Hypoxia of solid tumor compromises the therapeutic outcome of photodynamic therapy (PDT) that relies on localized O 2 molecules to produce highly cytotoxic singlet oxygen (1 O 2) species. Herein, we present a safe and versatile self-assembled PDT nanoagent, i.e., OxgeMCC-r single-atom enzyme (SAE), consisting of single-atom ruthenium as the active catalytic site anchored in a metal-organic framework Mn 3 [Co(CN) 6 ] 2 with encapsulated chlorin e6 (Ce6), which serves as a catalase-like nanozyme for oxygen generation. Coordination-driven self-assembly of organic linkers and metal ions in the presence of a biocompatible polymer generates a nanoscale network that adaptively encapsulates Ce6. The resulted OxgeMCC-r SAE possesses well-defined morphology, uniform size distribution and high loading capacity. When conducting the in situ O 2 generation through the reaction between endogenous H 2 O 2 and single-atom Ru species of OxgeMCC-r SAE, the hypoxia in tumor microenvironment is relieved. Our study demonstrates a promising self-assembled nanozyme with highly efficient single-atom catalytic sites for cancer treatment.
Integrated theranostic agents can provide comprehensive and efficient tools for simultaneous cancer diagnosis and therapy; however, limitations on efficiency and safety offer great room for improvement. Artesunate (AS), as an iron-dependent drug, has been investigated in cancer therapy, depending on free-radical generation for its action, which may reduce side effects commonly associated with conventional chemotherapy agents with low selectivity to target tumors. However, rapid clearance of its free form and limited availability of Fe ion in tumor sites become the main bottlenecks in cancer therapy. Herein, core−shell Mn 3 [Co(CN) 6 ] 2 @MIL-100(Fe) metal-organic frameworks (CS-MOFs) nanocube was designed using a layer-by-layer method, which holds great potential for synchronous co-delivery of AS and ferric ions for cancer therapy. Moreover, the heterogeneous hybrid CS-MOFs show single-and two-photon fluorescence, together with T 2 and enhanced T 1 magnetic resonance imaging ability. pH-responsive degradation of CS-MOFs enables on-demand Fe(III) and AS release in the tumor microenvironment. The intracellular ferric ions will further be reduced to ferrous ion that catalyze AS to generate carbon-centered free radicals and reactive oxygen species (ROS). The potential of this alternative antitumor modality under multimodality imaging is demonstrated both in vitro and in vivo. In addition, compared with free AS alone, the nanodrug system CS-MOFs@AS shows significantly enhanced tumor delivery specificity and negligible long-term toxicity. In vivo therapy results indicate that the antitumor efficacy of CS-MOFs@AS was 5.79 times greater than that of free AS, making it a promising Fe 2+ -mediated drugs delivery system.
Background: Osteosarcoma is a high-grade malignant bone neoplasm. Although the introduction of chemotherapy has reduced its mortality, more than 50% of patients develop chemoresistance and have an extremely poor prognosis due to pulmonary metastasis. Several molecular pathways contributing to osteosarcoma development and progression have recently been discovered. Various studies have addressed the genes involved in the metastasis of osteosarcoma. However, the highly complex molecular mechanisms of metastasis are still poorly understood. Recently, the decisive role of microRNAs in the regulation of molecular pathways has been uncovered. miRNAs may function as either oncogenes or tumor suppressors, depending on their target genes. miR-27a, a member of an evolutionarily conserved miRNA family, is abnormally increased in several types of cancers. It has been shown to be upregulated in osteosarcoma and plays a pro-metastatic role in osteosarcoma cell lines. However, the effects of miR-27a on osteosarcoma have not been clearly elucidated. The present study thus addressed the miR-27a sensitive mechanisms in osteosarcoma. Methods: In this study, three biological programs were used to predict whether MAP2K4 was a target of miR-27a. A specific miR-27a inhibitor was used to inhibit the endogenous activity of miR-27a in the human osteosarcoma cell line MG63. Cell proliferation, colony formation, migration and invasion assays were performed to assess the effects of miR-27a on the proliferation, metastasis and invasion of MG63 cells. The expression levels of several proteins evolved in the JNK/p38 signaling pathway were detected using western blot analysis. Results: The luciferase activity of the wild-type pGL3-MAP2K4 3'UTR vector was significantly inhibited after the miR-27a precursor or the control precursor was transfected into the MG63 cells. However, the luciferase activity was not inhibited after transfection of the mutant pGL3-MAP2K4 3'UTR vector. The inhibition of miR-27a increased the luciferase activity of the wild-type pGL3-MAP2K4 3'UTR vector after MG63 cells were transfected with the miR-27a inhibitor or the control inhibitor. Thus, MAP2K4 is a potential target of miR-27a and can be directly regulated by miR-27a. Inhibition of miR-27a significantly suppressed cell proliferation after 72 hours compared to the negative control group. Inhibition of miR-27a significantly suppressed colony formation of the MG63 cells by 39 6%. Transwell migration and invasion assays demonstrated that the number of migratory and invasive cells transfected with the miR-27a inhibitor was reduced by 63.5% and 69.1%, respectively. After transfection of the miR-27a inhibitor into the MG63 cells, the level of phospho-JNK1 and phospho-p38 increased by 25% and 29%, respectively, along with the up-regulation of MAP2K4 protein. Conclusion: This is the first study showing that miR-27a can function as an oncogene by targeting MAP2K4 in the osteosarcoma MG63 cell line. Inhibition of miR-27a increases MAP2K4 expression, which in turn inhibits cell pr...
Herein, a simple one‐pot way is designed to prepare a type of multifunctional metal–organic framework (MOF)‐based hybrid nanogels by in situ hybridization of dopamine monomer in the skeleton of MnCo. The resultant hybrid nanoparticles (named as MCP) show enhanced photothermal conversion efficiency in comparison with pure polydopamine or MnCo nanoparticles (NPs) synthesized under a similar method and, therefore, show great potential for photothermal therapy (PTT) in vivo. The MCP NPs are expected to possess T
1 positive magnetic resonance imaging ability due to the high‐spin Mn‐N6 (S = 5/2) in the skeleton of MnCo. To improve the therapy efficiency as a PTT agent, the MCP NPs are further modified with functional polyethylene glycol (PEG) and thiol terminal cyclic arginine–glycine–aspartic acid peptide, respectively: the first one is to increase the stability, biocompatibility, and blood circulation time of MCP NPs in vivo; the second one is to increase the tumor accumulation of MCP‐PEG NPs and improve their therapeutic efficiency as photothermal agent.
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