains stable. Finally, mediation analysis was conducted to explore the relationships between age, brain dynamic graph metrics, and both global and local efficiency based on community structure. The results indicated that the dynamic graph metrics of the SN primarily mediated the relationship between age and the decrease in global efficiency, while those of the DMN, language network, ECN, dorsal attention network, and SN primarily mediated the relationship between age and the increase in local efficiency. This pattern suggests a developmental trajectory in early childhood from global information integration to local information segregation, with the SN playing a pivotal role in this transformation. This study provides novel insights into the mechanisms by which early childhood brain functional development impacts information transmission efficiency through cross-community adjustments in functional networks.

Multifaceted Carbonized Metal-Organic Frameworks Synergize with Immune Checkpoint Inhibitors for Precision and Augmented Cuproptosis Cancer Therapy.

The discovery of cuproptosis, a copper-dependent mechanism of programmed cell death, has provided a way for cancer treatment. However, cuproptosis has inherent limitations, including potential cellular harm, the lack of targeting, and insufficient efficacy as a standalone treatment. Therefore, exogenously controlled combination treatments have emerged as key strategies for cuproptosis-based oncotherapy. In this study, a Cu2-xSe@cMOF nanoplatform was constructed for combined sonodynamic/cuproptosis/gas therapy. This platform enabled precise cancer cotreatment, with external control allowing the selective induction of cuproptosis in cancer cells. This approach effectively prevented cancer metastasis and recurrence. Furthermore, Cu2-xSe@cMOF was combined with the antiprogrammed cell death protein ligand-1 antibody (aPD-L1), and this combination maximized the advantages of cuproptosis and immune checkpoint therapy. Additionally, under ultrasound irradiation, the H2Se gas generated from Cu2-xSe@cMOF induced cytotoxicity in cancer cells. Further, it generated reactive oxygen species, which hindered cell survival and proliferation. This study reports an externally controlled system for cuproptosis induction that combines a carbonized metal-organic framework with aPD-L1 to enhance cancer treatment. This precision and reinforced cuproptosis cancer therapy platform could be valuable as an effective therapeutic agent to reduce cancer mortality and morbidity in the future.

Carbon-based Nanomaterials in Photothermal Therapy Guided by Photoacoustic Imaging: State of Knowledge and Recent Advances.

Carbon-based nanomaterials (CBNM)have been widely used in various fields due to their excellent physicochemical properties. In particular, in the area of tumor diagnosis and treatment, researchers have frequently reported them for their potential fluorescence, photoacoustic (PA), and ultrasound imaging performance, as well as their photothermal, photodynamic, sonodynamic, and other therapeutic properties. As the functions of CBNM are increasingly developed, their excellent imaging properties and superior tumor treatment effects make them extremely promising theranostic agents. This review aims to integrate the considered and researched information in a specific field of this research topic and systematically present, summarize, and comment on the efforts made by authoritative scholars. In this review, we summarized the work exploring carbon-based materials in the field of tumor imaging and therapy, focusing on PA imaging-guided photothermal therapy (PTT) and discussing their imaging and therapeutic mechanisms and developments. Finally, the current challenges and potential opportunities of carbon-based materials for PA imaging-guided PTT are presented, and issues that researchers should be aware of when studying CBNM are provided.

Correction: A Y1 receptor ligand synergized with a P-glycoprotein inhibitor improves the therapeutic efficacy of multidrug resistant breast cancer.

Correction for 'A Y1 receptor ligand synergized with a P-glycoprotein inhibitor improves the therapeutic efficacy of multidrug resistant breast cancer' by Yinjie Wang et al., Biomater. Sci., 2019, 7, 4748-4757, https://doi.org/10.1039/C9BM00337A.

Recent advances in sensor-integrated brain-on-a-chip devices for real-time brain monitoring.

Brain science has remained in the global spotlight as an important field of scientific and technological discovery. Numerous in vitro and in vivo animal studies have been performed to understand the pathological processes involved in brain diseases and develop strategies for their diagnosis and treatment. However, owing to species differences between animals and humans, several drugs have shown high rates of treatment failure in clinical settings, hindering the development of diagnostic and treatment modalities for brain diseases. In this scenario, microfluidic brain-on-a-chip (BOC) devices, which allow the direct use of human tissues for experiments, have emerged as novel tools for effectively avoiding species differences and performing screening for new drugs. Although microfluidic BOC technology has achieved significant progress in recent years, monitoring slight changes in neurochemicals, neurotransmitters, and environmental states in the brain has remained challenging owing to the brain's complex environment. Hence, the integration of BOC with new sensors that have high sensitivity and high selectivity is urgently required for the real-time dynamic monitoring of BOC parameters. As sensor-based technologies for BOC have not been summarized, here, we review the principle, fabrication process, and application-based classification of sensor-integrated BOC, and then summarize the opportunities and challenges for their development. Generally, sensor-integrated BOC enables real-time monitoring and dynamic analysis, accurately measuring minute changes in the brain and thus enabling the realization of in vivo brain analysis and drug development.

