查找使用阿拉丁产品的科研文献

A Biomimetic Nanoagonist for Synergistic Photodynamic/Ferroptosis/Disulfidptosis Therapy via Coinhibition of Glucose Metabolism and the SLC7A11/GSH/GPX4 Axis

Zijia Jiang,Yifan Zhao,Zequn Li,Huimei Jiang,Bai Lv,Jie Cao

Photodynamic therapy (PDT) faces significant challenges in clinical applications, including tumor hypoxia, the poor water solubility of photosensitizers, and insufficient targeting specificity. To address these limitations, we developed a biomimetic nanoagonist, 4T1@MFCB, by coloading a near-infrared photosensitizer (CyI) and a GLUT1 inhibitor (BAY-876) into a manganese/iron bimetallic metal–organic framework (MOF), followed by coating with the homologous 4T1 cell membrane. The manganese component catalyzes the decomposition of endogenous H2O2 to generate oxygen, alleviating tumor hypoxia and enhancing PDT efficacy, while the iron component promotes ferroptosis via the Fenton reaction. Meanwhile, BAY-876 inhibits glucose uptake, disrupting NADPH production and the cystine-to-cysteine reduction process, which leads to cystine accumulation and glutathione (GSH) depletion. These effects collectively suppress the Solute Carrier Family 7 Member 11(SLC7A11)/glutathione (GSH)/glutathione peroxidase 4 (GPX4) antioxidant axis, thereby triggering disulfidptosis. Under near-infrared irradiation, CyI mediates effective photodynamic and photothermal therapy (PTT). Both in vitro and in vivo studies demonstrate that 4T1@MFCB enables synergistic PDT/ferroptosis/disulfidptosis therapy, significantly inhibiting tumor growth without obvious systemic toxicity. This work highlights a multimodal treatment strategy that integrates metabolic intervention with nanocatalytic therapy, providing a promising approach for the precision treatment of hypoxic and therapy-resistant tumors.

GSH-Activated Cu-TCPP(Zn)/Ti3C2Tx Nanozymes for Fluorescence Imaging-Guided Synergistic Photodynamic/Chemodynamic Therapy of Oral Squamous Cell Carcinoma

Lidong Wang,Yongyan Sun,Yuting Sun,Changbin Zhang,Guixi Wang,Junnan He,Yan Zhao,Ming Li

Photodynamic therapy (PDT) holds promise for oral squamous cell carcinoma (OSCC) but is limited by the tumor microenvironment─specifically hypoxia, elevated glutathione (GSH), and the lack of tumor-selective photosensitizer activation. To overcome these barriers, we developed a GSH-activated nanoplatform Cu-TCPP(Zn)/Ti3C2Tx for fluorescence imaging-guided synergistic photodynamic/chemodynamic therapy (PDT/CDT). The system is constructed from two-dimensional Cu-TCPP(Zn) MOF nanosheets, where Cu2+ and Zn2+ completely quench the fluorescence and PDT activity of TCPP and surface-anchored Ti3C2Tx MXene. In the TME, overexpressed GSH reduces Cu2+ to Cu+ and abstracts Zn from the Zn–N4 complex, triggering nanocomposite disintegration to restore fluorescence, activate PDT, and simultaneously deplete GSH to reduce antioxidant defense. The resulting Cu+ catalyzes a Fenton-like reaction with endogenous H2O2 to generate •OH for CDT, while Ti3C2Tx acts as a catalase-like nanozyme, decomposing H2O2 into O2 to alleviate hypoxia, promote charge transfer, improve the utilization efficiency of photogenerated electrons, and enhance PDT efficacy. In vitro, the platform showed excellent biocompatibility and GSH-responsive activation, inducing 41.21% apoptosis in CAL-27 cells under 660 nm laser irradiation, significantly outperforming controls. In vivo, the nanocomposite accumulated efficiently in tumors via the EPR effect, suppressed tumor growth, and exhibited no observable systemic toxicity. This work provides a TME-responsive theranostic platform that integrates tumor-specific activation, GSH depletion, hypoxia alleviation, and enhanced ROS generation for precise and effective OSCC treatment.

