An injectable and thermosensitive hydrogel with nano-aided NIR-II phototherapeutic and chemical effects for periodontal antibacteria and bone regeneration.

Periodontitis is a common public health problem worldwide and an inflammatory disease with irregular defect of alveolar bone caused by periodontal pathogens. Both antibacterial therapy and bone regeneration are of great importance in the treatment of periodontitis. In this study, injectable and thermosensitive hydrogels with 3D networks were used as carriers for controlled release of osteo-inductive agent (BMP-2) and Near Infrared Region-II (NIR-II) phototherapy agents (T8IC nano-particles). T8IC nano-particles were prepared by reprecipitation and acted as photosensitizer under 808 nm laser irradiation. Besides, we promoted photodynamic therapy (PDT) through adding H2O2 to facilitate the antibacterial effect instead of increasing the temperature of photothermal therapy (PTT). Hydrogel + T8IC + Laser + BMP-2 + H2O2 incorporated with mild PTT (45 °C), enhanced PDT and sustained release of BMP-2. It was present with excellent bactericidal effect, osteogenic induction and biosafety both in vitro and in vivo. Besides, immunohistochemistry staining and micro-CT analyses had confirmed that PTT and PDT could promote bone regeneration through alleviating inflammation state. Altogether, this novel approach with synergistic antibacterial effect, anti-inflammation and bone regeneration has a great potential for the treatment of periodontitis in the future.

Efficacy of cataract surgeries performed during blindness prevention programs in Chongqing, China: a multicenter prospective study.

OBJECTIVE: To determine the efficacy of cataract surgeries in blindness prevention programs in Chongqing. METHODS: During February-December 2019, we prospectively enrolled 487 patients (592 eyes) undergoing cataract surgery during blindness prevention programs in 6 Chongqing district/county hospitals (experimental group) and 481 patients (609 eyes) undergoing cataract surgery in the First Affiliated Hospital of Chongqing Medical University (controls). Uncorrected visual acuity (UCVA), refractive status, best corrected visual acuity (BCVA), slit lamp examination, and visual function/quality of life (VF-QOL) questionnaire scores were evaluated preoperatively, and at 1 and 6 months postoperatively. RESULTS: In the experimental group, UCVA, BCVA, and VF-QOL scores at 1 and 6 months were better than the preoperative values (P < 0.05), but lower than the control-group values (P < 0.05). Rates of good UCVA and BCVA outcomes (≤ 0.5 logMAR) in the experimental group were 76.2% and 87.6%, respectively, at 1 month and 68.9% and 83.1%, respectively, at 6 months. Most eyes in the experimental (82.1%) and control (89.5%) groups had refractive errors within ± 1 D at 1 month. At 6 months, posterior capsule opacification (PCO) was more common in the experimental group (20.9% vs. 15.0%, P < 0.05). At 6 months, the main causes of visual impairment (UCVA > 0.5 logMAR) in the experimental group were uncorrected refractive errors (33.0%), PCO (29.5%), and fundus diseases (33.9%). CONCLUSION: Cataract surgeries in blindness prevention programs in Chongqing significantly improved visual acuity, VF, and QOL, but underperformed compared to surgeries in the tertiary teaching hospital.

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.

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.

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.

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.

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.

Organic Near-Infrared-II Nanophotosensitizer for Safe Cancer Phototheranostics and Improving Immune Microenvironment against Metastatic Tumor.

Current tumor immunotherapy has excellent application prospects compared with traditional radiotherapy and chemotherapy, but there are still limitations, such as considerable side effects. This problem can be partially solved by treating the local tumor to induce antitumor immunity. In our study, a novel organic photosensitizer Y8 was used to synthesize nanoparticles (Y8 NPs) via a simple nanoprecipitation method. Further investigation indicated the practical photodynamic and photothermal effects of Y8 NPs with 808 nm laser irradiation. Because of its long-wavelength absorption, Y8 NPs also have excellent imaging effects near-infrared-II region. In metastatic tumor-bearing murine models, Y8 NPs can effectively induce phototherapy, suppressing the growth of both primary and metastatic tumors without apparent systemic toxicity through local photodynamic and photothermal therapy synergistic enhancement of antitumor immunity. This study offers a promising therapeutic strategy for synergetic phototherapy and immunotherapy in tumor treatment.

