RESUMO
BACKGROUND: The combination of programmed cell death ligand-1 (PD-L1) immune checkpoint blockade (ICB) and immunogenic cell death (ICD)-inducing chemotherapy has shown promise in cancer immunotherapy. However, triple-negative breast cancer (TNBC) patients undergoing this treatment often face obstacles such as systemic toxicity and low response rates, primarily attributed to the immunosuppressive tumor microenvironment (TME). METHODS AND RESULTS: In this study, PD-L1-targeted theranostic systems were developed utilizing anti-PD-L1 peptide (APP) conjugated with a bio-orthogonal click chemistry group. Initially, TNBC was treated with azide-modified sugar to introduce azide groups onto tumor cell surfaces through metabolic glycoengineering. A PD-L1-targeted probe was developed to evaluate the PD-L1 status of TNBC using magnetic resonance/near-infrared fluorescence imaging. Subsequently, an acidic pH-responsive prodrug was employed to enhance tumor accumulation via bio-orthogonal click chemistry, which enhances PD-L1-targeted ICB, the pH-responsive DOX release and induction of pyroptosis-mediated ICD of TNBC. Combined PD-L1-targeted chemo-immunotherapy effectively reversed the immune-tolerant TME and elicited robust tumor-specific immune responses, resulting in significant inhibition of tumor progression. CONCLUSIONS: Our study has successfully engineered a bio-orthogonal multifunctional theranostic system, which employs bio-orthogonal click chemistry in conjunction with a PD-L1 targeting strategy. This innovative approach has been demonstrated to exhibit significant promise for both the targeted imaging and therapeutic intervention of TNBC.
Assuntos
Antígeno B7-H1 , Química Click , Imunoterapia , Piroptose , Neoplasias de Mama Triplo Negativas , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Antígeno B7-H1/metabolismo , Animais , Feminino , Imunoterapia/métodos , Camundongos , Piroptose/efeitos dos fármacos , Humanos , Linhagem Celular Tumoral , Microambiente Tumoral/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Doxorrubicina/farmacologia , Doxorrubicina/química , Doxorrubicina/uso terapêutico , Imagem Óptica/métodos , Pró-Fármacos/química , Pró-Fármacos/farmacologiaRESUMO
How to mildly structure a high intrinsic activity and stable catalytic electrode to realize long-term catalytic water splitting to produce hydrogen at a wide range of pH values at industrial high current is a challenge. Herein, this work creatively proposes to prepare industrial-grade catalytic electrodes with high efficiency and stability at high current density through carbon quantum dots (CDs) modification nickel sulfide on hydrophilic flexible filter paper via one-step mild chemical plating (denoted as CDs-Ni3 S2 @HFP). The intrinsic activity and surface area, electron transfer ability, and corrosion resistance of Ni3 S2 material are increased due to the regulation, homogenous, and high concentration doping of CDs. The overpotential of the flexible catalytic electrode is only 30, 35, and 87 mV in 1 m KOH, simulated seawater (1 m KOH + 0.5 m NaCl), and neutral electrolyte (0.5 m PBS) at a current density of 10 mA cm-2 . More attractively, the CDs-Ni3 S2 @HFP electrode achieves over 500 h of efficient and stable catalysis at industrial high current density (500 mA cm-2 ). Due to the advantages of mild, universal, and large-area preparation of catalytic materials, this work provides technical support for flexible catalytic electrodes in efficient catalysis toward water splitting, energy storage, and device preparation.
RESUMO
Graphene and other 2D materials, such as molybdenum disulfide, have been increasingly used in electronics, composites, and biomedicine. In particular, MoS2 and graphene hybrids have attracted a great interest for applications in the biomedical research, therefore stimulating a pertinent investigation on their safety in immune cells like macrophages, which commonly engulf these materials. In this study, M1 and M2 macrophage viability and activation are mainly found to be unaffected by few-layer graphene (FLG) and MoS2 at doses up to 50 µg mL-1 . The uptake of both materials is confirmed by transmission electron microscopy, inductively coupled plasma mass spectrometry, and inductively coupled plasma atomic emission spectroscopy. Notably, both 2D materials increase the secretion of inflammatory cytokines in M1 macrophages. At the highest dose, FLG decreases CD206 expression while MoS2 decreases CD80 expression. CathB and CathL gene expressions are dose-dependently increased by both materials. Despite a minimal impact on the autophagic pathway, FLG is found to increase the expression of Atg5 and autophagic flux, as observed by Western blotting of LC3-II, in M1 macrophages. Overall, FLG and MoS2 are of little toxicity in human macrophages even though they are found to trigger cell stress and inflammatory responses.
