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Tumor Microenvironment-Activated Degradable Multifunctional Nanoreactor for Synergistic Cancer Therapy and Glucose SERS Feedback.

ABSTRACT: Integration of disease diagnosis and therapy in vivo by nanotechnology is a challenge in the design of multifunctional nanocarriers. Herein, we report an intelligent and degradable nanoreactor, an assembly of the 4-mercaptobenzonitrile-decorated silver nanoparticles (AgNPs@MBN) and the glucose oxidase (GOx)-loaded metal-organic-framework (ZIF-8@GOx), which can be activated by tumor microenvironment to start the catalytic cascade-enhanced chemo-starvation synergistic therapy and simultaneous self-sense of cellular glucose level. Under the mild acidic microenvironment of tumor, the nanoreactor will collapse to release GOx that triggers a catalytic cascade reaction in vivo, depleting glucose, etching AgNPs@MBN, and producing toxic H₂O₂, Ag⁺, and Zn²⁺ ions, all of which work together to inhibit tumor growth. The AgNPs@MBN as SERS nanoprobe reads out glucose concentration noninvasively in tumor to achieve instant feedback of therapeutic progression. This work proposes a promising example of using enzyme-encapsulated biomineralized MOFs as an effective anticarcinogen for clinical applications.

SUBMITTER: Sun D

PROVIDER: S-EPMC7330608 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Tumor Microenvironment-Activated Degradable Multifunctional Nanoreactor for Synergistic Cancer Therapy and Glucose SERS Feedback.

Sun Dan D Qi Guohua G Ma Kongshuo K Qu Xiaozhang X Xu Weiqing W Xu Shuping S Jin Yongdong Y

iScience 20200616 7

Integration of disease diagnosis and therapy in vivo by nanotechnology is a challenge in the design of multifunctional nanocarriers. Herein, we report an intelligent and degradable nanoreactor, an assembly of the 4-mercaptobenzonitrile-decorated silver nanoparticles (AgNPs@MBN) and the glucose oxidase (GOx)-loaded metal-organic-framework (ZIF-8@GOx), which can be activated by tumor microenvironment to start the catalytic cascade-enhanced chemo-starvation synergistic therapy and simultaneous self ...[more]

PMID: 32615471

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Project description:INTRODUCTION:The genesis of cancer appears to be a complex matter, which is not simply based upon few genetic abnormalities/alteration. In fact, irregular microvasculature and aberrant interstitium of solid tumors impose significant pathophysiologic barrier functions against cancer treatment modalities, hence novel strategies should holistically target bioelements of tumor microenvironment (TME). In this study, we provide some overview and insights on TME and important strategies used to control the impacts of such pathophysiologic barriers. METHODS:We reviewed all relevant literature for the impacts of tumor interstitium and microvasculature within the TME as well as the significance of the implemented strategies. RESULTS:While tumorigenesis initiation seems to be in close relation with an emergence of hypoxia and alterations in epigenetic/genetic materials, large panoplies of molecular events emerge as intricate networks during oncogenesis to form unique lenient TME in favor of tumor progression. Within such irregular interstitium, immune system displays defective surveillance functionalities against malignant cells. Solid tumors show multifacial traits with coadaptation and self-regulation potentials, which bestow profound resistance against the currently used conventional chemotherapy and immunotherapy agents that target solely one face of the disease. CONCLUSION:The cancerous cells attain unique abilities to form its permissive microenvironment, wherein (a) extracellular pH is dysregulated towards acidification, (b) extracellular matrix (ECM) is deformed, (c) stromal cells are cooperative with cancer cells, (d) immune system mechanisms are defective, (e) non-integrated irregular microvasculature with pores (120-1200 nm) are formed, and (h) interstitial fluid pressure is high. All these phenomena are against cancer treatment modalities. As a result, to control such abnormal pathophysiologic traits, novel cancer therapy strategies need to be devised using multifunctional nanomedicines and theranostics.