Peroxidase-mimicking evodiamine/indocyanine green nanoliposomes for multimodal imaging-guided theranostics for oral squamous cell carcinoma.

Here, evodiamine (EVO) and the photosensitizer indocyanine green (ICG) were integrated into a liposomal nanoplatform for noninvasive diagnostic imaging and combinatorial therapy against oral squamous cell carcinoma (OSCC). EVO, as an active component extracted from traditional Chinese medicine, not only functioned as an antitumor chemotherapeutic agent but was also capable of 68Ga-chelation, thus working as a contrast agent for positron emission tomography/computed tomography (PET/CT) imaging. Moreover, EVO could exhibit peroxidase-like catalytic activity, converting endogenous tumor H2O2 into cytotoxic reactive oxygen species (ROS), enabling Chemo catalytic therapy beyond the well-known chemotherapy effect of EVO. As proven by in vitro and in vivo experiments, guided by optical imaging and PET/CT imaging, we show that the theragnostic liposomes have a significant inhibiting effect on in situ tongue tumor through photodynamic therapy combined with chemodynamic chemotherapy.

Fused-Ring Small-Molecule-Based Bathochromic Nano-agents for Tumor NIR-II Fluorescence Imaging-Guided Photothermal/Photodynamic Therapy.

Optical imaging in the second near-infrared (NIR-II) windows reduces much more autofluorescence and photon scattering from biological tissues and allows further tissue penetration depth and superior spatial resolution in living bodies. Herein, a fused-ring 2,2'-((2Z,2'Z)-((12,13-bis(2-ethylhexyl)-3,9-diundecyl-12,13-dihydro-[1,2,5]thiadiazolo[3,4-e]thieno[2,″3″:4',5']thieno[2',3':4,5]pyrrolo[3,2-g]thieno[2',3':4,5]thieno[3,2-b]indole-2,10-diyl)bis(methanylylidene))bis(5,6-difluoro-3-oxo-2,3-dihydro-1H-indene-2,1-diylidene))dimalononitrile (TPBT) molecule was explored as a multifunctional tumor theranostic reagent for photothermal/photodynamic therapy guided by NIR-II imaging. The TPBT molecule has an electron-deficient core with a ladder-type multi-fused ring and shows a narrow band gap that can enhance the near-infrared absorption. The J-aggregative TPBT NPs were formed by nanoprecipitation with great bathochromic shift in absorption and emission spectra, which endows them with ideal fluorescence imaging ability in the NIR-II region. Moreover, TPBT NPs present both higher photothermal conversion efficiency (∼36.5%) and effective ROS generation ability, making them excellent candidate for cancer photothermal/photodynamic therapy. Moreover, the biocompatible TPBT NPs can effectively passively target tumor sites due to their enhanced permeability and retention effect for more precision treatment. Thus, TPBT NPs as a multifunctional phototheranostic agent in the NIR-II region present promising potential in clinical cancer NIR-II imaging-guided phototherapy.

A population-based competing risk survival analysis of patients with salivary duct carcinoma.

BACKGROUND: Salivary duct carcinoma (SDC) is a rare malignancy with high risk of local recurrence and distant metastases of the salivary gland. This study was designed to summarize the clinical and pathological features and to further evaluate them as potential prognostic factors for SDC in the salivary gland. METHODS: Clinical data of 266 patients diagnosed with SDC between 2004 and 2015 were collected from the Surveillance, Epidemiology, and End Results (SEER) database. The prognostic factors affecting overall survival (OS) and cancer-specific survival (CSS) were determined by Kaplan-Meier analyses and Cox proportional hazards model. The nomogram was established to predict OS and CSS for SDC. The predictive accuracy of the nomograms was measured by concordance index (C-index). RESULTS: The 3- and 5-year OS of SDC patients were 67.41% and 47.86%, while the 3- and 5-year CSS were 84.6% and 60.7%, respectively. The primary site, T stage and M stage were identified as independent prognostic factors for OS by the multivariate analysis, whereas N stage, M stage, the presence of multiple primary carcinomas and the treatment modalities were identified as independent prognostic factors for CSS. The C-index values of the prognostic nomogram based the risk factors affecting SDC OS and CSS were 0.703 (0.646-0.760) and 0.771 (0.691-0.851), respectively. CONCLUSIONS: SDC is an aggressive malignancy with a high proportion of advanced stage and lymph node metastases. Patients with increasing age, submandibular gland malignancy, advanced T stage, advanced N stage, advanced M stage, high lymph node ratio (LNR) and the presence of multiple primary carcinomas tend to have unfavorable outcomes. Radiotherapy or chemotherapy improve CSS remarkably. These factors will aid in effective therapeutic treatment modalities for SDC.