Assuntos
Grafite , Molibdênio , Dissulfetos , Proteínas Filagrinas , Grafite/toxicidade , Humanos , Macrófagos , Molibdênio/toxicidadeRESUMO
The synthesis of eight perylenediimide-based glycoclusters was readily performed from hexa- and tetra-propargylated cores through azide-alkyne "click" conjugation. Variations in the carbohydrate epitope (Glc, Gal, Man, Fuc) and the linker arm provided molecular diversity. Interactions with LecA and LecB, two proteins involved in the adhesion of Pseudomonas aeruginosa to host tissues, were evaluated by microcalorimetry (ITC). In both cases high affinities were obtained with Kd values in the nanomolar range. Further evaluation of their anti-adhesive properties using cultured epithelial cells demonstrated their potent anti-adhesive activities against Pseudomonas aeruginosa with only 30-40% residual adhesion observed. The fluorescence properties of the PDI core were then investigated by confocal microscopy on cell-bacteria cultures. However, the red fluorescence signal of the PDI-based glycocluster was too weak to provide significant data. The present study provides another type of anti-adhesive glycocluster against bacterial infection with a large aromatic PDI core.
Assuntos
Adesinas Bacterianas/efeitos dos fármacos , Glicoconjugados/farmacologia , Imidas/farmacologia , Lectinas/antagonistas & inibidores , Perileno/análogos & derivados , Pseudomonas aeruginosa/efeitos dos fármacos , Sítios de Ligação/efeitos dos fármacos , Calorimetria , Adesão Celular/efeitos dos fármacos , Glicoconjugados/síntese química , Glicoconjugados/química , Imidas/síntese química , Imidas/química , Ligantes , Estrutura Molecular , Perileno/síntese química , Perileno/química , Perileno/farmacologia , Pseudomonas aeruginosa/química , Pseudomonas aeruginosa/citologiaRESUMO
Second near-infrared (NIR-II) carbon dots, with absorption or emission between 1000 and 1700 nm, are gaining increasing attention in the biomaterial field due to their distinctive properties, which include straightforward preparation processes, stable photophysical characteristics, excellent biocompatibility, and low cost. As a result, there is a growing focus on the controlled synthesis and modulation of the photochemical and photophysical properties of NIR-II carbon dots, with the aim to further expand their biomedical applications, a current research hotspot. This account aims to provide a comprehensive overview of the recent advancements in NIR-II carbon dots within the biomedical field. The review will cover the following topics: (i) the design, synthesis, and purification of NIR-II carbon dots, (ii) the surface modification strategies, and (iii) the biomedical applications, particularly in the domain of cancer theranostics. Additionally, this account addresses the challenges encountered by NIR-II carbon dots and will outline future directions in the realm of cancer theranostics. By exploring carbon-based NIR-II biomaterials, we can anticipate that this contribution will garner increased attention and contribute to the development of next-generation advanced functional carbon dots, thereby offering enhanced tools and strategies in the biomedical field.
