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A tumor microenvironment responsive nanosystem for chemodynamic/chemical synergistic theranostics of colorectal cancer.

ABSTRACT: Rationale: The synergism of new modalities alongside chemodynamic therapy into common chemotherapy has shown promising potential in clinical applications. This paper reports a tumor microenvironment-responsive nanosystem for chemodynamic/chemical synergistic therapy and magnetic resonance imaging (MRI). Methods: The biodegradable nanosystem is synthesized using a surface-modified chain transfer agent for surface-initiated living radical polymerization of the chemotherapeutic drug. Results: In this nanosystem, named CAMNSN@PSN38, the cycling time and solubility of the chemotherapeutic drug are improved. The nanoparticles delivered to tumor tissues gradually release the chemotherapeutic drug and Mn²⁺ through glutathione (GSH)-triggered biodegradation in the tumor microenvironment. SN38, the released chemotherapeutic drug, not only shows excellent chemical therapy effects but also improves the generation of H₂O₂. Furthermore, with the Fenton-like agent Mn²⁺, the generation of reactive oxygen species (ROS) is improved markedly. Finally, CAMNSN@PSN38 shows excellent inhibition of tumor growth in three colorectal cancer tumor models, with an improved accumulation of ROS and controlled release of SN38. Conclusions: The CAMNSN@PSN38-mediated chemodynamic/chemical synergistic therapy provides a promising paradigm for the treatment and MRI-guided therapy of colorectal cancer.

SUBMITTER: Wang L

PROVIDER: S-EPMC8419042 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAs an emerging therapeutic modality, chemodynamic therapy (CDT), converting hydrogen peroxide (H2O2) into highly toxic reactive oxygen species (ROS), has been developed for tumor-specific therapy. However, the deficiency of endogenous H2O2 and high concentration of glutathione (GSH) in the tumor microenvironment (TME) weaken the CDT-based tumor-therapeutic efficacy. Herein, a photothermal-enhanced tumor-specific cascade catalytic nanosystem has been constructed on the basis of glucose oxidase (GOD)-functionalized molybdenum (Mo)-based polyoxometalate (POM) nanoclusters, termed as GOD@POMs.MethodsGOD@POMs were synthesized by a facile one-pot procedure and covalently conjugation. Then, its structure was characterized by scanning electron microscope (SEM), transmission electron microscope (TEM), Fourier transform infrared (FTIR) spectroscopy and X-ray photoelectron spectroscopy (XPS). In addition, ultraviolet-visible-near-infrared (UV-vis-NIR) absorption spectrum and infrared thermal camera were applied to evaluate the catalytic and photothermal performance, respectively. Moreover, to confirm the therapeutic effects in vitro, cell counting kit-8 (CCK-8) assay, live/dead staining and ROS staining were performed. Furthermore, the biosafety of GOD@POMs was investigated via blood routine, blood biochemistry and hematoxylin and eosin (H&E) staining in Kunming mice. Besides, the C6 glioma tumor-bearing mice were constructed to evaluate its anti-tumor effects in vivo and its photoacoustic (PA) imaging capability. Notably, RNA sequencing, H&E, TdT-mediated dUTP nick end labeling (TUNEL) and Ki-67 staining were also conducted to disclose its underlying anti-tumor mechanism.ResultsIn this multifunctional nanosystem, GOD can effectively catalyze the oxidation of intratumoral glucose into gluconic acid and H2O2, achieving the cancer starvation therapy. Meanwhile, the generated gluconic acid decreases the pH in TME resulting in POM aggregation, which enables PA imaging-guided tumor-specific photothermal therapy (PTT), especially in the second near-infrared (NIR-II) biological window. Importantly, the Mo (VI) sites on POM can be reduced to Mo (V) active sites in accompany with GSH depletion, and then the post-produced Mo (V) transforms in situ overproduced H2O2 into singlet oxygen (1O2) via Russell mechanism, achieving self-enhanced CDT. Moreover, the PTT-triggered local tumor temperature elevation augments the synergistic nanocatalytic-therapeutic efficacy.ConclusionsConsequently, the integration of GOD-induced starvation therapy, H2O2 self-supply/GSH-depletion enhanced Mo-based CDT, and POM aggregation-mediated PTT endow the GOD@POMs with remarkable synergistic anticancer outcomes with neglectable adverse effects.

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A tumor microenvironment responsive nanosystem for chemodynamic/chemical synergistic theranostics of colorectal cancer.

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