Carbon-Based Stimuli-Responsive Nanomaterials: Classification and Application.

Carbon-based nanomaterials, including carbon nanotubes, carbon nanospheres, and carbon nanofibers, are becoming a research hotspot due to their unique structure and good mechanical, thermal, electrical, optical, and chemical properties. With the development of material synthesis technology, they can be functionalized and used in various fields such as energy, environment, and biomedicine. In particular, stimuli-responsive carbon-based nanomaterials have stood out in recent years because of their smart behavior. Researchers have applied carbon-based nanomaterials to different disease treatments based on their stimulus-response properties. In this paper, based on stimuli-responsive carbon-based nanomaterials' morphology, we categorize them into carbon nanotubes, carbon nanospheres, and carbon nanofibers according to their morphology. Then, their applications in probes, bioimaging, tumor therapy, and other fields are discussed. Finally, we address the advantages and disadvantages of carbon-based stimuli-responsive nanomaterials and discuss their future perspective.

Violet Phosphorus Nanosheet: A Biocompatible and Stable Platform for Stimuli-Responsive Multimodal Cancer Phototherapy.

As a functional 2D material, black phosphorus (BP) has garnered wide attention from many researchers in recent years. BP has a wide NIR absorption window and is a promising candidate for cancer phototherapy including photothermal therapy (PTT) and photodynamic therapy (PDT). However, due to its rapid degradation and short shelf-life in conventional water, the application of BP in the field of cancer therapy is limited. Violet phosphorus (VP), the more stable allotrope of phosphorus, has not yet been investigated for its function and biological application. In this study, VP nanosheets are successfully fabricated by liquid-phase exfoliation and demonstrated that their shelf-life in deionized water could be as long as 10 days, which is much longer than that of BP. Through in vivo and in vitro experiments, the PDT, PTT, and catalytic therapeutic effects of VP, as well as its excellent biosafety for the first time are shown. VP effectively inhibits tumor growth without causing major side effects. The current study provides new ideas and strategies for the biological application of 2D sheets of phosphorus isotope and lays the foundation for further studies on exploring the biomedical application of phosphorus isotopes.

A Totipotent "All-In-One" Peptide Sequentially Blocks Immune Checkpoint and Reverses the Immunosuppressive Tumor Microenvironment.

Immune checkpoint blockade combined with reversal of the immunosuppressive tumor microenvironment (TME) can dramatically enhance anti-tumor immunity, which can be achieved by using multiple-agent therapy. However, the optimal dose and order of administration of different agents remain elusive. To address this dilemma, multiple agents are often grafted together to construct "all-in-one" totipotent drugs, but this usually comes at the cost of a lack of synergy between the agents. Herein, by comprehensively analyzing the conserved sites of the immune checkpoint and TME drug targets, peptide secondary structures, assembly properties, and other physicochemical properties, a high-content peptide library is designed. By using the "3D-molecular-evolution" screening strategy, an efficient and totipotent "all-in-one" peptide (TAP) is obtained, which possesses the abilities of self-assembling, blocking the PD-1/PD-L1 axis, inhibiting Rbm38-eIF4E complex formation, and activating p53. It is shown that in mice treated with TAP, with either subcutaneous tumors or patient-derived xenografts, PD-L1 is blocked, with increased activation of both T and NK cells whilst reversing the immunosuppressive TME. Moreover, TAP can mitigate tumor activity and suppress tumor growth, showing superior therapeutic effect over antibody-based drugs.

MOF derived core-shell CuO/C with temperature-controlled oxygen-vacancy for real time analysis of glucose.