Assuntos
Carbono , Raios Infravermelhos , Pontos Quânticos , Carbono/química , Pontos Quânticos/química , Humanos , Neoplasias/tratamento farmacológico , Materiais Biocompatíveis/química , Materiais Biocompatíveis/síntese química , Animais , Nanomedicina TeranósticaRESUMO
Breast cancer (BC) poses a significant threat to women's health, with triple-negative breast cancer (TNBC) representing one of the most challenging and aggressive subtypes due to the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. Traditional TNBC treatments often encounter issues such as low drug efficiency, limited tumor enrichment, and substantial side effects. Therefore, it is crucial to explore novel diagnostic and treatment systems for TNBC. Multifunctional molecular probes (MMPs), which integrate target recognition as well as diagnostic and therapeutic functions, introduce advanced molecular tools for TNBC theranostics. Using an MMP system, molecular drugs can be precisely delivered to the tumor site through a targeted ligand. Real-time dynamic monitoring of drug release achieved using imaging technology allows for the evaluation of drug enrichment at the tumor site. This approach enables accurate drug release, thereby improving the therapeutic effect. Therefore, this review summarizes the recent advancements in MMPs for TNBC theranostics, encompassing the design and synthesis of MMPs as well as their applications in the field of TNBC theranostics.
RESUMO
Photodynamic therapy (PDT) is a treatment that employs exogenously produced reactive oxygen species (ROS) to kill cancer cells. ROS are generated from the interaction of excited-state photosensitizers (PSs) or photosensitizing agents with molecular oxygen. Novel PSs with high ROS generation efficiency is essential and highly required for cancer photodynamic therapy. Carbon dots (CDs), the rising star of carbon-based nanomaterial family, have shown great potential in cancer PDT benefiting from their excellent photoactivity, luminescence properties, low price, and biocompatibility. In recent years, photoactive near-infrared CDs (PNCDs) have attracted increasing interest in this field due to their deep therapeutic tissue penetration, superior imaging performance, excellent photoactivity, and photostability. In this review, we review recent progress in the designs, fabrication, and applications of PNCDs in cancer PDT. We also provide insights of future directions in accelerating the clinical progress of PNCDs.
RESUMO
Construction of ultra-stable, flexible, efficient and economical catalytic electrodes is of great significance for the seawater electrolysis for hydrogen production. This work is grounded in a one-step mild electroless plating method to construct industrial-grade super-stable overall water splitting (OWS) catalytic electrodes (Fe1-Ni1P@GF) by growing loose and porous spore-like Fe1-Ni1P conductive catalysts in situ on flexible glass fibre (GF) insulating substrates with precise elemental regulation. Cost-effective Fe regulation boosts the electronic conductivity and charge transfer ability to achieve the construction of high intrinsic activity and strong electron density electrodes. Fe1-Ni1P@GF exhibits remarkable catalytic performance in hydrogen and oxygen evolution reaction (HER and OER), providing current densities of 10 mA cm-2 for HER and 100 mA cm-2 for OER at overpotentials of 51 and 216 mV, respectively. Moreover, it achieves 10 mA cm-2 at 1.42 V for OWS, and exhibits stable operation for over 1440 h at 1000 mA cm-2 in quasi-industrial environment of 6.0 M KOH + 0.5 M NaCl, without any performance degradation. This strategy enables the preparation of universally applicable P-based electrodes (ternary, quaternary, etc.) and large-area flexible electrodes (paper or cotton), significantly expands the practicality of the electrodes and demonstrating promising potential for industrial applications.
RESUMO
Pulmonary exposure to some engineered nanomaterials can cause chronic lesions as a result of unresolved inflammation. Among 2D nanomaterials and graphene, MoS2 has received tremendous attention in optoelectronics and nanomedicine. Here an integrated approach is proposed to follow up the transformation of MoS2 nanosheets at the nanoscale and assesss their impact on lung inflammation status over 1 month after a single inhalation in mice. Analysis of immune cells, alveolar macrophages, extracellular vesicles, and cytokine profiling in bronchoalveolar lavage fluid (BALF) shows that MoS2 nanosheets induced initiation of lung inflammation. However, the inflammation is rapidly resolved despite the persistence of various biotransformed molybdenum-based nanostructures in the alveolar macrophages and the extracellular vesicles for up to 1 month. Using in situ liquid phase transmission electron microscopy experiments, the dynamics of MoS2 nanosheets transformation triggered by reactive oxygen species could be evidenced. Three main transformation mechanisms are observed directly at the nanoscale level: 1) scrolling of the dispersed sheets leading to the formation of nanoscrolls and folded patches, 2) etching releasing soluble MoO4 - , and 3) oxidation generating oxidized sheet fragments. Extracellular vesicles released in BALF are also identified as a potential shuttle of MoS2 nanostructures and their degradation products and more importantly as mediators of inflammation resolution.
