Remote Manipulation of TRPV1 Signaling by Near-Infrared Light-Triggered Nitric Oxide Nanogenerators for Specific Cancer Therapy.

Specific activation of transient receptor potential vanilloid member 1 (TRPV1) channels provides a new avenue for cancer treatment by inducing excessive Ca2+ influx. However, controllable manipulation of TRPV1 signaling for clinical application has remained elusive due to the challenge in finding a mild and effective method of exerting external stimulus without adverse side effects in living systems. Herein, a TRPV1-targeting near-infrared (NIR) triggered nitric oxide (NO)-releasing nanoplatform (HCuS@PDA-TRPV1/BNN6) based on polydopamine (PDA) coated hollow copper sulfide nanoparticles (HCuS NPs) is developed for specific cancer therapy. Upon NIR irradiation, the NO donor BNN6 encapsulated in NIR-responsive nanovehicles can locally generate NO to activate TRPV1 channels and induce Ca2+ influx. This NIR controlled mode enables the nanoplatform to exert its therapeutic effects below the apoptotic threshold temperature (43°C), minimizing the photothermal damage to normal tissue. Integrating this special NO-mediated therapy with HCuS NPs mediated chemodynamic therapy, the designed nanoplatform exhibits a boosted anticancer activity with negligible systematic toxicity. Together, this study provides a promising strategy for site-specific cancer therapy by spatiotemporally controlled activation of surface ion channels, thus offering a solution to an unmet clinical need in cancer treatment.

Tumor microenvironment-responsive artesunate loaded Z-scheme heterostructures for synergistic photo-chemodynamic therapy of hypoxic tumor.

Tumor microenvironment (TME) with the particular features of severe hypoxia, insufficient endogenous H2O2, and overexpression of glutathione (GSH) markedly reduced the antitumor efficacy of monotherapy. Herein, a TME-responsive multifunctional nanoplatform (Bi2S3@Bi@PDA-HA/Art NRs) was presented for synergistic photothermal therapy (PTT), chemodynamic therapy (CDT), and photodynamic therapy (PDT) to achieve better therapeutic outcomes. The Z-scheme heterostructured bismuth sulfide@bismuth nanorods (Bi2S3@Bi NRs) guaranteed excellent photothermal performance of the nanoplatform. Moreover, its ability to produce O2 and reactive oxygen species (ROS) synchronously could relieve tumor hypoxia and improve PDT outcomes. The densely coated polydopamine/ammonium bicarbonate (PDA/ABC) and hyaluronic acid (HA) layers on the surface of the nanoplatform enhanced the cancer-targeting capacity and induced the acidic TME-triggered in situ "bomb-like" release of Art. The CDT treatment was achieved by activating the released Art through intracellular Fe2+ ions in an H2O2-independent manner. Furthermore, decreasing the glutathione peroxidase 4 (GPX4) levels by Art could also increase the PDT efficiency of Bi2S3@Bi NRs. Owing to the synergistic effect, this nanoplatform displayed improved antitumor efficacy with minimal toxicity both in vitro and in vivo. Our design sheds light on the application of phototherapy combined with the traditional Chinese medicine monomer-artesunate in treating the hypoxic tumor.

Genetic changes in refractory relapsed acute myeloid leukemia with NPM1 mutation: A case report.

BACKGROUND: Acute myeloid leukemia is often associated with gene mutation or chromosome abnormality, which is an important factor affecting prognosis. The 5-year survival rate of patients with acute myeloid leukemia without hematopoietic stem cell transplantation is low. For patients who only received chemotherapy and whose first remission lasted > 5 years, there are few reports of gene spectrum changes between relapse and initial diagnosis. CASE SUMMARY: We report a 41-year-old woman who presented to our hospital with complaints of dizziness, poor appetite and wasting. She was diagnosed with acute myelomonocytic leukemia (M4b) with NPM1 mutation and only received chemotherapy. Her first remission lasted > 5 years. New genetic variants were detected upon relapse that may have been related to relapse and chemotherapy resistance. CONCLUSION: Mutations in WT1 (R394fs/A387fs)/PTPN11 T73I/ETV6 S350P and JAK2 W659R may be related to relapse and chemotherapy resistance in acute myeloid leukemia.

Ion channel-targeting near-infrared photothermal switch with synergistic effect for specific cancer therapy.

Despite significant achievement in chemotherapy, the off-target actions and low pharmaceutical selectivity of the therapeutic agents still limit their clinical efficacy. Herein, a multifunctional nanoplatform which integrates chemotherapy, chemodynamic therapy (CDT) and photoactivation of TRPV1 channels has been successfully established for specific cancer therapy. Polydopamine (PDA) coated hollow prussian blue nanocages (hPBNCs) are used as the photothermal switches and drug carriers for loading chemotherapeutic drug, doxorubicin (Dox). Conjugating with the TRPV1 antibodies enables the nanoplatform to bind specifically to TRPV1 channels on the plasma membrane of the TRPV1-positive cancer cells and then activate them by local heating upon NIR irradiation, leading to the over-influx of Ca2+. Critically, the laser irradiation can be carefully controlled to not only open the TRPV1 channels but also avoid burning of tumors by hyperthermia. Moreover, the exposed hPBNCs in the acidic tumor cells can decompose endogenous H2O2 into ˙OH by Fenton reaction to realize CDT, which further aggravates cancer cell apoptosis. Together with the chemotherapy caused by Dox, our nanoplatform displays an enhanced anticancer effect both in vitro and in vivo. Our work provides a powerful means for site-specific cancer synergetic therapy with high spatial and temporal resolution.

