Cancer Radiosensitization Nanoagent to Activate cGAS-STING Pathway for Molecular Imaging Guided Synergistic Radio/Chemo/Immunotherapy.

Immunotherapy has emerged as an innovative strategy with the potential to improve outcomes in cancer patients. Recent evidence indicates that radiation-induced DNA damage can activate the cyclic-GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway to enhance the antitumor immune response. Even so, only a small fraction of patients currently benefits from radioimmunotherapy due to the radioresistance and the inadequate activation of the cGAS-STING pathway. Herein, this work integrates hafnium oxide (HfO2) nanoparticles (radiosensitizer) and 7-Ethyl-10-hydroxycamptothecin (SN38, chemotherapy drug, STING agonist) into a polydopamine (PDA)-coated core-shell nanoplatform (HfO2@PDA/Fe/SN38) to achieve synergistic chemoradiotherapy and immunotherapy. The co-delivery of HfO2/SN38 greatly enhances radiotherapy efficacy by effectively activating the cGAS-STING pathway, which then triggers dendritic cells maturation and CD8+ T cells recruitment. Consequently, the growth of both primary and abscopal tumors in tumor-bearing mice is efficiently inhibited. Moreover, the HfO2@PDA/Fe/SN38 complexes exhibit favorable magnetic resonance imaging (MRI)/photoacoustic (PA) bimodal molecular imaging properties. In summary, these developed multifunctional complexes have the potential to intensify immune activation to realize simultaneous cancer Radio/Chemo/Immunotherapy for clinical translation.

Clinical study of extrahepatic biliary adenoma.

BACKGROUND: Biliary adenomas that occur in the extrahepatic biliary tree are rare. It is difficult to distinguish it from cholangiocarcinoma or cholangiolithiasis by various imaging examinations, and it is very easy to be misdiagnosed. AIM: To evaluate the cumulative experiences including clinical characteristics and treatments of nine patients diagnosed with extrahepatic biliary adenoma admitted to the First Affiliated Hospital of Xi'an Jiaotong University from 2016 to 2022. METHODS: A total of nine patients were included in our study. The laboratory examinations, disease diagnosis, therapy and pathological characteristics, and follow-up of every patient were evaluated. RESULTS: Our cohort consisted of six females and three males with an average diagnosis age of 65.1 years (range 46-87). Six extrahepatic biliary adenomas were located in the common bile ducts and three in the hepatic duct. On initial presentation, all of the patients have symptom of biliary origin, including obstructive jaundice (4/9, 44.4%), abdominal pain (6/9, 66.7%), and fever (3/9, 33.3%). Preoperative imaging examination considered bile duct carcinoma in 6 cases and bile duct calculi in 3 cases. All the patients received surgical treatment and were confirmed by pathology as biliary adenoma. The symptoms improved significantly in all 9 patients after surgery. Seven of nine patients recovered well at follow-up without tumor recurrence. One patient died 2 mo after the surgery due to heart failure. One patient developed jaundice again 8 mo after surgery, underwent endoscopic retrograde cholangiopancreatography and biliary stent placement. CONCLUSION: Benign extrahepatic biliary tumors are rare and difficult to diagnosis preoperatively. Intraoperative choledochoscopy and timely biopsy may offer great advantages.

Proton pump inhibitor-enhanced nanocatalytic ferroptosis induction for stimuli-responsive dual-modal molecular imaging guided cancer radiosensitization.