Enhanced Cerenkov radiation induced photodynamic therapy based on GSH-responsive biomimetic nanoplatform to trigger immunogenic cell death for tumor immunotherapy

Ruijie Qian,Yawen Guo,Xuemei Gao,Jianzhuang Ren,Dawei Jiang,Rui An,Ruihua Wang,Xuhua Duan,Xinwei Han

Cerenkov radiation (CR) can serve as a source of internal light to overcome the limited tissue penetration of external light in conventional photodynamic therapy (PDT). However, insufficient luminescence intensity hinders the clinical application of CR-PDT. Here, we developed a glutathione-responsive biomimetic nanoplatform by fusing cancer cell membranes and liposomes loaded with photosensitizer hematoporphyrin monomethyl ether (HMME) and a radiation energy amplifier Eu 3+ , named HMME-Eu@LEV. Colloidal Eu 3+ converts γ-radiation and CR from radioisotopes into fluorescence to enhance anti-tumor effects. Sequential administration ensures co-localization of HMME-Eu@LEV and radiopharmaceutical 18 F-fluorodeoxyglucose (FDG) at the tumor site, triggering enhanced CR-PDT and immunogenic cell death. Our observations indicated that luminescence resonance energy transfer between Eu 3+ and HMME was efficient, and Cerenkov luminescence from Eu@LEV+FDG was approximately 5.6-fold higher in intensity than that from FDG alone. As a result, abundant ROS were generated, and macrophages in the tumor microenvironment were polarized from M2 to M1. In addition, the immunosuppressive tumor microenvironment could be reversed by promoting the maturation of dendritic cells and infiltration of cytotoxic T lymphocytes. The activated immune system effectively inhibited the growth of primary tumors and spread of distant metastases. Our work demonstrates the feasibility of CR-PDT without an external light source and the critical role of nanomaterials in personalized medicine.

A TNBC-Targeting Nano-Radiosensitizer Reverses Radioresistance by Synergizing GSH Scavenging with Dual Inhibition of Trop2 and lncRNA MNX1-AS1

Zhiwei Yang,Bianfei Shao,Danni Wang,Hongwei Chen,Xiaohui Zhao,Minghui Zeng,Yimin Liu,Qingjian Li,Zhuofei Bi

Radioresistance in triple-negative breast cancer (TNBC) frequently results in local recurrence and distant metastasis, seriously affecting the prognosis of patients. The increased generation of cellular glutathione (GSH) and the upregulation of pro-malignant molecules are two major causes of radioresistance in TNBC, which need to be comprehensively considered in treatment. Herein, a TNBC-targeted reduction-responsive RNA interference (RNAi) nano-radiosensitizer (TREARA) was developed to reverse radioresistance by synergizing GSH depletion with combined inhibition of two promising pro-malignant molecules, Trophoblast cell surface antigen 2 (Trop2) and lncRNA Motor neuron and pancreas homeobox 1–antisense RNA1 (lncMNX1-AS1). Once arriving at the tumor sites with the prolonged circulation maintained by PEGylation, TREARA was rapidly internalized by tumor cells and blocked the Trop2-dominant pro-metastatic signaling through the anti-Trop2 antibody (αTrop2) modified on its surface. Subsequently, in response to the highly concentrated GSH in the cytoplasm, the shell of TREARA containing poly(disulfide amide) polymer (PDSA) was broken, unlashing the loaded lncMNX1-AS1 siRNA (siMNX1-AS1), which would suppress tumor progression by inactivating JAK3/STAT3 signaling. Benefiting from the integration of GSH-scavenging and dual-targeted inhibition of Trop2 and lncMNX1-AS1, TREARA significantly reversed radioresistance and restrained metastasis in murine models. Taken together, TREARA provides a promising comprehensive perspective for refractory radioresistant TNBC treatment.

