TME-responsive nanoplatform for multimodal imaging-guided synergistic precision therapy of esophageal cancer via inhibiting HIF-1α signal pathway.

Esophageal cancer (EC) is the sixth leading cause of cancer-related deaths, and its treatment poses significant challenges. In recent years, photodynamic, photothermal, and chemodynamic therapies have emerged as alternative strategies for tumor intervention. However, limitations such as poor tumor targeting, insufficient microenvironment responsiveness, and unclear mechanisms hinder their application. In this study, we found that hypoxia-inducible factor 1 alpha (HIF-1α) was highly expressed in clinical EC samples, which contributed to tumor malignancy and metastasis. We developed a carbon dots (CDs)-based tumor microenvironment (TME)-responsive nanoplatform, CDs-MnO2-Au-Cet (CMAC), designed for multimodal imaging-guided precision therapy in EC. Both in vitro and in vivo experiments demonstrated that CMAC effectively targeted and imaged EC cells and tissues. CMAC significantly inhibited tumor growth by inducing apoptosis and reducing lung metastasis. Mechanistically, CMAC administration led to a substantial downregulation of HIF-1α and its downstream targets, GLUT1 and MMP9. In summary, we presented a novel nanoplatform for imaging-guided synergistic therapy in EC, which demonstrated excellent anti-tumor growth and metastasis capabilities, along with favorable biocompatibility. This study laid the groundwork for developing innovative theranostic strategies for EC.

Layer-by-Layer Nanoparticles for Calcium Overload in situ Enhanced Reactive Oxygen Oncotherapy.

Background: Challenges such as poor drug selectivity, non-target reactivity, and the development of drug resistance continue to pose significant obstacles in the clinical application of cancer therapeutic drugs. To overcome the limitations of drug resistance in chemotherapy, a viable treatment strategy involves designing multifunctional nano-platforms that exploit the unique physicochemical properties of tumor microenvironment (TME). Methods: Herein, layer-by-layer nanoparticles with polyporous CuS as delivery vehicles, loaded with a sonosensitizer (tetra-(4-aminophenyl) porphyrin, TAPP) and sequentially functionalized with pH-responsive CaCO3, targeting group hyaluronic acid (HA) were designed and synthesized for synergistic treatment involving chemodynamic therapy (CDT), sonodynamic therapy (SDT), photothermal therapy (PTT), and calcium overload. Upon cleavage in an acidic environment, CaCO3 nanoparticles released TAPP and Ca2+, with TAPP generating 1O2 under ultrasound trigger. Exposed CuS produced highly cytotoxic ·OH in response to H2O2 and also exhibited a strong PTT effect. Results: CuS@TAPP-CaCO3/HA (CTCH) delivered an enhanced ability to release more Ca2+ under acidic conditions with a pH value of 6.5, which in situ causes damage to HeLa mitochondria. In vitro and in vivo experiments both demonstrated that mitochondrial dysfunction greatly amplified the damage caused by reactive oxygen species (ROS) to tumor, which strongly confirms the synergistic effect between calcium overload and reactive oxygen therapy. Conclusion: Collectively, the development of CTCH presents a novel therapeutic strategy for tumor treatment by effectively responding to the acidic TME, thus holding significant clinical implications.

Multimodal imaging and photothermal/chemodynamic therapy of cervical cancer using GSH-responsive MoS2@MnO2 theranostic nanoparticles.