Assuntos
Vesículas Extracelulares , Pneumonia , Animais , Camundongos , Molibdênio/química , Dissulfetos/química , Inflamação/induzido quimicamenteRESUMO
Graphene oxide (GO) is one of the most studied nanomaterials in many fields, including the biomedical field. Most of the nanomaterials developed for drug delivery and phototherapies are based on noncovalent approaches that lead to an unspecific release of physisorbed molecules in complex biological environments. Therefore, preparing covalently functionalized GO using straightforward and versatile methods is highly valuable. Phototherapies, including photothermal therapy (PTT) and photodynamic therapy (PDT), have shown great potential as effective therapeutic approaches against cancer. To overcome the limits of a single method, the combination of PTT and PDT can lead to a combined effect with a higher therapeutic efficiency. In this work, we prepare a folic acid (FA) and chlorin e6 (Ce6) double-functionalized GO for combined targeted PTT/PDT. This conjugate can penetrate rapidly into cancer cells and macrophages. A combined effect of PTT and PDT is observed, leading to a higher killing efficiency toward different types of cells involved in cancer and other diseases. Our work provides a simple protocol to prepare multifunctional platforms for the treatment of various diseases.
RESUMO
Controlled intracellular release of exogenous reactive oxygen species (ROS) is an innovative and efficient strategy for cancer treatment. Well-designed materials, which can produce ROS in targeted cells, minimizing side effects, still need to be explored as new generation nanomedicines. Here, red-emissive carbon nanodots (CNDs) with intrinsic theranostic properties are devised, and further modified with folic acid (FA) ligand through a controlled covalent functionalization for targeted cell imaging and intracellular production of ROS. We demonstrated that covalent functionalization is an effective strategy to prevent the aggregation of the dots, leading to superior colloidal stability, enhanced luminescence and ROS generation. Indeed, the functional nanodots possess a deep-red emission and good dispersibility under physiological conditions. Importantly, they show excellent targeting properties and generation of high levels of ROS under 660 nm laser irradiation, leading to efficient cell death. These unique properties enable FA-modified carbon nanodots to act as a multifunctional nanoplatform for simultaneous targeted imaging and efficient photodynamic therapy to induce cancer cell death.
Assuntos
Corantes Fluorescentes/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Pontos Quânticos/química , Espécies Reativas de Oxigênio/metabolismo , Carbono/química , Carbono/efeitos da radiação , Corantes Fluorescentes/química , Corantes Fluorescentes/efeitos da radiação , Ácido Fólico/química , Células HeLa , Humanos , Luz , Imagem Óptica , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/efeitos da radiação , Pontos Quânticos/efeitos da radiaçãoRESUMO
Correction for 'Controlled functionalization of carbon nanodots for targeted intracellular production of reactive oxygen species' by Ding-Kun Ji et al., Nanoscale Horiz., 2020, 5, 1240-1249, DOI: .
RESUMO
There is an increasing demand to develop effective methods for treating malignant diseases to improve healthcare in our society. Stimuli-responsive nanosystems, which can respond to internal or external stimuli are promising in cancer therapy and diagnosis due to their functionality and versatility. As a newly emerging class of nanomaterials, two-dimensional (2D) nanomaterials have attracted huge interest in many different fields including biomedicine due to their unique physical and chemical properties. In the past decade, stimuli-responsive nanosystems based on 2D nanomaterials have been widely studied, showing promising applications in cancer therapy and diagnosis, including phototherapies, magnetic therapy, drug and gene delivery, and non-invasive imaging. Here, we will focus our attention on the state-of-the-art of physically-triggered nanosystems based on graphene and two-dimensional nanomaterials for cancer therapy and diagnosis. The physical triggers include light, temperature, magnetic and electric fields.