Although radiotherapeutic efficiency has been revealed to be positively correlated with ferroptosis, the neutral/alkaline cytoplasm pH value of tumor cells remains an intrinsic challenge for efficient Fenton/Fenton-like reaction-based ferroptosis induction. Herein, PEGylated hollow mesoporous organosilica nanotheranostics (HMON)-GOx@MnO2 nanoparticles (HGMP NPs) were designed as a ferroptosis inducer, which could specifically release Mn2+ in tumor cells to activate the Fenton-like reaction for ferroptosis induction. Proton pump inhibitors (PPIs) were synchronously administered for cytoplasm pH level regulation by inhibiting V-H+-ATPases activity, enhancing Fenton-like reaction-based ferroptosis induction. Moreover, reactive oxygen species production was facilitated via the glucose oxidase triggered cascade catalytic reaction by utilizing intracellular ß-D-glucose for H2O2 self-supply and generation of additional cytoplasm H+. The PPI enhanced ferroptosis inducing nanosystem effectively inhibited tumor growth both in vitro and in vivo for tumor-specific ferroptosis induction and radiotherapy sensitization, suggesting that PPI administration could be an efficient adjuvant to reinforce Fenton/Fenton-like reaction-based ferroptosis induction for radiosensitization. STATEMENT OF SIGNIFICANCE: The cytoplasm pH value of tumor cells is typically neutral to alkaline, which is higher than that of the Fenton/Fenton-like reaction desired acidic environments, hindering its efficiency. In this study, PEGylated hollow mesoporous organosilica nanotheranostics (HMON)-GOx@MnO2 nanoparticles were synthesized as a ferroptosis inducer, which could specifically release Mn2+ via depleting glutathione and then activate the Fenton-like reaction in the tumor microenvironment. The glucose oxidase was applied for H2O2 self-supply and addition of cytoplasm H+ to further boost the Fenton-like reaction. We found that proton pump inhibitors (PPIs) increased intracellular acidification by inhibiting the activity of V-H+-ATPases to enhance the Fenton reaction-based ferroptosis induction, suggesting PPIs administration could be a feasible strategy to reinforce ferroptosis induction for radiosensitization.

Rapid synthesis of 'yolk-shell'-like nanosystem for MR molecular and chemo-radio sensitization.

Though amounts of attempts about nanomedicine for chemo-radiotherapy have been made, more efficient strategies for chemo-radio therapy enhancement still need to be studied and perfected. Herein, a 'yolk-shell'-like nanostructure (Bi2S3@mBixMnyOz nanosystem) was facilely constructed by directly using radiosensitizer Bi2S3 nanorods (NRs) as a partial sacrificial template. Then, the chemotherapeutic drug doxorubicin (DOX) loaded PEGylated Bi2S3@mBixMnyOz nanosystem (PBmB-DOX) was constructed, which could realize tumor microenvironment (TME)-responsive drug release for chemotherapy sensitivity enhancement. And the Bi2S3 NRs core could deposit more radiant energy to improve the radiotherapy sensitivity. Meanwhile, the compounds shell could catalyze H2O2 to generate O2, so as to alleviate tumor hypoxia for further chemo-radio therapy sensitization enhancement. More importantly, ferroptosis was participated in the process of PBmB-induced therapy via glutathione (GSH)-depletion mediated GPX4 inactivation, together with Mn ions induced chemodynamic therapy (Fenton-like reaction), which made additional contributions to increase the therapeutic efficacy. Last but not least, the GSH-stimulated degradation of compounds shell could contribute to self-enhanced T1-MR imaging activation, which allowed on-demand tumor diagnosis. In this work, the synthetic strategy that directly using Bi2S3 NRs as a partial sacrificial template to rapidly synthesize the 'yolk-shell'-like nanostructure for nanomedical application has rarely been reported before. And the in vitro and in vivo results suggest that our 'yolk-shell'-like PBmB-DOX nanosystem holds great promise to regulate TME for tumor-specific diagnosis and synergistic therapy.

Functionalized Au@Cu-Sb-S Nanoparticles for Spectral CT/Photoacoustic Imaging-Guided Synergetic Photo-Radiotherapy in Breast Cancer.