Design and synthesis of self-assembled ferulic acid-biotin nanoprodrugs with GSH/pH-responsive behavior and in vitro anticancer activity

Xiaoshuang Dai,Na Yao,Xinyu Liu,Ke Mei,Bin Sun,Ziqing Weng,Jianpeng Liu,Junda Liu,Ning Lei,Neng Qiu

Three FA-biotin conjugates were designed with 5-10 × higher cytotoxicity than FA. • These prodrugs self-assembled into nanoparticles, with FS6B forming optimal NPs. • FS6B NPs exhibited excellent stability and dual GSH/pH-responsive drug release. • FS6B NPs showed enhanced biotin receptor-mediated tumor targeting ability. • FS6B NPs exerted anticancer and anti-migration effects with minimal toxicity. Ferulic acid (FA) is widely recognized for its antioxidant and anti-inflammatory properties; however, its potential anticancer activity is limited by poor aqueous solubility and insufficient cellular uptake. In this work, a series of ferulic acid–biotin conjugates containing amino acid linkers of different lengths were synthesized and allowed to self-assemble into nanoparticles (FS4B, FS6B, and FS8B NPs). All nanoparticles had sizes below 200 nm, with FS6B NPs showing the best long-term stability for over 3 months. FS6B NPs exhibited glutathione- and pH-responsive release behavior and demonstrated over 10-fold stronger cytotoxicity toward 4T1 cells compared with free FA. Biotin-mediated cellular uptake was improved, accompanied by increased apoptosis induction. Furthermore, FS6B NPs significantly inhibited 4T1 cell migration, with a migration rate of 54.47%, in comparison with 72.51% for FA and 85.60% for the control. Meanwhile, FS6B NPs showed negligible toxicity toward normal cells and no detectable hemolytic activity. These results demonstrate that self-assembled FA-biotin nanoprodrugs possess favorable physicochemical properties and in vitro biological activity, providing insight into the structural modification and functional application of FA-based nanomaterials.

GSH-triggered CD44/FRβ dual-targeting nanoprodrug for acute myeloid leukemia eradication via cascade DNA damage and mitochondrial oxidative storm

Yanrong Shuai,Xiaojuan Miao,Yan Wang,Chaozheng Zhang,Yu Liu,Yuening Cao,Tingting Zhang,Jun Lu,Yilan Liu

Conventional DNA double-strand breaks (DSBs)-inducing chemotherapeutics for acute myeloid leukemia (AML) are often limited by poor solubility, non-selectivity, and drug resistance stemming from robust tumor DNA repair mechanisms. Here, we report a glutathione (GSH)-responsive, dual-targeting nano-prodrug, designated HA-FA@Etp-Olp, for efficient AML cell eradication. The HA-FA@Etp-Olp system was constructed through the conjugation of the PARP inhibitor Olaparib (Olp) with Etoposide (Etp) via a disulfide linkage, forming an Etp-Olp heterodimeric prodrug. This hydrophobic conjugate was encapsulated within a polymeric carrier composed of poly (ethylene glycol)-modified hyaluronic acid (HA) functionalized with folic acid (FA), self-assembling into well-refined nanoparticles. Exhibiting excellent circulatory stability, HA-FA@Etp-Olp achieved efficient accumulation within AML cells leveraging CD44/FR dual-receptor-mediated active targeting, followed by GSH-triggered disassembly and specific drug release in response to elevated intracellular GSH levels. Furthermore, HA-FA@Etp-Olp elicited a synergistic cytotoxic effect against AML through a dual-pronged mechanism: "DNA damage-repair blockade" cascade and significant augmentation of mitochondrial oxidative stress, effectively inducing apoptotic cell death. This strategy provides a promising targeted nanotherapeutic approach with enhanced efficacy and reduced systemic toxicity, demonstrating significant potential for the precise treatment of AML.

pH and GSH dual-responsive fluorescent nanoparticles from polydopamine coating mesoporous silica for controlled drug release and real-time detection

Hengquan Zhou,Guiying Li,Lei Guo,Qian Tao,Songmei Ma,Xunyong Liu

pH and GSH dual-responsive nanoparticles with fluorescence detection were successfully prepared from the polydopamine coating on the surface of mesoporous silica via disulfide bonds (MSN-SS-PDA). The average diameter of nanoparticles was about 80–100 nm with a well-ordered mesoporous structure. The outer layer of PDA was about 10.0 nm acting as a pH and GSH sensitive gatekeeper to control drug release. Doxorubicin (DOX) was loaded into mesoporous channels to evaluate the drug loading capacity and controlled release performance. TPE-4OH, an aggregation-induced emission (AIE) luminescence, was adhered to the surface of PDA for detection of drug release in real-time. The drug release from MSN-SS-PDA nanoparticles was enhanced under acidic solutions or high GSH concentrations. The fluorescence intensity decreased gradually with the drug release, which can be used for monitoring of release process. Besides, the nanoparticles exhibited good photothermal conversion capability due to the PDA layer under near-infrared light irradiation at 808 nm. These nanoparticles present a promising future for combination therapy and real-time tracking of the release process.

