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ACS Macro Letters May 2024The high glutathione (GSH) level of the tumor microenvironment severely affects the efficacy of photodynamic therapy (PDT). The current GSH depletion strategies have...
The high glutathione (GSH) level of the tumor microenvironment severely affects the efficacy of photodynamic therapy (PDT). The current GSH depletion strategies have difficulty meeting the dual needs of security and efficiency. In this study, we report a photosensitizer Chlorin e6 (Ce6) and hypoxia-activated prodrug tirapazamine (TPZ) coloaded cross-linked multifunctional polymersome (TPZ/Ce6@SSPS) with GSH-triggered continuous GSH depletion for enhanced photodynamic therapy and hypoxia-activated chemotherapy. At tumor sites, the disulfide bonds of TPZ/Ce6@SSPS react with GSH to realize decross-linking for on-demand drug release. Meanwhile, the generated highly reactive quinone methide (QM) can further deplete GSH. This continuous GSH depletion will amplify tumor oxidative stress, enhancing the PDT effect of Ce6. Aggravated tumor hypoxia induced by PDT activates the prodrug TPZ, resulting in an enhanced combination of PDT and hypoxia-activated chemotherapy. Both and results demonstrate the efficient GSH depletion and potent antitumor activities by TPZ/Ce6@SSPS. This work provides a strategy for the design of a continuous GSH depletion platform, which holds great promise for enhanced combination tumor therapy.
Topics: Glutathione; Photochemotherapy; Tirapazamine; Animals; Mice; Humans; Photosensitizing Agents; Prodrugs; Chlorophyllides; Porphyrins; Antineoplastic Agents; Cell Line, Tumor; Tumor Microenvironment
PubMed: 38683197
DOI: 10.1021/acsmacrolett.4c00125 -
Advanced Materials (Deerfield Beach,... Jun 2024Photodynamic therapy (PDT) has been approved for clinic. However, powerless efficiency for deep hypoxic tumor therapy remains an enormous challenge for PDT. Herein, a...
Photodynamic therapy (PDT) has been approved for clinic. However, powerless efficiency for deep hypoxic tumor therapy remains an enormous challenge for PDT. Herein, a hypoxia-sensitive nanotherapeutic system (FTCD-SRGD) based on fullerene (C) and anoxic activating chemical prodrug tirapazamine (TPZ) is rationally designed for multimodal therapy of deep hypoxic tumors. To enhance the accumulation and achieve specific drug release in tumor, the FTCD-SRGD is modified with cyclo(Arg-Gly-Asp-d-Phe-Lys) (cRGDfK) peptide and disulfide bonds. With the exacerbated hypoxic microenvironment created by C consuming O for generating reactive oxygen species (ROS), TPZ is activated to produce toxic radical species to ablate deep tumors, which achieves a synergistic treatment of C-mediated PDT and hypoxia-enhanced chemotherapy. Additionally, given this hypoxia-sensitive system-induced immunogenic cell death (ICD) activating anticancer cytotoxic T lymphocyte to result in more susceptible tumor to immunotherapy, FTCD-SRGD plus immune checkpoint inhibitor (anti-PD-L1) fully inhibit deep hypoxic tumors by promoting infiltration of effector T cells in tumors. Collectively, it is the first time to develop a multimodal therapy system with fullerene-based hypoxia-sensitive PS for deep tumors. The powerful multimodal nanotherapeutic system for combining hypoxia-enhanced PDT and immunotherapy to massacre deep hypoxic tumors can provide a paradigm to combat the present bottleneck of tumor therapy.
Topics: Fullerenes; Photosensitizing Agents; Animals; Photochemotherapy; Mice; Cell Line, Tumor; Tirapazamine; Humans; Combined Modality Therapy; Tumor Microenvironment; Reactive Oxygen Species; Neoplasms; Tumor Hypoxia; Prodrugs; Antineoplastic Agents
PubMed: 38450765
DOI: 10.1002/adma.202310875 -
Journal of Biochemical and Molecular... Apr 2024Normoxic inactivation of prolyl hydroxylase-2 (PHD-2) in tumour microenvironment paves the way for cancer cells to thrive under the influence of HIF-1α and NF-κB....