BACKGROUND: Radiotherapy (RT) is clinically well-established cancer treatment. However, radioresistance remains a significant issue associated with failure of RT. Phototherapy-induced radiosensitization has recently attracted attention in translational cancer research. METHODS: Cu-Sb-S nanoparticles (NPs) coated with ultra-small Au nanocrystals (Au@Cu-Sb-S) were synthesized and characterized. The biosafety profiles, absorption of near-infrared (NIR) laser and radiation-enhancing effect of the NPs were evaluated. In vitro and in vivo spectral computed tomography (CT) imaging and photoacoustic (PA) imaging were performed in 4T1 breast cancer-bearing mice. The synergetic radio-phototherapy was assessed by in vivo tumor inhibition studies. RESULTS: Au@Cu-Sb-S NPs were prepared by in situ growth of Au NCs on the surface of Cu-Sb-S NPs. The cell viability experiments showed that the combination of Au@Cu-Sb-S+NIR+RT was significantly more cytotoxic to tumor cells than the other treatments at concentrations above 25 ppm Sb. In vitro and in vivo spectral CT imaging demonstrated that the X-ray attenuation ability of Au@Cu-Sb-S NPs was superior to that of the clinically used Iodine, particularly at lower KeV levels. Au@Cu-Sb-S NPs showed a concentration-dependent and remarkable PA signal brightening effect. In vivo tumor inhibition studies showed that the prepared Au@Cu-Sb-S NPs significantly suppressed tumor growth in 4T1 breast cancer-bearing mice treated with NIR laser irradiation and an intermediate X-ray dose (4 Gy). CONCLUSION: These results indicate that Au@Cu-Sb-S integrated with spectral CT, PA imaging, and phototherapy-enhanced radiosensitization is a promising multifunctional theranostic nanoplatform for clinical applications.

Mitochondria-targeted aggregation-induced emission active near infrared fluorescent probe for real-time imaging.

Mitochondria are essential organelles in eukaryotic cells and act as the energy powerhouse and biosynthetic compartment. Fluorescent dyes are widely used powerful molecular tools for analytical sensing and optical imaging. Low photostability, short excitation and emission wavelengths, and aggregation-induced quenching effects restrict the application of traditional commercial mitochondrial fluorescent probes for bioimaging. In this study, using rhodamine as the acceptor and phenothiazine as the donor, we synthesized a novel mitochondrial-targeted near infrared (NIR) fluorescent probe, MIT-PZR. Due to low cytotoxicity, great photostability and high specificity for mitochondria targeting, MIT-PZR has enormous potential for cell imaging. Furthermore, with a sizeable Stokes shift (emission peak at 705 nm), MIT-PZR penetrated tissues providing stable red fluorescence for imaging in vivo. The histological assessment of various tissues after treatment with MIT-PZR indicated that it has good biocompatibility. Thus, MIT-PZR is a promising mitochondrial NIR fluorescent probe for future application in clinical diagnosis and modern biological research.

Multifunctional NIR-responsive poly(vinylpyrrolidone)-Cu-Sb-S nanotheranostic agent for photoacoustic imaging and photothermal/photodynamic therapy.

Ternary copper-based chalcogenide nanomaterials have become rather attractive due to the near-infrared (NIR) response in cancer theranostic fields. However, it is still challenging to further improve the theranostic efficiency of these nanomaterials. Herein, Cu-Sb-S nanoparticles (NPs) around 24 nm are synthesized facilely and functionalized with poly(vinylpyrrolidone) (PVP). Under the NIR irradiation, the resultant PVP-Cu-Sb-S NPs exhibit a relatively high photothermal conversion efficiency of 53.16% and a simultaneous reactive oxygen species (ROS) generation effect. Due to these outstanding photothermal/photodynamic effects, excellent tumor ablation results can be achieved by the combination of PVP-Cu-Sb-S NPs and 808 nm NIR laser treatments without obvious side effect. In addition, they show remarkable contrast enhancement according to in vitro and in vivo photoacoustic (PA) imaging. These PVP-Cu-Sb-S NPs could be served as a multifunctional nanotheranostic agent for PA imaging, photothermal/photodynamic cancer therapy. STATEMENT OF SIGNIFICANCE: Highly theranostic efficiency ternary copper-based chalcogenide nanomaterials has not been fully developed yet. Herein we report the PVP-Cu-Sb-S nanoparticles (NPs) with relatively high photothermal efficiency, simultaneous reactive oxygen species generation effect and photoacoustic imaging capability. The photothermal conversion efficiency of PVP-Cu-Sb-S NPs is higher than most of copper-based chalcogenide nanomaterials reported before. These findings provide a new kind of ternary copper-based chalcogenide with an enhanced theranostic effect, which could be served as a promising multifunctional nanotheranostic agent in the field of biomedical application.

