Multifunctional photodynamic/photothermal nano-agents for the treatment of oral leukoplakia.

Oral leukoplakia (OLK) has gained extensive attention because of the potential risk for malignant transformation. Photosensitizers (PSs) played an indispensable role in the photodynamic therapy (PDT) of OLK, but the poor light sensitivity greatly hampered its clinical application. Herein, a novel organic photosensitive ITIC-Th nanoparticles (ITIC-Th NPs) were developed for OLK photodynamic/photothermal therapy (PTT). ITIC-Th NPs present both high photothermal conversion efficiency (~ 38%) and suitable reactive oxygen species (ROS) generation ability under 660 nm laser irradiation, making them possess excellent PDT and PTT capability. In 4-nitroquinoline 1-oxide (4NQO)-induced oral precancerous animal models, ITIC-Th NPs effectively suppress the OLK's cancerization without apparent topical or systemic toxicity in vivo. This study offers a promising therapeutic strategy for PDT and PTT in OLK treatment, and this study is the first interdisciplinary research in the field of multimodal therapy for OLK.

Thrombus-targeted nano-agents for NIR-II diagnostic fluorescence imaging-guided flap thromboembolism multi-model therapy.

In oral and maxillofacial surgery, flap repair is essential to the quality of postoperative life. Still, thrombosis is fatal for the survival of the flaps. Besides, some postoperative thrombotic diseases, such as pulmonary embolism, also intimidate patients' life. The traditional diagnostic methods are still limited by a large amount of hardware and suffer from inconvenience, delay, and subjectivity. Moreover, the treatments mainly rely upon thrombolytics, such as urokinase (UK) plasminogen activator, which may cause bleeding risk, especially intracerebral hemorrhage. Herein, a kind of poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) containing a first near-infrared window (NIR-I) phototheranostic agent Y8 and urokinase plasminogen activator (UK) as the core, and modified with the fibrin-targeting peptide Gly-Pro-Arg-Pro-Pro (GPRPP) were developed for the flap and postoperative thromboembolism treatment (named GPRPP-Y8U@P). The conjugated molecule Y8 endows GPRPP-Y8U@P with the capacity of NIR-II imaging and excellent photothermal/photodynamic therapeutic effects. In vivo experiments demonstrated that GPRPP-Y8U@P could quickly locate thrombus by NIR-II fluorescence imaging, and semi-quantitative analysis of the embolized blood vessels' paraffin section verified its thrombolytic efficiency. Additionally, the urokinase trapped in the NPs would not result in nonspecific bleeding, tremendously improving physical security and curative effects with minimizing side effects. Overall, the advantages of GPRPP-Y8U@P, such as precise localization of the thrombus, thrombus ablation in the site, and mild side effects, demonstrated the attractiveness of this approach for effective clinical monitoring of thrombus therapy.

A small molecule protects mitochondrial integrity by inhibiting mTOR activity.

Apoptosis activation by cytochrome c release from mitochondria to cytosol is a normal cellular response to mitochondrial damage. Using cellular apoptosis assay, we have found small-molecule apoptosis inhibitors that protect cells from mitochondrial damage. Previously, we reported the discovery of a small molecule, Compound A, which blocks dopaminergic neuron death in a rat model of Parkinson's disease through targeting succinate dehydrogenase subunit B (SDHB) of complex II to protect the integrity of the mitochondrial respiratory chain. Here, we report a small molecule, Compound R6, which saves cells from apoptosis via mammalian target of rapamycin (mTOR)-mediated induction of autophagy. Additionally, we show that Compound R6 protects mitochondrial integrity and respiration after induction of the intrinsic apoptosis pathway. Encouragingly, and supporting the potential further application of Compound R6 as a tool for basic and medicinal research, a pharmacokinetics (PK) profiling study showed that Compound R6 is metabolically stable and can pass the blood-brain barrier. Moreover, Compound R6 accumulates in the brain of test animals via intravenous and intraperitoneal administration. Finally, we found that Compound R6 confers significant neuroprotective effects on a rat cerebral ischemia/reperfusion model, demonstrating its potential as a promising drug candidate for neurodegenerative diseases.

