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.
Photodynamic therapy (PDT), a wellknown clinical modality that involves photosensitizer, molecular oxygen (O 2 ), and excitation light to generate cytotoxic reactive oxygen species such as singlet oxygen ( 1 O 2 ), has been proven to be a selective method for treating a wide spectrum of localized and superficial cancers or other diseases. [1][2][3][4][5][6][7][8][9] In addition to destroying cancer cells through direct photodamage, PDT can also induce vascular damage in the tumor, and activate the response of immune system. [10][11][12][13] Possessing spatial and temporal control over the localization of the light irradiation, the O 2 -involved PDT can remarkably improve the selectivity and reduce the side effects when compared to other conventional modalities such as chemotherapy, surgery, and radiotherapy. [14][15][16] On the other hand, tumor hypoxia compromises therapeutic effect of PDT, as O 2 is an indispensable element during the process. Uncontrollable growth of tumor cells as well as dysregulated formation of tumor blood vessels inevitably result in the cancer hypoxia. [17,18] In addition, microvascular collapse caused by PDT would further compromise the O 2 supply and aggravate the hypoxia condition, thus preventing effective PDT of cancer. Consequently, a vicious circle occurs, as PDT not only consumes localized O 2 , but also cuts off the O 2 supply. [19][20][21] To date, three main strategies have been employed to overcome the pre-existing hypoxia and improve the therapeutic effect of PDT. The most popular approach relies on the integration of PDT with other therapeutic modalities for a synergistic therapy. [17,22,23] However, such complex structures are often costly, which limit their scalable production and reproducibility. Another strategy is the utilization of intelligent nanomaterials that can act as O 2 carriers for direct transportation of mole cular oxygen to tumor sites. For example, Hu and coworkers reported photosensitizer-loaded perfluorocarbon nanodroplets as an O 2 self-enriched PDT nanoplatform. [24] The last approach is to construct smart nanoplatforms for in situ generation of O 2 within solid tumors based on the characteristics Tumor hypoxia compromises the therapeutic efficiency of photodynamic therapy (PDT) as the local oxygen concentration plays an important role in the generation of cytotoxic singlet oxygen ( 1 O 2 ). Herein, a versatile mesoporous nanoenzyme (NE) derived from metal-organic frameworks (MOFs) is presented for in situ generation of endogenous O 2 to enhancethe PDT efficacy under bioimaging guidance. The mesoporous NE is constructed by first coating a manganese-based MOFs with mesoporous silica, followed by a facile annealing process under the ambient atmosphere. After removing the mesoporous silica shell and post-modifying with polydopamine and poly(ethylene glycol) for improving the biocompatibility, the obtained mesoporous NE is loaded with chlorin e6 (Ce6), a commonly used photosensitizer in PDT, with a high loading capacity. Upon the O 2 generation through the...
Nanomaterials with enzyme‐mimicking activity (nanozymes) show potential for therapeutic interventions. However, it remains a formidable challenge to selectively kill tumor cells through enzymatic reactions, while leaving normal cells unharmed. Herein, we present a new strategy based on a single‐site cascade enzymatic reaction for tumor‐specific therapy that avoids off‐target toxicity to normal tissues. A copper hexacyanoferrate (Cu‐HCF) nanozyme with active single‐site copper exhibited cascade enzymatic activity within the tumor microenvironment: Tumor‐specific glutathione oxidase activity by the Cu‐HCF single‐site nanozymes (SSNEs) led to the depletion of intracellular glutathione and the conversion of single‐site CuII species into CuI for subsequent amplified peroxidase activity through a Fenton‐type Harber–Weiss reaction. In this way, abundant highly toxic hydroxyl radicals were generated for tumor cell apoptosis. The results show that SSNEs could amplify the tumor‐killing efficacy of reactive oxygen species and suppress tumor growth in vivo.
Dauricine, a bioactive component of Asiatic Moonseed Rhizome, has been widely used to treat a large number of inflammatory diseases in traditional Chinese medicine. In our study, we demonstrated that dauricine inhibited colon cancer cell proliferation and invasion, and induced apoptosis by suppressing nuclear factor-kappaB (NF-kappaB) activation in a dose- and time-dependent manner. Addition of dauricine inhibited the phosphorylation and degradation of IkappaBalpha, and the phosphorylation and translocation of p65. Moreover, dauricine down-regulated the expression of various NF-kappaB-regulated genes, including genes involved cell proliferation (cyclinD1, COX2, and c-Myc), anti-apoptosis (survivin, Bcl-2, XIAP, and IAP1), invasion (MMP-9 and ICAM-1), and angiogenesis (VEGF). In athymic nu/nu mouse model, we further demonstrated that dauricine significantly suppressed colonic tumor growth. Taken together, our results demonstrated that dauricine inhibited colon cancer cell proliferation, invasion, and induced cell apoptosis by suppressing NF-kappaB activity and the expression profile of its downstream genes. These findings provide evidence for a novel role of dauricine in preventing or treating colon cancer through modulation of NF-kappaB singling pathway.