Non-invasive monitoring of in vivo hydrogel degradation and cartilage regeneration by multiparametric MR imaging.

Numerous biodegradable hydrogels for cartilage regeneration have been widely used in the field of tissue engineering. However, to non-invasively monitor hydrogel degradation and efficiently evaluate cartilage restoration in situ is still challenging. Methods: A ultrasmall superparamagnetic iron oxide (USPIO)-labeled cellulose nanocrystal (CNC)/silk fibroin (SF)-blended hydrogel system was developed to monitor hydrogel degradation during cartilage regeneration. The physicochemical characterization and biocompatibility of the hydrogel were evaluated in vitro. The in vivo hydrogel degradation and cartilage regeneration of different implants were assessed using multiparametric magnetic resonance imaging (MRI) and further confirmed by histological analysis in a rabbit cartilage defect model for 3 months. Results: USPIO-labeled hydrogels showed sufficient MR contrast enhancement and retained stability without loss of the relaxation rate. Neither the mechanical properties of the hydrogels nor the proliferation of bone-marrow mesenchymal stem cells (BMSCs) were affected by USPIO labeling in vitro. CNC/SF hydrogels with BMSCs degraded more quickly than the acellular hydrogels as reflected by the MR relaxation rate trends in vivo. The morphology of neocartilage was noninvasively visualized by the three-dimensional water-selective cartilage MRI scan sequence, and the cartilage repair was further demonstrated by macroscopic and histological observations. Conclusion: This USPIO-labeled CNC/SF hydrogel system provides a new perspective on image-guided tissue engineering for cartilage regeneration.

Glucose functionalized carbon quantum dot containing organic radical for optical/MR dual-modality bioimaging.

The organic paramagnetic compounds nitroxides have great potential as magnetic resonance imaging (MRI) contrast agents. Herein, we report the synthesis and characterization of glucose modified carbon quantum dot containing 2,2,6,6-tetramethyl-piperidinooxy (TEMPO) for targeted bimodal MR/optical imaging of tumor cells. CQD-TEMPO-Glu shows the greatest potentials for bioimaging applications in view of low cytotoxicity, good biocompatibility, green fluorescence emission and high T1 relaxivities. The in vitro MR and optical imaging results confirm enhanced cellular internalization of CQD-TEMPO-Glu in cancer cells through GLUT mediated endocytosis. These results confirm that CQD-TEMPO-Glu is expected to be widely exploited as dual-modal contrast for cancer imaging.

Conjugated Polymer Containing Organic Radical for Optical/MR Dual-Modality Bioimaging.

Optical/MRI bimodal probes have attracted much attention due to palmary soft tissue resolution and high imaging sensitivity. In this study, poly[fluorene-co-alt-p-phenylene] containing organic radical (PFP-TEMPO+) is successfully developed for optical and MRI dual-modality bioimaging. PFP-TEMPO+ displays advanced properties such as fluorescence emission, high photostablilty, reasonable T1 relaxation effect, low cytotoxicity, and good biocompatibility. Moreover, the ability of PFP-TEMPO+ for tumor tissues imaging confirms that it could be used as an optical and MRI imaging probe for in vivo imaging. The results of the present work disclose the potential applications of PFP-TEMPO+ as an optical and MRI contrast agent.

Gastrin-releasing peptide receptor-targeted gadolinium oxide-based multifunctional nanoparticles for dual magnetic resonance/fluorescent molecular imaging of prostate cancer.