The development of nanoparticles capable of inducing reactive oxygen species (ROS) formation has become an important strategy for cancer therapy. Simultaneously, the preparation of multifunctional nanoparticles that respond to the tumor microenvironment is crucial for the diagnosis and treatment of tumors. In this study, we designed a Molybdenum disulfide (MoS2) core coated with Manganese dioxide (MnO2), which possessed a good photothermal effect and could produce Fenton-like Mn2+ in response to highly expressed glutathione (GSH) in the tumor microenvironment, thereby generating a chemodynamic therapy (CDT). The nanoparticles were further modified with Methoxypoly(Ethylene Glycol) 2000 (mPEG-NH2) to improve their biocompatibility, resulting in the formation of MoS2@MnO2-PEG. These nanoparticles were shown to possess significant Magnetic Resonance Imaging (MRI) and Computed Tomography (CT) imaging capabilities, making them useful in tumor diagnosis. In vitro and in vivo experiments demonstrated the antitumor ability of MoS2@MnO2-PEG, with a significant killing effect on tumor cells under combined treatment. These nanoparticles hold great potential for CDT/photothermal therapy (PTT) combined antitumor therapy and could be further explored in biomedical research.

MRI/fluorescence dual-mode probe: its simple preparation method and imaging application in vitro.

Superparamagnetic nanoparticles have been widely used as contrast agents in magnetic resonance imaging (MRI). The combined use of multiple imaging modes can provide more accurate information for clinical diagnosis. In this paper, a MRI/fluorescence dual-mode imaging contrast agent was developed by a simple method. The method is to make the fluorescent carbon quantum dots (CDs) adsorbed on the surface of the magnetic composite with pore structure by ultrasonic dispersion. Replacing the traditional methods such as chemical bonding, the fluorescent material is coated on the surface of the composite material. The synthesized composite materials were characterized by the transmission electron microscopy method (TEM), Fourier transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS), and vibration sample magnetometer (VSM). The results of TEM, FTIR and XPS showed that CDs were successfully coated on the surface of C60@Fe3O4 magnetic composite. The VSM results show that the composite material still maintains superparamagnetism. The cytotoxicity of the material on SMMC-7721 liver cancer cells was detected by the MTT method, and the biocompatibility of the material was verified. By observing the fluorescence distribution in the cell, it is proved that the composite material successfully enters the cell and produces fluorescence. Finally, through the analysis of T2-weighted imaging, it is found that the addition of materials results in an enhanced dark contrast compared to control cells. Therefore, the composite nanomaterials synthesized in this paper can be used as MRI/fluorescence dual-mode imaging contrast agents.

Heparin detection based on the fluorescent turn-on probe of amino carbon quantum dots.

Amino-rich carbon quantum dots (CDs) were synthesized by hydrothermal treatment of ethylene glycol, glucose and polyethyleneimine. CDs have green fluorescence (excitation/emission peaks 435 nm/515 nm) and can be enhanced by the addition of heparin (Hep). A linear relationship between fluorescence intensity and heparin concentration was observed. The fluorescence turn-on probe used for Hep detection showed a very large detection range of 0.02-16 µM, covering different therapeutic ranges in clinical applications. The probe exhibited an ultra-low detection limit of 0.007 nM.

Polydopamine coated Au-Pt nanorods: Enhanced photothermal properties and efficient reactive oxygen scavengers.

As an emerging cancer treatment strategy, photothermal therapy (PTT) is precise, controllable, minimally invasive, low cost and less toxic side effects, thus photothermal transduction agents have been extensively investigated in recent years. Noble metal nanomaterials with unique localized surface plasmon resonance (LSPR) effects are particularly suitable as photothermal transduction agent, but the currently developed precious noble metal nano photothermal transduction agents face serious problems such as complex synthesis process, poor photothermal performance and high biotoxicity. Moreover, the large amount of reactive oxygen species (ROS) produced during PTT treatment could cause irreversible damage to the healthy tissues surrounding the tumor. In this work, we deposited platinum (Pt) on the tips of gold nanorods (AuNRs) to form dumbbell-shaped Au-Pt bimetallic nanorods (AuPtNRs), and functionalized AuPtNRs with biocompatible polydopamine (PDA) to obtain AuPt@PDA. With 808 nm laser irradiation, the prepared AuPt@PDA exhibited excellent photothermal stability, and its photothermal conversion efficiency (PCE) reached 81.78%, which was significantly higher than that of AuNRs (52.32%) and AuPtNRs (78.76%). With low cytotoxicity, AuPt@PDA decreased cell viability from 91.12% to 39.36% after PTT on cancer cells in vitro, while significantly reducing intracellular ROS levels generated by heat stress. Therefore, the excellent photothermal properties, high cancer cell killing and ROS scavenging activity of AuPt@PDA in PTT could be an ideal candidate for improving therapeutic efficacy while reducing the risk of toxic side effects due to heat stress-induced ROS formation.