Total syntheses of (-)-macrocalyxoformins A and B and (-)-ludongnin C.

The complex and diverse molecular architectures along with broad biological activities of ent-kauranoids natural products make them an excellent testing ground for the invention of synthetic methods and strategies. Recent efforts notwithstanding, synthetic access to the highly oxidized enmein-type ent-kauranoids still presents considerable challenges to synthetic chemists. Here, we report the enantioselective total syntheses of C-19 oxygenated enmein-type ent-kauranoids, including (-)-macrocalyxoformins A and B and (-)-ludongnin C, along with discussion and study of synthetic strategies. The enabling feature in our synthesis is a devised Ni-catalyzed decarboxylative cyclization/radical-polar crossover/C-acylation cascade that forges a THF ring concomitantly with the ß-keto ester group. Mechanistic studies reveal that the C-acylation process in this cascade reaction is achieved through a carboxylation followed by an in situ esterification. Biological evaluation of these synthetic natural products reveals the indispensable role of the ketone on the D ring in their anti-tumor efficacy.

Development and Validation of a Prognostic Signature Based on the Lysine Crotonylation Regulators in Head and Neck Squamous Cell Carcinoma.

Background: Lysine crotonylation (Kcr) is a newly identified posttranslational modification type regulated by various enzymes and coenzymes, including lysine crotonyltransferase, lysine decrotonylase, and binding proteins. However, the role of Kcr regulators in head and neck squamous cell carcinoma (HNSCC) remains unknown. The aim of this study was to establish and validate a Kcr-related prognostic signature of HNSCC and to assess the clinical predictive value of this signature. Methods: The mRNA expression profiles and clinicopathological data from The Cancer Genome Atlas (TCGA) database were downloaded to explore the clinical significance and prognostic value of these regulators in HNSCC. The least absolute shrinkage and selection operator (LASSO) Cox regression model was used to generate the Kcr-related prognostic signature for HNSCC. Subsequently, the GSE65858 dataset from the Gene Expression Omnibus (GEO) database was used to validate the signature. The prognostic value of the signature was evaluated using the Kaplan-Meier survival, receiver operating characteristic (ROC) curve, and univariate and multivariate Cox regression analyses. Results: We established a nine-gene risk signature associated with the prognosis of HNSCC based on Kcr regulators. High-risk patients demonstrated significantly poorer overall survival (OS) than low-risk patients in the training (TCGA) and validation (GEO) datasets. Then, the time-dependent receiver operating characteristic (ROC) curve analysis showed that the nine-gene risk signature was more accurate for predicting the 5-year OS than other clinical parameters, including age, gender, T stage, N stage, and histologic grade in the TCGA and GEO datasets. Moreover, the Cox regression analysis showed that the constructed risk signature was an independent risk factor for HNSCC. Conclusion: Our study identified and validated a nine-gene signature for HNSCC based on Kcr regulators. These results might contribute to prognosis stratification and treatment escalation for HNSCC patients.

Rhythm Mild-Temperature Photothermal Therapy Enhancing Immunogenic Cell Death Response in Oral Squamous Cell Carcinoma.

The low antitumor efficiency and unexpected thermo-tolerance activation of mild-temperature photothermal therapy (mPTT) severely impede the therapeutic efficacy, thereby the implementation of reasonable mPTT procedure to improve antitumor efficiency is of great significance for clinical transformation. Herein, a rhythm mPTT with organic photothermal nanoparticles (PBDB-T NPs) is demonstrated, synergistically increasing tumor elimination and intense immunogenic cancer cell death (ICD) to elicit tumor-specific immune responses for tumor treatment. Specifically, PBDB-T NPs are characterized by favorable biocompatibility, excellent and controllable photothermal properties, exhibit the properties of noninvasive diagnostic imaging, and effective mPTT against oral squamous cell carcinoma (OSCC). Encouragingly, a temperature-dependent release of damage-associated molecular patterns (DAMPs) is discovered during the mPTT-induced ICD. Meanwhile, orchestrated rhythm mPTT referring to radiotherapy procedure amplifies and balances antitumor efficiency and abundant DAMPs generation to gain optimal immune activation within clinical-recommended hyperthermia temperature compared with conventional PTT. The in vitro and in vivo results show that the rhythm mPTT unites the killing effect and ICD induction, generating strong mPTT efficacy and active tumor-specific adaptive immune responses. The study offers a promising strategy and a new opportunity for the clinical application of mPTT.

