Therapeutic nanosystems which can be triggered by the distinctive tumor microenvironment possess great selectivity and safety to treat cancers via in situ transformation of nontoxic prodrugs into toxic therapeutic agents. Here, we constructed intelligent, magnetic targeting, and tumor microenvironment-responsive nanocatalysts that can acquire oxidation therapy of cancer via specific reaction at tumor site. The magnetic nanoparticle core of iron carbide-glucose oxidase (Fe 5 C 2 -GOD) achieved by physical absorption has a high enzyme payload, and the manganese dioxide (MnO 2 ) nanoshell as an intelligent "gatekeeper" shields GOD from premature leaking until reaching tumor tissue. Fe 5 C 2 -GOD@MnO 2 nanocatalysts maintained inactive in normal cells upon systemic administration. On the contrary, after endocytosis by tumor cells, tumor acidic microenvironment induced decomposition of MnO 2 nanoshell into Mn 2+ and O 2 , meanwhile releasing GOD. Mn 2+ could serve as a magnetic resonance imaging (MRI) contrast agent for real-time monitoring treatment process. Then the generated O 2 and released GOD in nanocatalysts could effectively exhaust glucose in tumor cells, simultaneously generating plenty of H 2 O 2 which may accelerate the subsequent Fenton reaction catalyzed by the Fe 5 C 2 magnetic core in mildly acidic tumor microenvironments. Finally, we demonstrated the tumor site-specific production of highly toxic hydroxyl radicals for enhanced anticancer therapeutic efficacy while minimizing systemic toxicity in mice.
The clinical application of photothermal therapy (PTT) is severely limited by the tissue penetration depth of excitation light, and enzyme therapy is hampered by its low therapeutic efficiency. As a two-dimensional ultrathin nanosheet with high absorbance in the near-infrared-II (NIR-II) region, the titanium carbide (Ti 3 C 2 ) nanosheet can be used as a substrate to anchor functional components, like nanozymes and nanodrugs. Here, we decorate Pt artificial nanozymes on the Ti 3 C 2 nanosheets to synthesize Ti-based MXene nanocomposites (Ti 3 C 2 T x -Pt-PEG). In the tumor microenvironment, the Pt nanoparticles exhibit peroxidase-like (POD-like) activity, which can in situ catalyze hydrogen peroxide to generate hydroxyl radicals ( • OH) to induce cell apoptosis and necrosis. Meanwhile, the composite shows a desirable photothermal effect upon NIR-II light irradiation with a low power density (0.75 W cm −2 ). Especially, the POD-like activity is significantly enhanced by the elevated temperature arising from the photothermal effect of Ti 3 C 2 T x . Therefore, satisfactory synergistic PTT/enzyme therapy has been accomplished, accompanied by an applicable photoacoustic imaging capability to monitor and guide the therapeutic process. This work may provide an approach for hyperthermia-amplified nanozyme catalytic therapy, especially based on metal catalysts and MXene nanocomposites. KEYWORDS: Ti 3 C 2 T x MXene, platinum nanoparticles, NIR-II light, photothermal, nanozyme
Reactive oxygen species (ROS)-based therapeutic modalities including chemodynamic therapy (CDT) and photodynamic therapy (PDT) hold great promise for conquering malignant tumors. However, these two methods tend to be restricted by the overexpressed glutathione (GSH) and hypoxia in the tumor microenvironment (TME). Here, we develop biodegradable copper/manganese silicate nanosphere (CMSN)-coated lanthanide-doped nanoparticles (LDNPs) for trimodal imaging-guided CDT/PDT synergistic therapy. The tridoped Yb3+/Er3+/Tm3+ in the ultrasmall core and the optimal Yb3+/Ce3+ doping in the shell enable the ultrabright dual-mode upconversion (UC) and downconversion (DC) emissions of LDNPs under near-infrared (NIR) laser excitation. The luminescence in the second near-infrared (NIR-II, 1000–1700 nm) window offers deep-tissue penetration, high spatial resolution, and reduced autofluorescence when used for optical imaging. Significantly, the CMSNs are capable of relieving the hypoxic TME through decomposing H2O2 to produce O2, which can react with the sample to generate 1O2 upon excitation of UC photons (PDT). The GSH-triggered degradation of CMSNs results in the release of Fenton-like Mn2+ and Cu+ ions for •OH generation (CDT); simultaneously, the released Mn2+ ions couple with NIR-II luminescence imaging, computed tomography (CT) imaging, and magnetic resonance (MR) imaging of LDNPs, performing a TME-amplified trimodal effect. In such a nanomedicine, the TME modulation, bimetallic silicate photosensitizer, Fenton-like nanocatalyst, and NIR-II/MR/CT contrast agent were achieved “one for all”, thereby realizing highly efficient tumor theranostics.