Project description:Rationale: Glucose oxidase (GOx)-based biocatalytic nanoreactors can cut off the energy supply of tumors for starvation therapy and deoxygenation-activated chemotherapy. However, these nanoreactors, including mesoporous silica, calcium phosphate, metal-organic framework, or polymer nanocarriers, cannot completely block the reaction of GOx with glucose in the blood, inducing systemic toxicity from hydrogen peroxide (H2O2) and anoxia. The low enzyme loading capacity can reduce systemic toxicity but limits its therapeutic effect. Here, we describe a real 'ON/OFF' intelligent nanoreactor with a core-shell structure (GOx + tirazapamine (TPZ))/ZIF-8@ZIF-8 modified with the red cell membrane (GTZ@Z-RBM) for cargo delivery. Methods: GTZ@Z-RBM nanoparticles (NPs) were prepared by the co-precipitation and epitaxial growth process under mild conditions. The core-shell structure loaded with GOx and TPZ was characterized for hydrate particle size and surface charge. The GTZ@Z-RBM NPs morphology, drug, and GOx loading/releasing abilities, system toxicity, multimodal synergistic therapy, and tumor metastasis suppression were investigated. The in vitro and in vivo outcomes of GTZ@Z-RBM NPs were assessed in 4T1 breast cancer cells. Results: GTZ@Z-RBM NPs could spatially isolate the enzyme from glucose in a physiological environment, reducing systemic toxicity. The fabricated nanoreactor with high enzyme loading capacity and good biocompatibility could deliver GOx and TPZ to the tumors, thereby exhausting glucose, generating H2O2, and aggravating hypoxic microenvironment for starvation therapy, DNA damage, and deoxygenation-activated chemotherapy. Significantly, the synergistic therapy effectively suppressed the breast cancer metastasis in mice and prolonged life without systemic toxicity. The in vitro and in vivo results provided evidence that our biomimetic nanoreactor had a powerful synergistic cascade effect in treating breast cancer. Conclusion: GTZ@Z-RBM NPs can be used as an 'ON/OFF' intelligent nanoreactor to deliver GOx and TPZ for multimodal synergistic therapy and tumor metastasis suppression.

Project description:Background: Studies have shown that the expression of histone deacetylases (HDACs) is significantly related to the tumor microenvironment (TME) in gastric cancer. However, the expression of a single molecule or several molecules does not accurately reflect the TME characteristics or guide immunotherapy in gastric cancer. Methods: We constructed an HDAC score (HDS) based on the expression level of HDACs. The single-cell transcriptome was used to analyze the underlying factors contributing to differences in immune infiltration between patients with a high and low HDS. In vitro and in vivo experiments validated the strategy of transforming cold tumors into hot tumors to guide immunotherapy. Results: According to the expression characteristics of HDACs, we constructed an HDS model to characterize the TME. We found that patients with a high HDS had stronger immunogenicity and could benefit more from immunotherapy than those with a low score. The AUC value of the HDS combined with the combined positive score (CPS)for predicting the efficacy of immunotherapy was as high as 0.96. By single-cell and paired bulk transcriptome sequencing analysis, we found that the infiltration levels of CD4+ T cells, CD8+ T cells and NK cells were significantly decreased in the low HDS group, which may be induced by MYH11+ fibroblasts, CD234+ endothelial cells and CCL17+ pDCs via the MIF signaling pathway. Inhibition of the MIF signaling pathway was confirmed to potentially enhance immune infiltration. In addition, our analysis revealed that GPX4 inhibitors might be effective for patients with a low HDS. GPX4 knockout significantly inhibited PD-L1 expression and promoted the infiltration and activation of CD8+ T cells. Conclusion: We constructed an HDS model based on the HDAC expression characteristics of gastric cancer. This model was used to evaluate TME characteristics and predict immunotherapy efficacy. Inhibition of the MIF signaling pathway in the TME and GPX4 expression in tumor cells may be an important strategy for cold tumor synergistic immunotherapy for gastric cancer.

Dataset Information

Tumor Microenvironment-Activated Degradable Multifunctional Nanoreactor for Synergistic Cancer Therapy and Glucose SERS Feedback.

Publications

Tumor Microenvironment-Activated Degradable Multifunctional Nanoreactor for Synergistic Cancer Therapy and Glucose SERS Feedback.

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