NIR-II Absorbed Dithienopyrrole-Benzobisthiadiazole Based Nanosystems for Autophagy Inhibition and Calcium Overload Enhanced Photothermal Therapy.

Although the current cancer photothermal therapy (PTT) can produce a powerful therapeutic effect, tumor cells have been proved a protective mechanism through autophagy. In this study, a novel hybrid theranostic nanoparticle (CaCO3@CQ@pDB NPs, CCD NPs) is designed and prepared by integrating a second near-infrared (NIR-II) absorbed conjugated polymer DTP-BBT (pDB), CaCO3, and autophagy inhibitor (chloroquine, CQ) into one nanosystem. The conjugated polymer pDB with asymmetric donor-acceptor structure shows strong NIR-II absorbing capacity, of which the optical properties and photothermal generation mechanism of pDB are systematically analyzed via molecular theoretical calculation. Under NIR-II laser irradiation, pDB-mediated PTT can produce powerful killing ability to tumor cells. At the same time, heat stimulates a large amount of Ca2+ inflow, causing calcium overload induced mitochondrial damage and enhancing the apoptosis of tumor cells. Besides, the released CQ blocks the self-protection mechanism of tumor cells and greatly enhances the attack of PTT and calcium overload therapy. Both in vitro and in vivo experiments confirm that CCD NPs possess excellent NIR-II theranostic capacity, which provides a new nanoplatform for anti-tumor therapy and builds great potential for future clinical research.

A novel acceptor-donor-acceptor structured molecule-based nanosystem for tumor mild photothermal therapy.

Although photothermal therapy (PTT) is effective at killing tumor cells, it can inadvertently damage healthy tissues surrounding the tumor. Nevertheless, lowering the treatment temperature will reduce the therapeutic effectiveness. In this study, we employed 2,2'-((2Z,2'Z)-((4,4,9,9-Tetrahexyl-4,9-dihydro-s-indaceno[1,2-b:5,6-b']dithiophene-2,7-diyl)bis(methanylylidene))bis(3-oxo-2,3-dihydro-1H-indene-2,1-diylidene)) dimalononitrile (IDIC), a molecule possessing a conventional acceptor-donor-acceptor (A-D-A) structure, as a photothermal agent (PTA) to facilitate effective mild photothermal therapy (mPTT). IDIC promotes intramolecular charge transfer under laser irradiation, making it a promising candidate for mPTT. To enhance the therapeutic potential of IDIC, we incorporated quercetin (Qu) into IDIC to form IDIC-Qu nanoparticles (NPs), which can inhibit heat shock protein (HSP) activity during the process of mPTT. Moreover, IDIC-Qu NPs exhibited exceptional water dispersibility and passive targeting abilities towards tumor tissues, attributed to its enhanced permeation and retention (EPR) effect. These advantageous properties position IDIC-Qu NPs as a promising candidate for targeted tumor treatment. Importantly, the IDIC-Qu NPs demonstrated controllable photothermal effects, leading to outstanding in vitro cytotoxicity against cancer cells and effective in vivo tumor ablation through mPTT. IDIC-Qu NPs nano-system enriches the family of organic PTAs and holds significant promise for future clinical applications of mPTT.

Engineered Luminescent Oncolytic Vaccinia Virus Activation of Photodynamic-Immune Combination Therapy for Colorectal Cancer.

Oncolytic virus therapy is currently regarded as a promising approach in cancer immunotherapy. It has greater therapeutic advantages for colorectal cancer that is prone to distant metastasis. However, the therapeutic efficacy and clinical application of viral agents alone for colorectal cancer remain suboptimal. In this study, an engineered oncolytic vaccinia virus (OVV-Luc) that expresses the firefly luciferase gene is developed and loaded Chlorin e6 (Ce6) onto the virus surface through covalent coupling, resulting in OVV-Luc@Ce6 (OV@C). The OV@C infiltrates tumor tissue and induces endogenous luminescence through substrate catalysis, resulting in the production of reactive oxygen species. This unique system eliminates the need for an external light source, making it suitable for photodynamic therapy (PDT) in deep tissues. Moreover, this synergistic effect between PDT and viral immunotherapy enhances dendritic cell maturation, macrophage polarization, and reversal of the immunosuppressive microenvironment. This synergistic effect has the potential to convert a "cold" into a "hot" tumor, it offers valuable insights for clinical translation and application.

Nanomedicine Strategies in Conquering and Utilizing the Cancer Hypoxia Environment.