Rapid controlled synthesis of gold-platinum nanorods with excellent photothermal properties under 808 nm excitation.

Noble metal nanomaterials are particularly suitable as photothermal transduction agents (PTAs) with high photothermal conversion efficiency (PCE) due to local surface plasmon resonance (LSPR). Studies on different gold-platinum (Au-Pt) bimetal nanoparticles exhibiting the LSPR effect have provided a new idea for the synthesis of excellent PTAs. But there is no simple and scalable method for the controllable synthesis of Au-Pt nanoparticles with adjustable LSPR wavelength range. In this work, the effects of Ag+ and K2PtCl4 on the deposition of Pt on the surface of gold nanorods (AuNRs) were investigated. A fast, precise, and controlled synthesis of dumbbell-like Pt-coated AuNRs (Au@Pt NRs) under mild conditions is proposed. The synthesized Au@Pt NRs have a longitudinal LSPR wavelength of 812 nm, which is very close to a common laser wavelength of 808 nm. The Au@Pt NRs exhibit excellent photothermal properties when irradiated with a laser. The temperature increased by more than 36 °C after irradiation for 10 min, with a PCE of about 78.77%, which is much higher than that of AuNRs (57.33%). In addition, even after four on/off cycles, the Au@Pt NRs are able to maintain the photothermal properties and retain their optical properties, indicating that they have excellent photothermal stability and reusability.

Gold nanoclusters modified mesoporous silica coated gold nanorods: Enhanced photothermal properties and fluorescence imaging.

Photothermal therapy (PTT) is a non-invasive therapy that is widely used in cancer treatment. Gold nanorods (AuNRs) are particularly suitable as a photothermal reagent due to their unique localized surface plasmon resonance (LSPR) properties. However, bare gold nanorods are not stable enough during radiation to collect enough energy to kill tumor cells. In addition, they showed some biologically toxic originated from the poor colloidal stability and surfactants cetyltrimethyl ammonium bromide (CTAB), making it difficult to apply them directly to clinical research. To solve these problems, a novel nanocomposite was structured by coating silica shell and gold nanocluster on the outer layer of the gold nanorod (AuNRs@SiO2@AuNCs). Compared with the bare gold nanorod, the nanocomposite with the core-shell structure showed superior photothermal effect. The photothermal conversion temperature reached 63 °C under a lower irradiation power. The photothermal conversion efficiency was enhanced to 77.6%. Its photothermal performance remained constant after five cycles of near-infrared laser irradiation, indicating excellent photothermal stability. In vitro cell imaging experiments show that AuNRs@SiO2@ AuNCs can effectively enter tumor cells. By 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) analysis, cancer cells can be effectively killed when exposed to a near-infrared laser. During the synthesis process, the silica and gold nanoclusters replaced the toxic CTAB molecular layer on the surface of AuNRs. Therefore, AuNRs@SiO2@AuNCs has good biocompatibility and fluorescence characteristics. These results suggest that such AuNRs@SiO2@AuNCs nanocomposite shows great potential in imaging guided photothermal therapy for cancer.

pH and redox dual-sensitive drug delivery system constructed based on fluorescent carbon dots.