Strict conditions such as hypoxia, overexpression of glutathione (GSH), and high concentration of hydrogen peroxide (H2O2) in the tumor microenvironment (TME) limit the therapeutic effects of reactive oxygen species (ROS) for photodynamic therapy (PDT), chemodynamic therapy (CDT), and sonodynamic therapy (SDT). Here we fabricated a biocatalytic Janus nanocomposite (denoted as UPFB) for ultrasound (US) driven SDT and 808 nm near-infrared (NIR) light mediated PDT by combining core–shell–shell upconversion nanoparticles (UCNPs, NaYF4:20%Yb,1%Tm@NaYF4:10%Yb@NaNdF4) and a ferric zirconium porphyrin metal organic framework [PCN-224(Fe)]. Our design not only substantially overcomes the inefficient PDT effect arising from the inadequate Förster resonance energy transfer (FRET) process from UCNPs (donor) to MOFs (acceptor) with only NIR laser irradiation, but also promotes the ROS generation via GSH depletion and oxygen supply contributed by Fe3+ ions coordinated in UPFB as a catalase-like nanozyme. Additionally, the converted Fe2+ from the foregoing process can achieve CDT performance under acidic conditions, such as lysosomes. Meanwhile, UPFB linked with biotin exhibits a good targeting ability to rapidly accumulate in the tumor region, verified by fluorescence imaging and T 2-weighted magnetic resonance imaging (MRI). In a word, it is believed that the synthesis and antitumor detection of UPFB heterostructures render them suitable for application in cancer therapeutics.
The therapeutic effect of traditional chemodynamic therapy (CDT) agents is severely restricted by their weakly acidic pH and glutathione (GSH) overexpression in the tumor microenvironment. Here, fusiform-like copper(II)-based tetrakis(4-carboxy phenyl)porphyrin (TCPP) nanoscale metal–organic frameworks (nMOFs) were designed and constructed for the first time (named PCN-224(Cu)-GOD@MnO2). The coated MnO2 layer can not only avoid conjugation of glucose oxidase (GOD) to damage normal cells but also catalyzes the generation of O2 from H2O2 to enhance the oxidation of glucose (Glu) by GOD, which also provides abundant H2O2 for the subsequent Cu+-based Fenton-like reaction. Meanwhile, the Cu2+ chelated to the TCPP ligand is converted to Cu+ by the excess GSH in the tumor, which reduces the tumor antioxidant activity to improve the CDT effect. Next, the Cu+ reacts with the plentiful H2O2 by enzyme catalysis to produce a toxic hydroxyl radical (•OH), and singlet oxygen (1O2) is synchronously generated from combination with Cu+, O2, and H2O via the Russell mechanism. Furthermore, the nanoplatform can be used for both TCPP-based in vivo fluorescence imaging and Mn2+-induced T 1-weighted magnetic resonance imaging. In conclusion, fusiform-like PCN-224(Cu)-GOD@MnO2 nMOFs facilitate the therapeutic efficiency of chemodynamic and starvation therapy via combination with relief hypoxia and GSH depletion after acting as an accurate imaging guide.
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