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Visualization nanozyme based on tumor microenvironment "unlocking" for intensive combination therapy of breast cancer.

ABSTRACT: Nanozymes as artificial enzymes that mimicked natural enzyme-like activities have received great attention in cancer therapy. However, it remains a great challenge to design nanozymes that precisely exert its activity in tumor without producing off-target toxicity to surrounding normal tissues. Here, we report a synergetic enhancement strategy through the combination between nanozyme and tumor vascular normalization to destruct tumors, which was based on tumor microenvironment (TME) "unlocking." This nanozyme that we developed not only has photothermal properties but also can produce reactive oxygen species efficiently under the stimulation of TME. Moreover, this nanozyme also showed remarkable imaging performance in fluorescence imaging in the second near-infrared region and magnetic resonance imaging for visualization tracing in vivo. The process of combination therapy showed remarkable therapeutic effect for breast cancer. This study provides a therapeutic strategy by the cooperation between multifunctional nanozyme and tumor vascular normalization for intensive combination therapy of breast cancer.

SUBMITTER: Wang Z

PROVIDER: S-EPMC7695480 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Visualization nanozyme based on tumor microenvironment "unlocking" for intensive combination therapy of breast cancer.

Wang Zhiyi Z Li Ziyuan Z Sun Zhaoli Z Wang Shuren S Ali Zeeshan Z Zhu Sihao S Liu Sha S Ren Qiushi Q Sheng Fugeng F Wang Baodui B Hou Yanglong Y

Science advances 20201127 48

Nanozymes as artificial enzymes that mimicked natural enzyme-like activities have received great attention in cancer therapy. However, it remains a great challenge to design nanozymes that precisely exert its activity in tumor without producing off-target toxicity to surrounding normal tissues. Here, we report a synergetic enhancement strategy through the combination between nanozyme and tumor vascular normalization to destruct tumors, which was based on tumor microenvironment (TME) "unlocking." ...[more]

PMID: 33246959

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Project description:BackgroundBreast cancer, with its high morbidity and mortality rates, is a significant global health burden. Traditional treatments-surgery, chemotherapy, and radiotherapy-are widely used but come with drawbacks such as recurrence, metastasis, and significant side effects, including damage to healthy tissues. To address these limitations, new therapeutic strategies are being developed. Peroxidases (POD) can catalyze excess H2O2 in the tumor microenvironment to generate reactive oxygen species (ROS), which induce cancer cell apoptosis by disrupting redox homeostasis and modulating apoptosis-related proteins. However, natural enzymes face challenges like poor stability, high cost, and sensitivity to environmental conditions, limiting their application in breast cancer treatment. Nanozymes, nanomaterials with enzyme-like activity, offer a promising alternative by overcoming these limitations.MethodsIn this study, we successfully prepared Au@Pd nanozymes with peroxidase activity by depositing metallic Pd on Au nanoparticles (Au NPs) synthesized using a trisodium citrate reduction method and ascorbic acid reduction. The in vitro validation was conducted through a series of experiments, including ROS detection, flow cytometry, CCK-8 assay, DNA damage assessment, live/dead cell staining, Western blot (WB), and qPCR. Tumor treatment was performed via tail vein injection of the drug, followed by HE staining of the treated tissues and biochemical analysis of the blood.ResultsAu@Pd nanozymes can effectively accumulate at the tumor site through the EPR effect and exert peroxidase-like activity, catalyzing the excess H2O2 in the tumor microenvironment to produce ROS. This triggers apoptosis pathways and DNA damage, leading to the downregulation of the anti-apoptotic protein Bcl-2, upregulation of the pro-apoptotic protein Bax, and induction of apoptosis-related genes, demonstrating strong anti-tumor effects.ConclusionsThis study developed an efficient nanozyme-mediated catalytic therapy strategy targeting the tumor microenvironment for the treatment of breast cancer cells.

Project description:Background: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with very few treatment options. Although tumor-targeted nanomedicines hold great promise for the treatment of TNBC, the tumor microenvironment (TME) continues to be a major cause of failure in nanotherapy and immunotherapy. To overcome this barrier, we designed a new synergistic cascade strategy (SCS) that uses mild hyperthermia and smart drug delivery system (SDDS) to alter TME resistance in order to improve drug delivery and therapeutic efficacy of TNBC. Methods: Mild hyperthermia was produced by microwave (MW) irradiation. SDDS were formulated with thermosensitive polymer-lipid nanoparticles (HA-BNPs@Ptx), composed of polymer PLGA, phospholipid DPPC, hyaluronic acid (HA, a differentiation-44-targeted molecule, also known as CD44), 1-butyl-3-methylimidazolium-L-lactate (BML, a MW sensitizer), and paclitaxel (Ptx, chemotherapy drug). 4T1 breast tumor-bearing mice were treated with two-step MW combined with HA-BNPs@Ptx. Tumors in mice were pretreated with first MW irradiation prior to nanoparticle injection to modify and promote TME and promoting nanoparticle uptake and retention. The second MW irradiation was performed on the tumor 24 h after the injection of HA-BNPs@Ptx to produce a synergistic cascade effect through activating BML, thus, enhancing a hyperthermia effect, and instantly releasing Ptx at the tumor site. Results: Multifunctional CD44-targeted nanoparticles HA-BNPs@Ptx were successfully prepared and validated in vitro. After the first MW irradiation of tumors in mice, the intratumoral perfusion increased by two times, and the nanoparticle uptake was augmented by seven times. With the second MW irradiation, remarkable antitumor effects were obtained with the inhibition rate up to 88%. In addition, immunohistochemical analysis showed that SCS therapy could not only promote tumor cell apoptosis but also significantly reduce lung metastasis. Conclusion: The SCS using mild hyperthermia combined with SDDS can significantly improve the efficacy of TNBC treatment in mice by modifying TME and hyperthermia-mediated EPR effects.

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Visualization nanozyme based on tumor microenvironment "unlocking" for intensive combination therapy of breast cancer.

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Visualization nanozyme based on tumor microenvironment "unlocking" for intensive combination therapy of breast cancer.

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