Mitochondria-targeting multifunctional nanoplatform for cascade phototherapy and hypoxia-activated chemotherapy.

Despite considerable progress has been achieved in hypoxia-associated anti-tumor therapy, the efficacy of utilizing hypoxia-activated prodrugs alone is not satisfied owing to the inadequate hypoxia within the tumor regions. In this work, a mitochondrial targeted nanoplatform integrating photodynamic therapy, photothermal therapy and hypoxia-activated chemotherapy has been developed to synergistically treat cancer and maximize the therapeutic window. Polydopamine coated hollow copper sulfide nanoparticles were used as the photothermal nanoagents and thermosensitive drug carriers for loading the hypoxia-activated prodrug, TH302, in our study. Chlorin e6 (Ce6) and triphenyl phosphonium (TPP) were conjugated onto the surface of the nanoplatform. Under the action of TPP, the obtained nanoplatform preferentially accumulated in mitochondria to restore the drug activity and avoid drug resistance. Using 660 nm laser to excite Ce6 can generate ROS and simultaneously exacerbate the cellular hypoxia. While under the irradiation of 808 nm laser, the nanoplatform produced local heat which can increase the release of TH302 in tumor cells, ablate cancer cells as well as intensify the tumor hypoxia levels. The aggravated tumor hypoxia then significantly boosted the anti-tumor efficiency of TH302. Both in vitro and in vivo studies demonstrated the greatly improved anti-cancer activity compared to conventional hypoxia-associated chemotherapy. This work highlights the potential of using a combination of hypoxia-activated prodrugs plus phototherapy for synergistic cancer treatment.

MOF-derived porous ZnO-Co3O4 nanocages as peroxidase mimics for colorimetric detection of copper(ii) ions in serum.

Sensitive detection of copper ions (Cu2+) in biological samples is extremely important since an abnormal level of Cu2+ is linked with many diseases. Herein, we demonstrated a novel turn-on colorimetric sensor for selective detection of Cu2+ both in buffered solution and serum samples based on porous bimetallic transition metal oxide nanocages (ZnO-Co3O4 NCs) as peroxidase mimics. The ZnO-Co3O4 NCs were prepared by using ZnCo-zeolitic-imidazolate-framework (ZnCo-ZIF) as precursors via direct calcination. With the high peroxidase-like activity, the obtained ZnO-Co3O4 NCs can catalyze the oxidation of tetramethylbenzidine (TMB) in the presence of H2O2 to form a blue colored product. The inhibition effect of cysteine (Cys) on the catalytic activity of ZnO-Co3O4 NCs and its strong binding ability toward Cu2+ enabled the ZnO-Co3O4 NCs/Cys system to be utilized for sensitive detection of Cu2+, in which the catalytic activity of ZnO-Co3O4 NCs/Cys can be recovered by the introduction of Cu2+ with an obvious color change of the solution. The linear range for Cu2+ determination was 2 to 100 nM with a detection limit of 1.08 nM. More importantly, this colorimetric sensor has been successfully applied to detect Cu2+ in serum without pretreatment. Our findings are expected to expand the scope of application of nanozyme and shed light on early disease diagnosis.

ATP induced alteration in the peroxidase-like properties of hollow Prussian blue nanocubes: a platform for alkaline phosphatase detection.

Breaking the pH limitation of the enzyme-like activity of nanomaterials is of great importance for extending their applications in environmental and biomedical fields. Herein, to mimic the role of histidine residues in horseradish peroxidase (HRP), adenosine 5'-triphosphate (ATP) is reported to improve the peroxidase-like activity of hollow Prussian blue nanocubes (hPBNCs). Due to the inherited porous structures, hPBNCs can expose all the binding sites as far as possible to ATP to significantly amplify their catalytic activity and broaden their applicable pH range up to pH 12. Introduction of ATP provides the possibility of realizing efficient catalytic reactions under alkaline conditions. Upon binding with hPBNCs, ATP can enhance the stability of hPBNCs, increase the affinities of the catalysts towards substrates and improve the conductivity of hPBNCs as well as change the decomposed product from H2O2. Moreover, on the basis of the different catalytic activities of hPBNCs towards ATP, adenosine 5'-diphosphate and adenosine 5'-monophosphate, hPBNCs-ATP is utilized to construct a novel colorimetric sensor for the detection of alkaline phosphatase (ALP) activity in biological fluids, which is significantly important for the clinical diagnosis of ALP-related diseases.

Expanded mesoporous silica-encapsulated ultrasmall Pt nanoclusters as artificial enzymes for tracking hydrogen peroxide secretion from live cells.

Design of synthetic structures that possess the similar functions to natural enzymes held great promise in environmental detection and biomedical application. Herein, a new concept for the fabrication of solid-supported catalysts as peroxidase mimic have been proposed to realize high-catalytic activity and stability by utilizing expanded mesoporous silica (EMSN)-encapsulated Pt nanoclusters. Compared with PtNCs, the introduction of amino group modified EMSN would enrich H2O2 on the surface of PtNCs and increase the catalytic sites for H2O2 decomposition, which gave rise to the higher catalytic activity of EMSN-PtNCs over a broad pH range, especially in weakly acidic and neural solutions. This would facilitate their applications for real-time monitoring the secretion of H2O2 from living cancer cells stimulated by various anticancer drugs. Our findings not only pave the way to use porous matrix as the structural component for the design of the biomimetic catalysts, but also provide a simple and reliable platform to monitor H2O2 released from living cells in real time, which holds great potential for elucidating the biological roles of H2O2 and underlying molecular mechanisms of drug cytotoxicity as well as drug therapeutic effects.