Assuntos
Luz , Campos Magnéticos , Nanoestruturas , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Animais , Grafite/administração & dosagem , Humanos , Nanoestruturas/administração & dosagem , Nanoestruturas/efeitos da radiação , Nanomedicina TeranósticaRESUMO
Supramolecular self-assembly between perylenediimide-based glycoclusters and a red-emitting fluorophore produces structurally uniform and stable glyco-dots amenable to targeted fluorogenic imaging of liver and triple-negative breast cancer cells.
Assuntos
Corantes Fluorescentes/química , Imidas/química , Neoplasias Hepáticas/diagnóstico por imagem , Imagem Óptica/métodos , Perileno/análogos & derivados , Neoplasias de Mama Triplo Negativas/diagnóstico por imagem , Linhagem Celular Tumoral , Humanos , Perileno/químicaRESUMO
A 2D "glycosheet" based on supramolecular self-assembly between 2D MoS2 and fluorescent glycoligands is developed. The composite 2D material is proven suitable for targeted intracellular production of reactive oxygen species (singlet oxygen) by the sequential control of a receptor endocytosis and light irradiation.
RESUMO
Here we demonstrate that 2D MoS2 can enhance the receptor-targeting and imaging ability of a fluorophore-labelled ligand. The 2D MoS2 has an enhanced working concentration range when compared with graphene oxide, resulting in the improved imaging of both cell and tissue samples.
RESUMO
Recently, there has been increasing interest in the construction of graphene oxide (GO) based fluorogenic composite materials (FCMs) for the detection of ligand-protein recognitions, which modulate numerous physiological and pathological processes in nature. In the sensing systems developed, GO has been used as a platform to assemble, and thus quench the fluorescence of dye-labelled ligands for the fluorogenic (fluorescence off-on) detection of proteins through the competitive formation of ligand-protein complexes, disassembling the GO composite. Here we show that the size, structure and loading concentration of GO may largely impact the sensing performance of GO-based FCMs. We synthesized four glycodyes that incorporate diverse natural glycoligands (as recognition groups) coupled with fluorescent dyes (as both the graphene binding and signal reporting group) with different emission wavelengths for comparison with GOs with different sizes. We determined that with the increase of size, the quenching ability of GO for the glycodyes increased, whereas the GO with a moderate size showed the best sensing performance for lectins (proteins that recognize glycoligands). The plausible mechanism of action was proposed. This research suggests that judicious quality control of GO is crucial for the construction of GO-based FCMs as biosensors.
RESUMO
Intercellular glycoligand-receptor interactions are implicated in a number of disease-related processes. Effective tools that target these receptors may facilitate disease theranostics. However, owing to their low binding affinity, multivalent presentation of glycoligands is needed to increase the avidity with transmembrane receptors. While previous strategies focus on the covalent coupling of glycoligands to a synthetic backbone, we show here that the use of graphene oxide (GO) greatly enhances the cellular and tissue imaging ability of a small-molecule fluorescence glycoprobe. We determine that GO with an optimum size may serve as a clustering platform to reinforce the interaction of the glycoprobe with its selective receptor on a cancer cell. This phenomenon has been consistently observed with the xenograft tissue of a tumor-bearing mouse. Using this principle we have further constructed a supramolecular glycocomposite by co-assembling the glycoprobe and an anticancer drug onto a single GO surface. In addition to imaging ability, this material displays improved toxicity for liver cancer cells that over express the glycoprotein receptor, when compared to the control cells.
RESUMO
We have developed a novel class of simple materials for sensing monosaccharides by the functionalization of graphene oxide (GO) with boronate-based fluorescence probes (BA1 and BA2). The composite materials were characterized by atomic force microscopy, Raman spectroscopy, and UV-vis/fluorescence spectroscopy. The strong fluorescence of the BA probes is quenched in the presence of GO through fluorescence resonance energy transfer. The BA@GO composite sensors formed provide a useful platform for fluorogenic detection of monosaccharides based on the strong affinity between the boronic acid receptor and monosaccharides. The BA@GO composite sensor displayed a "turn-on" fluorescence response with a good linear relationship toward fructose over a range of other saccharides.