Introducing oxygen-vacancy into the surface of the non-enzymatic sensor is supposed to be an effective way to improve inherently low catalytic activity and specificity of non-enzymatic sensors. In this work, CuO/C was synthesized at different temperatures using metal-organic frameworks as sacrificial templates to receive additional content of oxygen-vacancy. The product with the highest oxygen vacancy was found at 400 °C (named CuO/C-400 °C), which increased catalytically active sites and enhanced the charge-transfer efficiency. The sensing performance was afterward explored by amperometry under an optimal applied potential at 0.5 V (vs. SCE), presenting a broad detection range from 5.0 µM to 25.325 mM (R2 = 0.9998) with a sensitivity of 244.71 µA mM- 1 cm- 2, and a detection limit of 1 µM. Furthermore, the reliability and selectivity of CuO/C-400 °C sensors were extensively explored in the presence of artificial serum/saliva samples with gradient glucose concentrations. The human blood samples were also detected with high recoveries compared with the clinical Hexokinase method. Hence, the prepared CuO/C-400 °C sensor with a broad detection range and high selectivity can be applied for the diabetes diagnosis ex vivo without further dilution for real-time analysis in practical applications.

Peptide nano 'bead-grafting' for SDT-facilitated immune checkpoints blocking.

Combination therapies based on immune checkpoint blockade (ICB) are currently the mainstay of cancer treatment, in which the synergetic delivery of multiple drugs is the essential step. Although nanoparticle drugs (NPDs) show satisfactory anticancer effects, the promotion of active co-delivery of NPDs is premature, since the processes are usually difficult to predict and control. Targeting peptide self-assemblies have been widely used as carriers for small-molecular drugs, but remain elusive for NPDs. We describe here peptide-based nano 'bead-grafting' for the active delivery of quantum-dot NPDs through a co-assembly method. Based on a 'de novo' design, we used a 'one-bead-one-compound (OBOC)' combinatorial chemical screening method to select a peptide RT with high affinity for the immune checkpoint CD47, which could also form biocompatible nanofibers and efficiently trap Ag2S quantum dots along the self-assembly path. This system can combine ICB therapy and sonodynamic therapy (SDT) to effectively inhibit tumor growth. Moreover, the tumor antigen produced by SDT can activate the adaptive immune system, which enhances the anti-tumor immune response of the ICB and shows efficient inhibition of both primary and distant tumors. This study provides a new strategy for the active control and delivery of NPDs and a new option for ICB therapy with immune checkpoints that are highly susceptible to systemic side effects.

Triarylboron-Doped Acenethiophenes as Organic Sonosensitizers for Highly Efficient Sonodynamic Therapy with Low Phototoxicity.

The development of efficient organic sonosensitizers is crucial for sonodynamic therapy (SDT) in the field of cancer treatment. Herein, a new strategy for the development of efficient organic sonosensitizers based on triarylboron-doped acenethiophene scaffolds is presented. The attachment of boron to the linear acenethiophenes lowers the lowest unoccupied molecular orbital (LUMO) energy, resulting in redshifted absorptions and emissions. After encapsulation with the amphiphilic polymer DSPE-mPEG2000 , it is found that the nanostructured BAnTh-NPs and BTeTh-NPs (nanoparticles of BAnTh and BTeTh) shows efficient hydroxyl radical (• OH) generation under ultrasound (US) irradiation in aqueous solution with almost no phototoxicity, which can overcome the shortcomings of O2 -dependent SDT and avoid the potential cutaneous phototoxicity issue. In vitro and in vivo therapeutic results validate that boron-doped acenethiophenes as sonosensitizers enable high SDT efficiency with low phototoxicity and good biocompatibility, indicating that boron-functionalization of acenes is a promising strategy toward organic sonosensitizers for SDT.

Near-Infrared-Absorbing B-N Lewis Pair-Functionalized Anthracenes: Electronic Structure Tuning, Conformational Isomerism, and Applications in Photothermal Cancer Therapy.

B-N-fused dianthracenylpyrazine derivatives are synthesized to generate new low gap chromophores. Photophysical and electrochemical, crystal packing, and theoretical studies have been performed. Two energetically similar conformers are identified by density functional theory calculations, showing that the core unit adopts a curved saddle-like shape (x-isomer) or a zig-zag conformation (z-isomer). In the solid state, the z-isomer is prevalent according to an X-ray crystal structure of a C6F5-substituted derivative (4-Pf), but variable-temperature nuclear magnetic resonance studies suggest a dynamic behavior in solution. B-N fusion results in a large decrease of the HOMO-LUMO gap and dramatically lowers the LUMO energy compared to the all-carbon analogues. 4-Pf in particular shows significant absorbance at greater than 700 nm while being almost transparent throughout the visible region. After encapsulation in the biodegradable polymer DSPE-mPEG2000, 4-Pf nanoparticles (4-Pf-NPs) exhibit good water solubility, high photostability, and an excellent photothermal conversion efficiency of ∼41.8%. 4-Pf-NPs are evaluated both in vitro and in vivo as photothermal therapeutic agents. These results uncover B-N Lewis pair functionalization of PAHs as a promising strategy toward new NIR-absorbing materials for photothermal applications.