Normoxic inactivation of prolyl hydroxylase-2 (PHD-2) in tumour microenvironment paves the way for cancer cells to thrive under the influence of HIF-1α and NF-κB. Henceforth, the present study is aimed to identify small molecule activators of PHD-2. A virtual screening was conducted on a library consisting of 265,242 chemical compounds, with the objective of identifying molecules that exhibit structural similarities to the furan chalcone scaffold. Further, PHD-2 activation potential of screened compound was determined using in vitro 2-oxoglutarate assay. The cytotoxic activity and apoptotic potential of screened compound was determined using various staining techniques, including 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide, 4',6-diamidino-2-phenylindole (DAPI), 1,1',3,3'-tetraethylbenzimi-dazolylcarbocyanine iodide (JC-1), and acridine orange/ethidium bromide (AO/EB), against MCF-7 cells. 7,12-Dimethylbenz[a]anthracene (DMBA) model of mammary gland cancer was used to study the in vivo antineoplastic efficacy of screened compound. [(E)-1-(4-fluorophenyl)-3-(furan-2-yl) prop-2-en-1-one] (BBAP-7) was screened and validated as a PHD-2 activator by an in vitro 2-oxo-glutarate assay. The IC of BBAP-7 on MCF-7 cells is 18.84 µM. AO/EB and DAPI staining showed nuclear fragmentation, blebbing and condensation in MCF-7 cells following BBAP-7 treatment. The red-to-green intensity ratio of JC-1 stained MCF-7 cells decreased after BBAP-7 treatment, indicating mitochondrial-mediated apoptosis. DMBA caused mammary gland dysplasia, duct hyperplasia and ductal carcinoma in situ. Carmine staining, histopathology, and scanning electron microscopy demonstrated that BBAP-7, alone or with tirapazamine, restored mammary gland surface morphology and structural integrity. Additionally, BBAP-7 therapy significantly reduced oxidative stress and glycolysis. The findings reveal that BBAP-7 activates PHD-2, making it a promising anticancer drug.
Topics: Humans; Prolyl Hydroxylases; Chalcones; Antineoplastic Agents; Acridine Orange; Apoptosis; Chalcone; Carcinoma; Tumor Microenvironment; Benzimidazoles; Carbocyanines
PubMed: 38486411
DOI: 10.1002/jbt.23679 -
Journal of Nanobiotechnology Jun 2024Hypoxia-activated prodrug (HAP) is a promising candidate for highly tumor-specific chemotherapy. However, the oxygenation heterogeneity and dense extracellular matrix...
BACKGROUND
Hypoxia-activated prodrug (HAP) is a promising candidate for highly tumor-specific chemotherapy. However, the oxygenation heterogeneity and dense extracellular matrix (ECM) of tumor, as well as the potential resistance to chemotherapy, have severely impeded the resulting overall efficacy of HAP.
RESULTS
A HAP potentiating strategy is proposed based on ultrasound responsive nanodroplets (PTP@PLGA), which is composed of protoporphyrin (PpIX), perfluoropropane (PFP) and a typical HAP, tirapazamine (TPZ). The intense vaporization of PFP upon ultrasound irradiation can magnify the sonomechanical effect, which loosens the ECM to promote the penetration of TPZ into the deep hypoxic region. Meanwhile, the PpIX enabled sonodynamic effect can further reduce the oxygen level, thus activating the TPZ in the relatively normoxic region as well. Surprisingly, abovementioned ultrasound effect also results in the downregulation of the stemness of cancer cells, which is highly associated with drug-refractoriness.
CONCLUSIONS
This work manifests an ideal example of ultrasound-based nanotechnology for potentiating HAP and also reveals the potential acoustic effect of intervening cancer stem-like cells.
Topics: Humans; Tirapazamine; Protoporphyrins; Fluorocarbons; Prodrugs; Cell Line, Tumor; Nanoparticles; Neoplastic Stem Cells; Antineoplastic Agents; Ultrasonic Waves; Animals; Extracellular Matrix; Mice; Neoplasms
PubMed: 38907270
DOI: 10.1186/s12951-024-02623-0 -
Journal of Colloid and Interface Science Apr 2024Microwave hyperthermia (MH) is an emerging treatment for solid tumors, such as breast cancer, due to its advantages of minimally invasive and deep tissue penetration....