Metal-organic-frameworks (MOFs) possess high porosity, large surface area, and tunable functionality are promising candidates for synchronous diagnosis and therapy in cancer treatment. Although large number of MOFs has been discovered, conventional MOF-based nanoplatforms are mainly limited to the sole MOF source with sole functionality. In this study, surfactant modified Prussian blue (PB) core coated by compact ZIF-8 shell (core-shell dual-MOFs, CSD-MOFs) has been reported through a versatile stepwise approach. With Prussian blue as core, CSD-MOFs are able to serve as both magnetic resonance imaging (MRI) and fluorescence optical imaging (FOI) agents. We show that CSD-MOFs crystals loading the anticancer drug doxorubicin (DOX) are efficient pH and near-infrared (NIR) dual-stimuli responsive drug delivery vehicles. After the degradation of ZIF-8, simultaneous NIR irradiation to the inner PB MOFs continuously generate heat that kill cancer cells. Their efficacy on HeLa cancer cell lines is higher compared with the respective single treatment modality, achieving synergistic chemo-thermal therapy efficacy. In vivo results indicate that the anti-tumor efficacy of CSD-MOFs@DOX+NIR was 7.16 and 5.07 times enhanced compared to single chemo-therapy and single thermal-therapy respectively. Our strategy opens new possibilities to construct multifunctional theranostic systems through integration of two different MOFs.
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.
Aging, noise, and ototoxic drug-induced hair cell (HC) loss are the major causes of sensorineural hearing loss. Aminoglycoside antibiotics are commonly used in the clinic, but these often have ototoxic side effects due to the accumulation of oxygen-free radicals and the subsequent induction of HC apoptosis. Blebbistatin is a myosin II inhibitor that regulates microtubule assembly and myosin-actin interactions, and most research has focused on its ability to modulate cardiac or urinary bladder contractility. By regulating the cytoskeletal structure and reducing the accumulation of reactive oxygen species (ROS), blebbistatin can prevent apoptosis in many different types of cells. However, there are no reports on the effect of blebbistatin in HC apoptosis. In this study, we found that the presence of blebbistatin significantly inhibited neomycin-induced apoptosis in HC-like HEI-OC-1 cells. We also found that blebbistatin treatment significantly increased the mitochondrial membrane potential (MMP), decreased ROS accumulation, and inhibited pro-apoptotic gene expression in both HC-like HEI-OC-1 cells and explant-cultured cochlear HCs after neomycin exposure. Meanwhile, blebbistatin can protect the synaptic connections between HCs and cochlear spiral ganglion neurons. This study showed that blebbistatin could maintain mitochondrial function and reduce the ROS level and thus could maintain the viability of HCs after neomycin exposure and the neural function in the inner ear, suggesting that blebbistatin has potential clinic application in protecting against ototoxic drug-induced HC loss.
Phothermal therapy has received increasing attention in recent years as a potentially effective way to treat cancer. In pursuit of a more biocompatible photothermal agent, we utilize biosafe materials including ellagic acid (EA), polyvinylpyrrolidone (PVP), and iron element as building blocks, and we successfully fabricate a homogeneous nanosized Fe-EA framework for the first time by a facile method. As expected, the novel nanoagent exhibits no obvious cytotoxicity and good hemocompatibility in vitro and in vivo. The microenvironment responsiveness to both pH and hydrogen peroxide makes the NPs biodegradable in tumor tissues, and the framework should be easily cleared by the body. Photothermal potentials of the nanoparticles are demonstrated with relevant features of strong NIR light absorption, moderately effective photothermal conversion efficiency, and good photothermal stability. The in vivo photothermal therapy also achieved effective tumor ablation with no apparent toxicity. On the other hand, it also exhibits T2 MR imaging ability originated from ferric ions. Our work highlights the promise of the Fe-EA framework for imaging-guided photothermal therapy.
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