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Gold nanoclusters as a GSH activated mitochondrial targeting photosensitizer for efficient treatment of malignant tumors.

ABSTRACT: Gold nanoclusters (Au NCs), which have the characteristics of small size, near infrared (NIR) absorption and long triplet excited lifetime, have been used as a new type of photosensitizer for deep tissue photodynamic therapy (PDT). However, the therapeutic efficiency of the nano-system based on Au NCs still needs to be improved. Herein, we proposed a strategy using Mito-Au₂₅@MnO₂ nanocomposites to achieve enhanced PDT. Au₂₅(Capt)₁₈ ^- nanoclusters were applied as photosensitizers and further modified with peptides to target mitochondrial and MnO₂ nanosheets to consume glutathione (GSH). In the presence of GSH, Mito-Au₂₅@MnO₂ dis-integrated and Mito-Au₂₅ nanoparticles realized accurate mitochondrial targeting. Under the irradiation of 808 nm light, the nanocomposite ensured highly efficient PDT both in vitro and in vivo via oxidation pressure elevation and mitochondrial targeting in cancer cells.

SUBMITTER: Fan C

PROVIDER: S-EPMC9034094 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Gold nanoclusters as a GSH activated mitochondrial targeting photosensitizer for efficient treatment of malignant tumors.

Fan Chen C Zhai Shuyang S Hu Wei W Chi Siyu S Song Dan D Liu Zhihong Z

RSC advances 20210616 35

Gold nanoclusters (Au NCs), which have the characteristics of small size, near infrared (NIR) absorption and long triplet excited lifetime, have been used as a new type of photosensitizer for deep tissue photodynamic therapy (PDT). However, the therapeutic efficiency of the nano-system based on Au NCs still needs to be improved. Herein, we proposed a strategy using Mito-Au25@MnO2 nanocomposites to achieve enhanced PDT. Au25(Capt)18 - nanoclu ...[more]

PMID: 35478781

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Project description:Tumor imaging tools with high specificity and sensitivity are needed to aid the boundary recognition in solid tumor diagnosis and surgical resection. In this study, we developed a near infra-red (NIR) probe (P6) for in vitro/in vivo tumor imaging on the basis of the dual strategy of cancer cell targeting and stimulus-dependent activation. The selective imaging capacity towards cancer cells of P6 was thoroughly investigated, and the potential mechanisms of endocytosis were preliminary explored. Methods: GSH-activated biotin labelled NIR probe (P6) was designed, synthesized and characterized. The GSH responsive properties were systematically illustrated through UV-vis, fluorescent tests and LC-MS analysis. In vitro fluorescent imaging of probe P6 was collected in various living cancer cell lines (i.e. SW480, HGC-27, H460, BxPC-3, KHOS) and normal cell lines (i.e. BEAS-2B, HLF-1, THP1) under confocal laser scanning microscopy. Probe P6 was further applied to image primary human cancer cells which were freshly isolated from the peritoneal carcinoma and rectal cancer patients. Serial sections of human tumor tissues were collected and sent for H&E (hematoxylin-eosin) staining and P6 imaging. Live fluorescent and photoacoustic imaging were used to investigate the in vivo imaging of P6 in both tumor and normal tissues in HGC-27 and KHOS xenograft model. Results: Probe P6 could be recognized and transported into cancer cells by tumor specific biotin receptors and efficiently be triggered by GSH to release fluorophore 4. In fact, the cellular uptake of P6 could be partially blocked by the addition of free biotin. Furthermore, probe P6 could image various cancer cell lines, as well as primary cancer cells, exhibiting a ten-fold increase in fluorescence intensity over normal cells. In freshly dissected cancer tissues, P6 fluorescent imaging distinguished the cancerous area under confocal laser scanning microscopy, which was exact the same area as indicated by H&E staining. We also found that P6 exhibited superior selectivity against cancer tissues by local injection. Conclusion: In this study, we developed a dual-modal NIR probe P6 with enhanced cellular uptake into cancer cells and environmental stimulus triggered fluorescence. Our strategy provided a novel insight into the development of imaging tools that could be potentially used for fluorescent image-guided cancer boundary recognition and possibly cancer diagnosis.

Project description:Antibodies have been shown to be a potent therapeutic tool. However, their use for targeting brain diseases, including neurodegenerative diseases and brain cancers, has been limited, particularly because the blood-brain barrier (BBB) makes brain tissue hard to access by conventional antibody-targeting strategies. In this review, we summarize new antibody therapeutic approaches to target brain tumors, especially malignant gliomas, as well as their potential drawbacks. Many different brain delivery platforms for antibodies have been studied such as liposomes, nanoparticle-based systems, cell-penetrating peptides (CPPs), and cell-based approaches. We have already shown the successful delivery of single-chain fragment variable (scFv) with CPP as a linker between two variable domains in the brain. Antibodies normally face poor penetration through the BBB, with some variants sufficiently passing the barrier on their own. A "Trojan horse" method allows passage of biomolecules, such as antibodies, through the BBB by receptor-mediated transcytosis (RMT). Such examples of therapeutic antibodies are the bispecific antibodies where one binding specificity recognizes and binds a BBB receptor, enabling RMT and where a second binding specificity recognizes an antigen as a therapeutic target. On the other hand, cell-based systems such as stem cells (SCs) are a promising delivery system because of their tumor tropism and ability to cross the BBB. Genetically engineered SCs can be used in gene therapy, where they express anti-tumor drugs, including antibodies. Different types and sources of SCs have been studied for the delivery of therapeutics to the brain; both mesenchymal stem cells (MSCs) and neural stem cells (NSCs) show great potential. Following the success in treatment of leukemias and lymphomas, the adoptive T-cell therapies, especially the chimeric antigen receptor-T cells (CAR-Ts), are making their way into glioma treatment as another type of cell-based therapy using the antibody to bind to the specific target(s). Finally, the current clinical trials are reviewed, showing the most recent progress of attractive approaches to deliver therapeutic antibodies across the BBB aiming at the specific antigen.

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Gold nanoclusters as a GSH activated mitochondrial targeting photosensitizer for efficient treatment of malignant tumors.

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Gold nanoclusters as a GSH activated mitochondrial targeting photosensitizer for efficient treatment of malignant tumors.

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