Microwave hyperthermia (MH) is an emerging treatment for solid tumors, such as breast cancer, due to its advantages of minimally invasive and deep tissue penetration. However, MH induced tumor hypoxia is still an obstacle to breast tumor treatment failure. Therefore, an original nanoengineering strategy was proposed to exacerbate hypoxia in two stages, thereby amplifying the efficiency of activating tirapazamine (TPZ). And a novel microwave-sensitized nanomaterial (GdEuMOF@TPZ, GEMT) is designed. GdEuMOF (GEM) nanoparticles are certified excellent microwave (MW) sensitization performance, thus improving tumor selectivity to achieve MH. Meanwhile MW can aggravate the generation of thrombus and caused local circulatory disturbance of tumor, resulting in the Stage I exacerbated hypoxia environment passively. Due to tumor heterogeneity and uneven hypoxia, GEMT nanoparticles under microwave could actively deplete residual oxygen through the chemical reaction, exacerbating hypoxia level more evenly, thus forming the Stage II of exacerbated hypoxia environment. Consequently, a two-stage exacerbated hypoxia GEMT nanoparticles realize amplifying activation of TPZ, significantly enhance the efficacy of microwave hyperthermia and chemotherapy, and effectively inhibit breast cancer. This research provides insights into the development of progressive nanoengineering strategies for effective breast tumor therapy.
Topics: Humans; Female; Tirapazamine; Antineoplastic Agents; Breast Neoplasms; Microwaves; Neoplasms; Hypoxia; Hyperthermia, Induced; Cell Line, Tumor
PubMed: 38163404
DOI: 10.1016/j.jcis.2023.12.149 -
Small (Weinheim An Der Bergstrasse,... Jun 2024Radiofrequency ablation (RFA) is one of the most common minimally invasive techniques for the treatment of solid tumors, but residual malignant tissues or small...
Radiofrequency ablation (RFA) is one of the most common minimally invasive techniques for the treatment of solid tumors, but residual malignant tissues or small satellite lesions after insufficient RFA (iRFA) are difficult to remove, often leading to metastasis and recurrence. Here, Fe-TPZ nanoparticles are designed by metal ion and (TPZ) ligand complexation for synergistic enhancement of RFA residual tumor therapy. Fe-TPZ nanoparticles are cleaved in the acidic microenvironment of the tumor to generate Fe and TPZ. TPZ, an anoxia-dependent drug, is activated in residual tumors and generates free radicals to cause tumor cell death. Elevated Fe undergoes a redox reaction with glutathione (GSH), inducing a strong Fenton effect and promoting the production of the highly toxic hydroxyl radical (•OH). In addition, the ROS/GSH imbalance induced by this treatment promotes immunogenic cell death (ICD), which triggers the release of damage-associated molecular patterns, macrophage polarization, and lymphocyte infiltration, thus triggering a systemic antitumor immune response and noteworthy prevention of tumor metastasis. Overall, this integrated treatment program driven by multiple microenvironment-dependent pathways overcomes the limitations of the RFA monotherapy approach and thus improves tumor prognosis. Furthermore, these findings aim to provide new research ideas for regulating the tumor immune microenvironment.
PubMed: 38898764
DOI: 10.1002/smll.202311244 -
Colloids and Surfaces. B, Biointerfaces Feb 2024Activated M1-type macrophages, which produce inflammatory factors that exacerbate rheumatoid arthritis (RA), represent crucial target cells for inhibiting the disease...
Activated M1-type macrophages, which produce inflammatory factors that exacerbate rheumatoid arthritis (RA), represent crucial target cells for inhibiting the disease process. In this study, we developed a novel photoresponsive targeted drug delivery system (TPNPs-HA) that can effectively deliver the hypoxia-activated prodrug tirapazamine (TPZ) specifically to activated macrophages. After administration, this metal-organic framework, PCN-224, constructed uing the photosensitizer porphyrin, exhibits the ability to generate excessive toxic reactive oxygen species (ROS) when exposed to near-infrared light. Additionally, the oxygen-consumed hypoxic environment further activates the chemotherapeutic effect of TPZ, thus creating a synergistic combination of photodynamic therapy (PDT) and hypoxia-activated chemotherapy (HaCT) to promote the elimination of activated M1-type macrophages. The results highlight the significantly potential of this photoresponsive nano-delivery system in providing substantial relief for RA. Furthermore, these findings support its effectiveness in inhibiting the disease process of RA, thereby offering new possibilities for the development of precise and accurate strategies for RA.
Topics: Humans; Metal-Organic Frameworks; Tirapazamine; Photochemotherapy; Photosensitizing Agents; Hypoxia; Arthritis, Rheumatoid; Nanoparticles; Cell Line, Tumor; Neoplasms
PubMed: 38181689
DOI: 10.1016/j.colsurfb.2023.113707 -
Biochemical and Biophysical Research... Apr 2024
PubMed: 38368673
DOI: 10.1016/j.bbrc.2024.149630