Rational assembly of RGD/MoS2/Doxorubicin nanodrug for targeted drug delivery, GSH-stimulus release and chemo-photothermal synergistic antitumor activity

Chunhong Mo,Zhao Wang,Jianying Yang,Yiqiang Ouyang,Qian Mo,Shuting Li,Ping He,Limin Chen,Xinchun Li

Herein, we present the facile design and construction of a nanodrug system integrating targeted drug delivery and synergistic chemo-photothermal antitumor activity . MoS 2 nanosheets were synthesized and modified by α ν β 3 integrin binding peptide (Arg-Gly-Asp, RGD) using lipoic acid functionalized polyethylene glycol (LA-PEG-COOH), forming a well dispersed and targeted delivery nanocarrier . Further, covalent coupling of antitumor drug , thiolated doxorubicin (DOX) via disulfide linkage resulted in a novel nanodrug, RGD/MoS 2 /DOX. The prepared nanocarrier showed favorable stability, biocompatibility and photothermal conversion efficiency. Fluorescence imaging revealed that Hela cells could endocytose far more nanodrug than H9c2 normal myocardial cells due to the targeted delivery characteristic. Particularly, GSH-induced disulfide bond cleavage facilitated the effective release of DOX from the nanodrug in the tumor microenvironment . The survival rate of Hela cells incubated with the nanodrug for 48 h was 22.2 ± 1.2%, which dramatically reduced to 8.9 ± 1.4% in combination with 808 nm NIR irradiation, demonstrating powerful photothermal induced tumor-killing efficacy. In contrast, the survival rates of H9c2 cells treated by the nanodrug and free DOX were 68.5 ± 2.6% and 6.7 ± 2.6%, respectively, an indication of the notably alleviated cardiotoxicity of the designed nanodrug. The cell apoptosis experiment further verified the synergistic chemo-photothermal effect, thus paving a way toward design of high-efficiency and low-toxicity antitumor nanodrug.

Folate-mediated magnetic and pH/GSH dual-responsive metal-polymer-coordinated nanocomplexes for joint chemo/chemodynamic anti-breast cancer therapy

Zhuo Lan,Xiaopei Tan,Cheng Chen,Yu Cao,Yu Wan,Shun Feng

Cu2+-pyropheophorbide-a-cystine conjugate-mediated multifunctional mesoporous silica nanoparticles for photo-chemodynamic therapy/GSH depletion combined with immunotherapy cancer

Haiying Xu,Zhongping Su,Hui Zhang,Ying Zhang,Yujun Bao,Huanli Zhang,Xiaodan Wu,Rui Yan,Zhiqiang Wang,Yingxue Jin

Photodynamic therapy (PDT) and chemodynamic therapy (CDT) can activate immunogenicity, so PDT and CDT combined immunotherapy is a promising treatment strategy. However, insufficient hydrogen peroxide activity, hypoxia, and overexpressed glutathione in the tumor microenvironment (TME) significantly impaired the ability to activate immunogenicity. Thus, in this paper, self-reinforcing conjugates Cu 2+ -Pyropheophorbide-a-Cysteine (CuPPaCC), combined synergetic NIR and pH triggered PDT/CDT with glutathione depletion ability was constructed. CuPPaCC was encapsulated in mesoporous silica, and spherical HSCuPPaCC nanoparticles were prepared by Hyaluronic acid (HA) on the silica surface by Schiff base modification. HSCuPPaCC has tumor-specific targeting via HA mediated. In acidic solution, the Schiff base of HSCuPPaCC is destroyed and CuPPaCC is released (>70%), with excellent pH response release function. The results of the MTT analysis showed that the PDT/CDT synergistic anti-tumor effect was significant. HSCuPPaCC was activated in TME, catalyzing the decomposition of hydrogen peroxide to generate hydroxyl radicals and oxygen, alleviating TME hypoxia, replenishing oxygen to PDT, and significantly down regulating hypoxia factor HIF-1α expression. HSCuPPaCC has an excellent dual ROS mechanism and a dual depleting GSH mechanism resulting in a surge in intracellular ROS levels to efficiently kill cancer cells, enhance the ability to induce immunogenicity, and make tumors more sensitive to checkpoint PD-L1 blockade therapy. With the CT26 mouse model, not only the primary tumor was eradicated, but also the distal tumor at the end of treatment was completely suppressed by HSCuPPaCC combined with anti-PD-L1 immune checkpoint blockade therapy.