Hypoxia-Targeting Multifunctional Nanoparticles for Sensitized Chemotherapy and Phototherapy in Head and Neck Squamous Cell Carcinoma.

PURPOSE: Chemotherapy in head and neck squamous cell carcinoma (HNSCC) has many systemic side effects, as well as hypoxia-induced chemoresistance. To reduce side effects and enhance chemosensitivity are urgently needed. METHODS: We synthesized a drug delivery system (named CECMa NPs) based on cisplatin (CDDP) and metformin (chemotherapeutic sensitizer), of which chlorin e6 (Ce6) and polyethylene glycol diamine (PEG) were synthesized as the shell, an anti-LDLR antibody (which can target to hypoxic tumor cells) was modified on the surface to achieve tumor targeting. RESULTS: The NPs possessed a great synergistic effect of chemotherapy and phototherapy. After laser stimulation, both CDDP and metformin can be released in situ to achieve anti-tumor effects. Meanwhile, PDT and PTT triggered by a laser have anticancer effects. Furthermore, compared with free cisplatin, CECMa exhibits less systemic toxicity with laser irradiation in the xenograft mouse tumor model. CONCLUSION: CECMa effectively destroyed the tumors via hypoxia targeting multimodal therapy both in vitro and in vivo, thereby providing a novel strategy for targeting head and neck squamous cell carcinoma.

Metformin enhances gefitinib efficacy by interfering with interactions between tumor-associated macrophages and head and neck squamous cell carcinoma cells.

BACKGROUND: Tumor-associated macrophages (TAMs) play an important role in drug resistance in many tumors, including head and neck squamous cell carcinoma (HNSCC). However, how TAMs interact with HNSCC cells to induce drug resistance, especially under hypoxic conditions, is unclear. In this study, we investigated the mechanism of TAM-induced gefitinib resistance in HNSCC cells and sought for novel therapeutic strategies. METHODS: The effects of hypoxia-treated HNSCC cells on the migration and polarization of macrophages were analyzed. Recombinant cytokine proteins and neutralizing antibodies were used as controls. In addition, we assessed the cytotoxic effects of gefitinib on HNSCC cells treated with M2-type macrophage conditioned medium, and carried out a cytokine antibody array analysis, thereby revealing the key factor CCL15. The relationship between serum CCL15 expression levels and prognosis in HNSCC patients was analyzed. In addition, we performed bioinformatic analyses to pursue the mechanisms of CCL15-induced gefitinib resistance. Finally, metformin was used to evaluate the sensitizing effects of gefitinib treatment on HNSCC cells in vitro and in vivo. RESULTS: We found that HNSCC cells recruited macrophages by secreting VEGF and polarized the macrophages to the M2 phenotype through IL-6. Conversely, we found that M2-type TAMs promoted HNSCC cell resistance to gefitinib through paracrine CCL15 signaling. The serum CCL15 levels in HNSCC patients showed a significant correlation with patient prognosis. Furthermore, we found that M2-type TAMs could suppress the sensitivity of HNSCC cells to gefitinib through the CCL15-CCR1-NF-κB pathway. In addition, we found that metformin not only inhibited CCL15 expression in M2-type TAMs enhanced by hypoxia, but also suppressed CCR1 surface expression in HNSCC cells. Encouragingly, we found that metformin sensitized HNSCC cells to gefitinib treatment in vitro and in vivo. CONCLUSIONS: Based on our data we conclude that we have identified a novel interaction between M2-type TAMs and HNSCC cells that contributes to gefitinib resistance. We also found that metformin inhibited the cross-talk between macrophages and tumor cells, thereby eliciting therapeutic effects both in vitro and in vivo.