Herein, a pH and redox dual-responsive drug delivery system (CDs-Pt(iv)-PEG) was developed based on fluorescence carbon dots (CDs). In this system, cisplatin(iv) prodrug (Pt(iv)) was selected as a model drug to reduce toxic side effects. The aldehyde-functionalized monomethoxy polyethylene glycol (mPEG-CHO) was conjugated to CDs-Pt(iv) to form pH sensitive benzoic imine bond. Owing to the slightly acidic tumor extracellular microenvironment (pH 6.8), the benzoic imine bond was then hydrolyzed, leading to charge reversal and decrease in the hydration radius of the drug-carrying, which facilitated in vivo circulation and tumor targeting. Notably, the cytotoxicity of the drug delivery system on cancer cells was comparable to that of cisplatin, while the side effects on normal cells were significantly reduced. In addition, the system realized recognition of cancer cells by the high-contrast fluorescent imaging. In conclusion, the CDs-Pt(iv)-PEG system provided a promising potential for effective delivery of anticancer drugs and cancer cells screening.

Construction and application of targeted drug delivery system based on hyaluronic acid and heparin functionalised carbon dots.

Thrombosis is a main complication of cancer. It can increase the mortality of cancer patients. Therefore, the anticoagulant heparin (Hep) as an adjuvant therapy was introduced to the drug delivery system based on doxorubicin hydrochloride (DOX)-carbon dots (CDs)-Hyaluronic acid (HA), which obviously enhanced the blood compatibility of the system. Drug release process of the CDs-HA-Hep/DOX system was dual-responsive by HA and pH value. Results of in vitro MTT and scratch tests demonstrated that the drug delivery system could targetedly inhibit growth and migration of cancerous cells. In addition, the system allows visual tracking of the drug based on fluorescence of CDs.

A fluorometric method for mercury(II) detection based on the use of pyrophosphate-modified carbon quantum dots.

Pyrophosphate-modified carbon quantum dots (PP-CDs) are demonstrated to be a viable fluorescent nanoprobe for mercury(II) (Hg2+) detection. Hg2+ reacts with the pyrophosphate groups on the surface of PP-CDs to form a non-fluorescent complex. This results in quenching of the green fluorescence which has excitation/emission peaks at 400/513 nm. Static quenching is shown to be the dominant mechanism. The probe works in 0.1 µM to 1.4 µM Hg2+ concentration range, and the limit of detection is 2 nM. The PP-CDs were also used to visualize Hg2+ inside human hepatocyte LO2 cells. Graphical abstract Schematic representation of pyrophosphate-modified carbon quantum dots (CDs) for selective and sensitive fluorometric determination of mercury(II). Hg(II) quenches the blue fluorescence of the CDs, and glutathione restores it. The method was used to detect Hg(II) in spiked tap water and inside cells.

A "turn-on" fluorescent probe for glutathione detection based on the polyethylenimine-carbon dots-Cu2+ system.

Glutathione (GSH) plays critical roles in many physiological processes usually present in live cells, and altered levels have been linked to some clinical pathological conditions. However, current techniques of GSH detection with fluorescence assay strategies remain poorly researched. In this work, branched polyethylenimine-functionalized carbon dots (PEI-CDs) are synthesized by simple hydrothermal treatment of glucose and PEI. The fluorescence of the PEI-CDs could be efficiently quenched by Cu2+ and then recovered by some biothiols. Basing on this, a "turn-on" fluorescent probe for detecting GSH has been developed using PEI-CDs-Cu2+ system. Compared with traditional probes for GSH detection, a significant advantage of the PEI-CDs-Cu2+ system is that it can be used for GSH detection at both low and high concentrations with different concentration combinations of PEI-CDs and Cu2+. More specifically, two good linear relationships are achieved in the ranges of 0-80 µM and 0-1400 µM for GSH, respectively. Correspondingly, the detection limits of GSH are 0.33 µM and 9.49 µM, respectively. The quantum yields (QYs) of PEI-CDs and PEI-CDs-Cu2++GSH was 9.6% and 4.2%, respectively. Moreover, the PEI-CDs-Cu2+ has excellent optical stability and good biocompatibility. Additionally, it is worth noting that the developed probe has successfully realized the visualization of GSH detection in MGC-803 cells.