Metal-Organic Framework-Mediated Synergistic Hypoxia-Activated Chemo-Immunotherapy Induced by High Intensity Focused Ultrasound for Enhanced Cancer Theranostics.

High intensity focused ultrasound (HIFU) has attracted considerable attention as a noninvasive, efficient, and economic therapeutic modality for solid tumors. However, HIFU surgery has its intrinsic limitation in completely ablating tumors, leading to residual tumor tissue. Furthermore, the severely hypoxic environment ensuring after surgery can exacerbate the unrestricted proliferation and metabolism of residual tumor cells, leading to tumor recurrence and metastasis. To address these limitations, a versatile HIFU-specific metal-organic framework nanosystem (called ADMOFs) is developed by coordinating hypoxia-activated prodrug AQ4N, Mn2+ , and DOX based on the postoperative response to changes in the tumor microenvironment. ADMOFs loaded with AQ4N/Mn2+ exhibited remarkable tumor-targeting behavior in vivo and enhanced photoacoustic/magnetic resonance imaging effects, enabling more accurate guidance for HIFU surgery. After surgery, the ADMOFs exploited the severely hypoxic tumor environment induced by HIFU, overcoming hypoxia-associated drug resistance, and inducing immunogenic cell death. Finally, it effectively inhibited tumor growth and eliminated lung metastasis. Transcriptome studies revealed that this strategy significantly up-regulated genes involved in apoptosis, cell cycle, and HIF-1 signaling pathway while downregulating genes related to tumor proliferation and metastasis. These findings suggest that combining hypoxia-activated chemo-immunotherapy with HIFU is a promising strategy for enhancing cancer theranostics.

Integrated Transcriptome and Metabolome Analyses Provide Insights into the Coloring Mechanism of Dark-red and Yellow Fruits in Chinese Cherry [Cerasus pseudocerasus (Lindl.) G. Don].

Chinese cherry [Cerasus pseudocerasus (Lindl.) G. Don] is an important fruit tree from China that has excellent ornamental, economic, and nutritional values with various colors. The dark-red or red coloration of fruit, an attractive trait for consumers, is determined by anthocyanin pigmentation. In this study, the coloring patterns during fruit development in dark-red and yellow Chinese cherry fruits were firstly illustrated by integrated transcriptome and widely-targeted metabolome analyses. Anthocyanin accumulation in dark-red fruits was significantly higher compared with yellow fruits from the color conversion period, being positively correlated to the color ratio. Based on transcriptome analysis, eight structural genes (CpCHS, CpCHI, CpF3H, CpF3'H, CpDFR, CpANS, CpUFGT, and CpGST) were significantly upregulated in dark-red fruits from the color conversion period, especially CpANS, CpUFGT, and CpGST. On contrary, the expression level of CpLAR were considerably higher in yellow fruits than in dark-red fruits, especially at the early stage. Eight regulatory genes (CpMYB4, CpMYB10, CpMYB20, CpMYB306, bHLH1, CpNAC10, CpERF106, and CpbZIP4) were also identified as determinants of fruit color in Chinese cherry. Liquid chromatography-tandem mass spectrometry identified 33 and 3 differential expressed metabolites related to anthocyanins and procyanidins between mature dark-red and yellow fruits. Cyanidin-3-O-rutinoside was the predominant anthocyanin compound in both fruits, while it was 6.23-fold higher in dark-red than in yellow fruits. More accumulated flavanol and procyanidin contents resulted in less anthocyanin content in flavonoid pathway in yellow fruits due to the higher expression level of CpLAR. These findings can help understand the coloring mechanism of dark-red and yellow fruits in Chinese cherry, and provide genetic basis for breeding new cultivars.

Characteristics and Geological Significance of Lacustrine Hydrothermal Sedimentary Rocks in the Yingejing Sag in Bayingebi Basin, Inner Mongolia, Northwestern China.

In order to promote site screening for high-level radioactive waste (HLW) disposal purposes, the characteristics of argillaceous rock (potential host rock) from the Yingejing Sag of the Bayingebi Basin, Northwest China have been well discussed. Results show that (1) Unlike argillaceous host rocks in foreign countries, the argillaceous rock mainly consists of analcite, dolomite, and albite; the contents of clay minerals are only about 10%. Five typical structures could be categorized, dominating by the massive structure. (2) Geochemical characteristics have the characteristics of abundance in deep source gas and liquid trace elements, a gentle right dip in the distribution pattern of rare-earth elements. (3) Petrological and geochemical characteristics determine the argillaceous rock as the genesis of lacustrine hydrothermal sedimentary rock. The hydrothermal sedimentary model also has been constructed, mainly controlled by tectonic activity of the Altyn Tagh fault from 100 to 120 Ma. The massive argillites with analcite and dolomite would lay the foundation for confirming the site for HLW disposal purposes in China.

Hypoxia-Specific Metal-Organic Frameworks Augment Cancer Immunotherapy of High-Intensity Focused Ultrasound.

As a noninvasive treatment modality, high-intensity focused ultrasound (HIFU)-induced antitumor immune responses play a vital role in surgery prognosis. However, limited response intensity largely hinders postoperative immunotherapy. Herein, a hypoxia-specific metal-organic framework (MOF) nanosystem, coordinated by Fe3+, hypoxic-activated prodrug AQ4N, and IDO-1 signaling pathway inhibitor NLG919, is developed for the potentiating immunotherapy of HIFU surgery. The loaded AQ4N enhances the photoacoustic imaging effects to achieve accurate intraoperative navigation. Within the HIFU-established severe hypoxic environment, AQ4N is activated sequentially, following which it cooperates with Fe3+ to effectively provoke immunogenic cell death. In addition, potent NLG919 suppresses IDO-1 activity and degrades the immunosuppressive tumor microenvironment aggravated by postoperative hypoxia. In vivo studies demonstrate that the MOF-mediated immunotherapy greatly inhibits the growth of primary/distant tumors and eliminates lung metastasis. This work establishes a robust delivery platform to improve immunotherapy and the overall prognosis of HIFU surgery with high specificity and potency.

Banoxantrone Coordinated Metal-Organic Framework for Photoacoustic Imaging-Guided High Intensity Focused Ultrasound Therapy.

Photoacoustic (PA) imaging with high spatial resolution has great potential as desired monitoring means in the high-intensity focused ultrasound (HIFU) surgery of tumor. However, its penetration depth in the tissue is insufficient for achieving accurate intraoperative navigation, leading to residual tumor tissue. Nanomedicine provides a new opportunity for PA imaging to guide HIFU surgery. Studies have found that the hypoxic heterogeneity of tumor is effectively reversed by HIFU. Herein, a specific metal-organic framework nanosystem, constructed by coordination of banoxantrone (AQ4N) and Mn2+ , is designed based on HIFU to reverse the hypoxic heterogeneity of tumors. It can provide exogenous light-absorbing substances, thus improving the penetrability of PA imaging signal through the deep tissue and achieving clearer PA imaging for guiding HIFU surgery. In turn, AQ4N, in the hypoxic homogenous environment of the tumor provided by HIFU, is activated sequentially to specifically treat the residual hypoxic tumor cells. This combination treatment manifests higher tumor suppressors activation and lower expression of genes related to tumor progression. This strategy addresses the dissatisfaction with PA imaging-guided HIFU therapy and is promising for translation into a clinical combination regimen.