GSH-derived carbon dot-mediated interfacial electron transfer modulates pH-Dependent redox catalysis of Ce-MOF nanozymes for wound healing

Yaping Chen,Kaichen Zeng,Yunxin Ye,Xinyi Sun,Ling Yan,Ziya Lao,Yifan Wu,Tao Luo,Li Yang,Lvhua Guo

In situ integration creates an electronically coupled Ce MOF-CD nanozyme. • Interfacial electron transfer regulates the Ce 3+ /Ce 4+ redox balance. • pH-dependent catalysis switches from ROS generation to superoxide removal. • Ce MOF-CD reduces inflammation and accelerates MRSA-infected wound healing. Infected wounds require therapeutic materials that can control bacterial infection without aggravating oxidative tissue damage. Here, glutathione-derived carbon dots (GSH-CDs) were introduced during the formation of a cerium metal-organic framework (Ce MOF) through an in situ integration strategy to construct a carbon-dot-integrated Ce MOF nanozyme (Ce MOF-CD). Electronic-structure analyses supported interfacial electron redistribution from GSH-CDs toward Ce MOF, accompanied by changes in the local electronic environment and Ce 3+ /Ce 4+ distribution of the Ce active centers. Ce MOF-CD exhibited a distinct pH-dependent redox catalytic preference, with oxidase-like catalysis favored under acidic conditions and superoxide dismutase-like activity becoming more pronounced near neutrality. Accordingly, Ce MOF-CD markedly reduced the viability of MRSA and E. coli and disrupted established biofilms under acidic conditions. Under near-neutral cellular conditions, it reduced intracellular oxidative stress, attenuated inflammatory activation, and promoted repair-associated macrophage polarization. In an MRSA-infected wound model, Ce MOF-CD reduced bacterial burden and local inflammation, promoted tissue reconstruction, and accelerated wound closure with favorable biosafety. Overall, GSH-CDs-mediated interfacial electronic regulation modulates the pH-dependent redox catalytic behavior of Ce MOF, enabling antibacterial activity to be coordinated with oxidative-stress regulation during infected wound healing. Download: Download high-res image (393KB) Download: Download full-size image

All-in-one HN@Cu-MOF nanoparticles with enhanced reactive oxygen species generation and GSH depletion for effective tumor treatment

Shuhui Chen,Yu Yan,Yixuan Chen,Kaili Wang,Yawen Zhang,Xinlong Wang,Xurui Li,Jian Wen,Yue Yuan

Non-invasive cancer therapies, especially those based on reactive oxygen species, including photodynamic therapy (PDT), have gained much interest. As emerging photodynamic nanocarriers, metal–organic frameworks (MOFs) based on porphyrin can release reactive oxygen species (ROS) to destroy cancer cells. However, due to the inefficient production of ROS by photosensitizers and the over-expression of glutathione (GSH) in the tumor microenvironment (TME), their therapeutic effect is not satisfactory. Therefore, herein, we developed a multi-functional nanoparticle, HN@Cu-MOF, to enhance the efficacy of PDT. We combined chemical dynamic therapy (CDT) and nitric oxide (NO) therapy by initiating sensitization to PDT and cell apoptosis in the treatment of tumors. The Cu2+-doped MOF reacted with GSH to form Cu+, exhibiting a strong CDT ability to generate hydroxyl radicals (˙OH). The Cu-MOF was coated with HN, which is hyaluronic acid (HA) modified by a nitric oxide donor. HN can target tumor cells over-expressing the CD44 receptor and consume GSH in the cells to release NO. Both cell experiments and in vivo experiments showed an excellent tumor inhibitory effect upon the treatment. Overall, the HN@Cu-MOF nanoparticle-integrated NO gas therapy and CDT with PDT led to a significant enhancement in GSH consumption and a remarkable elevation in ROS production.