Cancer with a complex pathological process is a major disease to human welfare. Due to the imbalance between oxygen (O2) supply and consumption, hypoxia is a natural characteristic of most solid tumors and an important obstacle for cancer therapy, which is closely related to tumor proliferation, metastasis, and invasion. Various strategies to exploit the feature of tumor hypoxia have been developed in the past decade, which can be used to alleviate tumor hypoxia, or utilize the hypoxia for targeted delivery and diagnostic imaging. The strategies to alleviate tumor hypoxia include delivering O2, in situ O2 generation, reprogramming the tumor vascular system, decreasing O2 consumption, and inhibiting HIF-1 related pathways. On the other side, hypoxia can also be utilized for hypoxia-responsive chemical construction and hypoxia-active prodrug-based strategies. Taking advantage of hypoxia in the tumor region, a number of methods have been applied to identify and keep track of changes in tumor hypoxia. Herein, we thoroughly review the recent progress of nanomedicine strategies in both conquering and utilizing hypoxia to combat cancer and put forward the prospect of emerging nanomaterials for future clinical transformation, which hopes to provide perspectives in nanomaterials design.

NIR diagnostic imaging of triple-negative breast cancer and its lymph node metastasis for high-efficiency hypoxia-activated multimodal therapy.

BACKGROUND: Triple-negative breast cancer (TNBC) possesses special biological behavior and clinicopathological characteristics, which is highly invasive and propensity to metastasize to lymph nodes, leading to a worse prognosis than other types of breast cancer. Thus, the development of an effective therapeutic method is significant to improve the survival rate of TNBC patients. RESULTS: In this work, a liposome-based theranostic nanosystem (ILA@Lip) was successfully prepared by simultaneously encapsulating IR 780 as the photosensitizer and lenvatinib as an anti-angiogenic agent, together with banoxantrone (AQ4N) molecule as the hypoxia-activated prodrug. The ILA@Lip can be applied for the near-infrared (NIR) fluorescence diagnostic imaging of TNBC and its lymph node metastasis for multimodal therapy. Lenvatinib in ILA@Lip can inhibit angiogenesis by cutting oxygen supply, thereby leading to enhanced hypoxia levels. Meanwhile, large amounts of reactive oxygen species (ROS) were produced while IR 780 was irradiated by an 808 nm laser, which also rapidly exhausted oxygen in tumor cells to worsen tumor hypoxia. Through creating an extremely hypoxic in TNBC, the conversion of non-toxic AQ4N to toxic AQ4 was much more efficiency for hypoxia-activated chemotherapy. Cytotoxicity assay of ILA@Lip indicated excellent biocompatibility with normal cells and tissues, but showed high toxicity in hypoxic breast cancer cells. Also, the in vivo tumors treated by the ILA@Lip with laser irradiation were admirably suppressed in both subcutaneous tumor model and orthotopic tumor models. CONCLUSION: Utilizing ILA@Lip is a profound strategy to create an extremely hypoxic tumor microenvironment for higher therapeutic efficacy of hypoxia-activated chemotherapy, which realized collective suppression of tumor growth and has promising potential for clinical translation.

Space and Bond Synergistic Conjugation Controlling Multiple-Aniline NIR-II Absorption for Photoacoustic Imaging Guided Photothermal Therapy.

Currently, clinical photothermal therapy (PTT) is greatly limited by the poor tissue penetration of the excitation light sources in visible (390-780 nm) and first near-infrared (NIR-I, 780-900 nm) window. Herein, based on space and bond synergistic conjugation, a multiple-aniline organic small molecule (TPD), is synthesized for high-efficiency second near-infrared (NIR-II, 900-1700 nm) photoacoustic imaging guided PTT. With the heterogeneity of six nitrogen atoms in TPD, the lone electrons on the nitrogen atom and the π bond orbital on the benzene ring form multielectron conjugations with highly delocalized state, which endowed TPD with strong NIR-II absorption (maximum peak at 925 nm). Besides, according to the single molecular reorganization, the alkyl side chains on TPD make more free space for intramolecular motion to enhance the photothermal conversion ability. Forming TPD nanoparticles (NPs) in J-aggregation, they show a further bathochromic-shifted absorbance (maximum peak at 976 nm) as well as a high photothermal conversion efficiency (66.7%) under NIR-II laser irradiation. In vitro and in vivo experiments demonstrate that TPD NPs can effectively inhibit the growth of tumors without palpable side effects. The study provides a novel NIR-II multiple-aniline structure based on multielectron hyperconjugation, and opens a new design thought for photothermal agents.

NIR absorptive croconic acid/quercetin/CaO2 nanoplatform for tumor calcium overload therapy combined mild photothermal therapy.