Cholesterol Metabolism Modulation Nanoplatform Improves Photo-Immunotherapeutic Effect in Oral Squamous Cell Carcinoma.

Impressive results in cancer treatment have been obtained through immunotherapy. However, abnormally high cholesterol metabolism in the tumor microenvironment (TME) leads to poor immunogenicity or even immunosuppression, which dramatically reduces the clinical response of patients with oral squamous cell carcinoma (OSCC) to immunotherapy. In this study, a cholesterol-modulating nanoplatform (PYT NP) is developed to restore the normal immune microenvironment, significantly inhibiting SQLE (an essential gene for cholesterol biosynthesis in tumor cells) by releasing terbinafine, thereby reducing cholesterol in the TME and suppressing tumor cell proliferation. In addition, the nanoplatform is equipped with a second near-infrared (NIR-II) photosensitizer, Y8, which triggers immunogenic cell death of tumor cells, thereby promoting intra-tumor infiltration and immune activation via the production of damage-associated molecular patterns for photoimmunotherapy. PYT NPs show great promise in stimulating strong cholesterol-modulating anticancer immunity combined with photoimmunotherapy, opening up a new avenue for sensitized OSCC immunotherapy.

Novel semiconducting nano-agents incorporating tirapazamine for imaging guided synergistic cancer hypoxia activated photo-chemotherapy.

For cancer treatment, the traditional monotherapy has the problems of low drug utilization rate, poor efficacy and easy recurrence of the cancer. Herein, nanoparticles (NPs) based on a novel semiconducting molecule (ITTC) are developed with excellent photostability, high photothermal conversion efficiency and good 1O2 generation ability. The chemotherapy of the hypoxia-activated prodrug tirapazamine (TPZ) was improved accordingly after oxygen consumption by the photodynamic therapy of ITTC NPs. Additionally, the metabolic process of ITTC NPs in vivo could be monitored in real time for fluorescence imaging guided phototherapy, which presented great passive targeting ability to the tumor site. Remarkably, both in vitro and in vivo experiments demonstrated that the combination of ITTC NPs and TPZ presented excellent synergistic tumor ablation through photothermal therapy, photodynamic therapy and hypoxia-activated chemotherapy with great potential for clinical applications in the future.

Novel NIR-II semiconducting molecule incorporating sorafenib for imaging guided synergetic cancer phototherapy and anti-angiogenic therapy.

Tumor tissues are not only independent of cancer cells, but also tumor blood vessels. Thus, targeting the tumor blood vessels is as important as targeting the tumor for cancer treatment. Herein, an organic semiconducting molecule named T8IC is developed for the potential phototeranostics in the second near-infrared window (NIR-II, 1000-1700 nm). The T8IC molecule with an electronic-rich core and electron-deficient side edge shows a typical semiconducting structure, which makes the bandgap narrow. With the addition of anti-angiogenic agent sorafenib into T8IC, TS nanoparticles (NPs) were formed by nanoprecipitation with synergetic anti-angiogenic and phototheranostic effects. Compared to the molecular state, the J-aggregative TS NPs were formed with great bathochromic-shifts in both the absorption spectrum (maximum increased from 755 nm to 826 nm) and the emission spectrum (maximum increased from 840 nm to 1030 nm), which endow them with the ideal deep tumor NIR-II fluorescence imaging ability. Besides, TS NPs present both high photothermal conversion efficiency (∼32.47%) and good ROS generation ability, making them possess excellent cancer phototherapy capability. Guided by NIR-II fluorescence imaging, the tumor blood vessels can be cut off via sorafenib and cancer cells can be killed via T8IC simultaneously, making TS NPs show promising potential for the synergistic therapeutic effect in clinical applications.