Ten-Gram-Scale Mechanochemical Synthesis of Ternary Lanthanum Coordination Polymers for Antibacterial and Antitumor Activities.

As rare-earth coordination polymers (CPs) have appreciable antimicrobial properties, ternary lanthanum CPs have been widely synthesized and investigated in recent years. Here, we report convenient, solvent-free reactions between the lanthanum salt and two ligands at mild temperatures that form ternary lanthanum nanoscale CPs with 10-gram-scale. The structural features and morphologies were characterized using a scanning electron microscope (SEM), Fourier transform infrared spectrometer (FT-IR), ultraviolet-visible (UV-Vis), X-ray diffractometer (XRD), X-ray Photoelectron Spectroscopy (XPS), Brunauer-Emmett-Teller (BET), elemental analysis, inductively coupled plasma mass spectrometry (ICP-MS), electrospray ionization mass spectrometry (ESI-MS), nuclear magnetic resonance (NMR), dynamic light scattering (DLS) and analyzer, and thermogravimetric and differential thermal analyzer (TG-DTA). Furthermore, the in vitro antibacterial activities of these ternary hybrids were studied using the zone of inhibition (ZOI) method, minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), and transmission electron microscope (TEM) and were found to have excellent antibacterial properties. The in vitro antitumor activities were performed in determining the absorbance values by CCK-8 (Cell Counting Kit-8) assay. This facile synthetic method would potentially enable the mass production of ternary lanthanum CPs at room temperature, which can be promising candidates as antibacterial compounds and antitumor agents.

Multifunctional TiO2/C nanosheets derived from 3D metal-organic frameworks for mild-temperature-photothermal-sonodynamic-chemodynamic therapy under photoacoustic image guidance.

The sythesis of composite nanosheets with multiple functions remains signifcantly challenging. In this study, we developed multifunctional H-TiO2/C-PEG nanosheets as theranostic agents combining sonodynamic therapy and a low-power-mild-photothermal-enhanced Fenton effect. The two-dimensional H-TiO2/C composite nanosheets were synthesized by reducing metal-organic frameworks (MOF)-derived from H-TiO2/C composite nanoparticles (NPs) by hydrogen. The resulting H-TiO2/C was introduced into polyethylene (PEG) to improve water solubility and increase the size of the particles to allow a higher level of H-TiO2/C accumulation at the tumor site through the enhanced permeability and retention effect. The H-TiO2/C nanosheets had excellent sonodynamic therapy (SDT) effects and could also achieve low-power mild photothermal therapy guided by photoacoustic imaging with high photothermal conversion efficiency (η = 56.2 %). Also, a strong photothermal effect accelerated the rate of the Fenton reaction to enhance the efficacy of chemodynamic therapy (CDT). Importantly, combination therapy can achieve signifcant antitumour efficacy whilst the strong biocompatibility of the particles minimising adverse effects in normal cells. This study provides a promising strategy for the development of novel two-dimensional composite materials that are safe and have multifunctional diagnostic and therapeutic properties.

Recent Advance in Biological Responsive Nanomaterials for Biosensing and Molecular Imaging Application.

In recent decades, as a subclass of biomaterials, biologically sensitive nanoparticles have attracted increased scientific interest. Many of the demands for physiologically responsive nanomaterials in applications involving the human body cannot be met by conventional technologies. Due to the field's importance, considerable effort has been expended, and biologically responsive nanomaterials have achieved remarkable success thus far. This review summarizes the recent advancements in biologically responsive nanomaterials and their applications in biosensing and molecular imaging. The nanomaterials change their structure or increase the chemical reaction ratio in response to specific bio-relevant stimuli (such as pH, redox potentials, enzyme kinds, and concentrations) in order to improve the signal for biologically responsive diagnosis. We use various case studies to illustrate the existing issues and provide a clear sense of direction in this area. Furthermore, the limitations and prospects of these nanomaterials for diagnosis are also discussed.

Programmed Stimuli-Responsive Carbon Dot-Nanogel Hybrids for Imaging-Guided Enhanced Tumor Phototherapy.