With excellent biocompatibility, stable chemical and optical properties, small organic molecules-based agents have always been a research hotspot in cancer photothermal therapy (PTT). In this work, a novel croconic acid-based molecule (CR) was designed and synthesized as an ideal photothermal agent (PTA), which showed abundant near-infrared (NIR) light absorption, high photothermal conversion ability, and excellent photothermal stability. By loading CR and quercetin (Qu) in CaO2, and coated with DSPE-PEG2000, a multifunctional theranostic nanoparticle (CCQ) was successfully prepared for calcium overloading mitochondrial metabolism inhibition synergetic mild PTT. Upon entering tumor microenvironment, CCQ can produce abundant H2O2 and a large amount of calcium ions, which lead to the imbalance of calcium concentration in the internal environment of tumor cells and induced mitochondrial apoptosis. With the existence of Qu, CCQ can effectively inhibit the expression of heat shock proteins (Hsp) during the PTT process, which weaken the heat resistance of tumors, ablate tumors at lower temperature (~45 °C), and reduce the damage to normal tissues. Guided by photoacoustic imaging (PAI), CCQ showed excellent multimodal therapeutic effect of tumors. This study provided a novel CR organic molecule-based theranostic nanoplatform that can be used to treat tumors via calcium overload therapy synergetic PTT at safe temperatures, which has promising potential for the future clinical cancer treatment.

Integrated clinical analysis and data mining assessed the impact of NOX4 on the immune microenvironment and prognosis of pancreatic cancer.

Background: The tumor microenvironment (TME) of pancreatic cancer is complex. which forms forms a microenvironment with high immunosuppression, ischemia and hypoxia, which promotes tumor proliferation and migration, inhibit the anti-tumor immune response. NOX4 plays an important role in tumor microenvironment and has a significant relationship with the occurrence, development and drug resistance of tumor. Methods: Firstly, NOX4 expression in pancreatic cancer tissues under different pathological conditions was detected by applying immunohistochemical staining of tissue microarray (TMA). Transcriptome RNA sequencing data and clinical data of 182 pancreatic cancer samples were downloaded and collated from the UCSC xena database. 986 NOX4-related lncRNAs were filtered by Spearman correlation analysis. prognosis-related NOX4-related lncRNAs and NRlncSig Score were finally obtained by univariate and multivariate Cox regression with Least Absolute Shrinkage and Selection Operator (Lasso) analysis in pancreatic cancer patients. we plotted Kaplan -Meier and time-dependent ROC curves (ROC) to assess the validity in predicting the prognosis of pancreatic cancer. The ssGSEA analysis was applied to explore the immune microenvironment of pancreatic cancer patients as well as to discuss the immune cells and immune status separately. Results: We found that a mature tumor marker, NOX4, play different roles in different clinical subgroups by immunohistochemical analysis and clinical data. Finally, 2 NOX4-related lncRNAs were determined by least absolute shrinkage and selection operator (LASSO) analysis, univariate Cox analysis and multivariate COX analysis. The ROC curve and DCA curve showed that NRS Score had better predictive ability than independent prognosis-related lncRNA and other clinicopathologic indicators. We obtained the relative abundance of 28 infiltrating immune cells by ssGSEA analysis and found a significant positive correlation between the abundance of anti-tumor immune cells and tumor-promoting immune cells in the risk-classified microenvironment. No matter NRS Score or AC092667.2, RP11-349A8.3 was significantly correlated with immune infiltrating cells. Meanwhile, the IC50 of conventional chemotherapeutic agents in high-score group were significantly lower than those in low-score group. Conclusion: As a mature tumor marker, NOX4-related lncRNAs provide new research strategies for prognostic evaluation, molecular mechanism and clinical treatment of pancreatic cancer.

The Ethanolic Extract of Lindera aggregata Modulates Gut Microbiota Dysbiosis and Alleviates Ethanol-Induced Acute Liver Inflammation and Oxidative Stress SIRT1/Nrf2/NF-κB Pathway.

This study is an attempt to evaluate the therapeutic effect of the ethanolic extract of Lindera aggregata on the liver and intestinal microbiota in rats with alcohol-induced liver injury (ALI). Rats were treated with 70 mg probiotics, 1 g/kg, 2 g/kg, and 3 g/kg ethanolic extract of Lindera aggregata, respectively, for 10 days. We found that Lindera aggregata could significantly reduce the biochemical parameters in the serum of ALD rats. Lindera aggregata alleviates oxidative stress and inflammation by upregulating SIRT1 and Nrf2 and downregulating COX2 and NF-κB. The results of 16S rRNA gene sequencing showed that the medium dose of Lindera aggregata had the best effect on the growth of beneficial bacteria. Diversity analysis and LEfSe analysis showed that beneficial bacteria gradually occupied the dominant niche. The relative abundance of potential pathogens in the gut decreased significantly. We demonstrated that the ethanolic extract of Lindera aggregata can alleviate the oxidative stress and inflammation induced by alcohol through the SIRT1/Nrf2/NF-κB pathway and can modulate the disturbance of gut microbiota induced by alcohol intake.