For harmonizing the contradiction of nanotheranostic agents between enhanced tumor accumulation and penetration, efficient cell internalization and fast elimination are key tactics for promoting their clinical applications. Herein, programmed stimuli-responsive poly(N-isopropylacrylamide)-carbon dot (PNIPAM-CD) hybrid nanogels are designed to address the abovementioned conflicts. The enlarged particle size of PNIPAM-CDs enables one to effectively improve their accumulation at tumor sites. Once the hybrid nanogels are docked in tumors and exposed to deep-red-light (660 nm) irradiation, heat and reactive oxygen species (ROS) are generated from the CDs, consequently activating photothermal therapy (PTT) and photodynamic therapy (PDT) effects and meanwhile inducing partial degradation of PNIPAM-CDs for deep tissue penetration. Further, enhanced cellular internalization of the functional components can be achieved owing to the pH-responsive charge reversal and temperature-dependent hydrophilic/hydrophobic conversion characteristics of PNIPAM-CDs. Finally, the overexpressed glutathione (GSH) in tumor cells would trigger further cleavage of the partially degraded hybrid nanogels, which is beneficial for their rapid clearance from the body. This work not only proposed a novel strategy to fabricate nanotheranostic agents using just a single functional component (i.e., the versatile CDs) to simplify the preparation process but also achieved effective delivery of agents into tumor cells by overcoming the multiple biological barriers to enhance therapeutic efficacy and decrease side effects.

Peptide-Derived Biosensors and Their Applications in Tumor Immunology-Related Detection.

Small-molecular targeting peptides possess features of biocompatibility, affinity, and specificity, which is widely applied in molecular recognition and detection. Moreover, peptides can be developed into highly ordered supramolecular assemblies with boosting binding affinities, diverse functions, and enhanced stabilities suitable for biosensors construction. In this Review, we summarize recent progress of peptide-based biosensors for precise detection, especially on tumor-related analysis, as well as further provide a brief overview of the progress in tumor immune-related detection. Also, we are looking forward to the prospective future of peptide-based biosensors.

NCs-Delivered Pesticides: A Promising Candidate in Smart Agriculture.

Pesticides have been used extensively in the field of plant protection to maximize crop yields. However, the long-term, unmanaged application of pesticides has posed severe challenges such as pesticide resistance, environmental contamination, risk in human health, soil degradation, and other important global issues. Recently, the combination of nanotechnology with plant protection strategies has offered new perspectives to mitigate these global issues, which has promoted a rapid development of NCs-based pesticides. Unlike certain conventional pesticides that have been applied inefficiently and lacked targeted control, pesticides delivered by nanocarriers (NCs) have optimized formulations, controlled release rate, and minimized or site-specific application. They are receiving increasing attention and are considered as an important part in sustainable and smart agriculture. This review discussed the limitation of traditional pesticides or conventional application mode, focused on the sustainable features of NCs-based pesticides such as improved formulation, enhanced stability under harsh condition, and controlled release/degradation. The perspectives of NCs-based pesticides and their risk assessment were also suggested in this view for a better use of NCs-based pesticides to facilitate sustainable, smart agriculture in the future.

The Neuropeptide Y1 Receptor Ligand-Modified Cell Membrane Promotes Targeted Photodynamic Therapy of Zeolitic Imidazolate Frameworks for Breast Cancer.

Zeolitic imidazolate frameworks (ZIFs), widely regarded as promising materials for application in catalysis and separation, hold an increasingly significant position in drug delivery systems for their high drug loading capacity. Focused specifically on the rational design of targeting and bioresponsive nanovehicles, a neuropeptide Y1 receptor ligand (Y1L)-modified cell membrane camouflaged bioresponsive ZIF system (Y1L-RBC@ZIF-90@Ce6) was constructed for targeted photodynamic therapy of breast cancer. The biomimetic ZIF-based nanocarrier enhanced tumor accumulation by both neuropeptide Y1 receptor-targeted guidance and long-term stability. Y1L served as a good ligand-mediated selective targeting molecule for breast cancer, and red blood cell membrane-camouflaged nanocomposites displayed favorable biocompatibility. With the dual response of the ZIF to pH and adenosine triphosphate, the stimulus responsive photosensitizer Chlorin e6 delivery system effectively suppressed tumors in vivo. This work offers a platform for developing much safer and more efficient photodynamic therapy for the treatment of Y1R-overexpressed breast cancer.