Bombesin (BBN), an analog of gastrin-releasing peptide (GRP), specifically binds to GRP receptors, which are overexpressed in human prostate cancer (PC). Here, we synthesized a BBN-modified gadolinium oxide (Gd2O3) nanoprobe containing fluorescein (Gd2O3-5(6)-carboxyfluorescein [FI]-polyethylene glycol [PEG]-BBN) for targeted magnetic resonance (MR)/optical dual-modality imaging of PC. The Gd2O3-FI-PEG-BBN nanoparticles exhibited a relatively uniform particle size with an average diameter of 52.3 nm and spherical morphology as depicted by transmission electron microscopy. The longitudinal relaxivity (r1) of Gd2O3-FI-PEG-BBN (r1 =4.23 mM-1s-1) is comparable to that of clinically used Magnevist (Gd-DTPA). Fluorescence microscopy and in vitro cellular MRI demonstrated GRP receptor-specific and enhanced cellular uptake of the Gd2O3-FI-PEG-BBN in PC-3 tumor cells. Moreover, Gd2O3-FI-PEG-BBN showed more remarkable contrast enhancement than the corresponding nontargeted Gd2O3-FI-PEG according to in vivo MRI and fluorescent imaging. Tumor immunohistochemical analysis further demonstrated improved accumulation of the targeted nanoprobe in tumors. BBN-conjugated Gd2O3 may be a promising nanoplatform for simultaneous GRP receptor-targeted molecular cancer diagnosis and antitumor drug delivery in future clinical applications.

[Value of PI-RADS v2 scores combined with prostate specific antigen in diagnosis of peripheral zone prostate cancer: a logistic regression analysis].

OBJECTIVE: To assess the value of Prostate Imaging and Reporting and Data System: Version 2 (PI-RADS v2) combined with prostate specific antigen (PSA) in the diagnosis of peripheral zone (PZ) prostate cancer (PCa). METHODS: The preoperative magnetic resonance imaging and PSA data were ananlyzed for 69 patients with pathologically confirmed PCa and 109 non-PCa patients. PI-RADS v2 scores (1-5) was used to evaluate the risk of PZ PCa. The total PSA (tPSA) level, free to total PSA ratio (f/t PSA), PSA density (PSAD), PZ-PSAD and PI-RADS v2 scores were compared between the PCa and non-PCa patients. Logistic regression models were established with parameters that differed significantly the two groups. The receiver opearting characteristics (ROC) curve was constructed based on the P values derived from the logical regression models and PI-RADS scores to assess the diagnostic efficiency. RESULTS: PI-RADS v2 score, tPSA, f/t PSA, PSAD and PZ-PSAD differed significantly between the two groups (P<0.01). Four predictive multivariate models were established: Logit P=-6.825+1.024PI-RADS v2+ 0.223tPSA (A), Logit P=-4.354+1.586PI-RADS v2-12.7841f/tPSA (B), Logit P=-8.993+1.630PI-RADS v2+17.091PSAD (C), and Logit P=-9.434+1.596PI-RADS v2+10.494PZ-PSAD (D), whose area under the ROC curves was 0.908, 0.891, 0.944, and 0.961, respectively, all significantly greater than that of PI-RADS v2 score (P<0.05). CONCLUSION: Compared with PI-RADS v2 score alone, the combination of PI-RADS v2 score and PSA in the logistic regression model can improve the diagnostic efficiency of PZ PCa and offers better confidence in the decision of biopsy in suspected cases.

Mitochondrial targeted fluorescent probe with AIE characteristics for bioimaging.

In this work, a new benzothiazole based mitochondrial tracker, Bth-Mito, is synthesized by with 2-benzothiazoleacetonitrile and 4-(diethylamino)-benzaldehyde. Bth-Mito is weakly fluorescent when dissolved in the good solvent but becomes highly emissive in poor solvents, showing a phenomenon of aggregation-induced emission. Bth-Mito shows the greatest potentials for bioimaging applications in view of low cytotoxicity and high photostability. Bth-Mito could penetrate cells to give stable green fluorescence, even after continuous irradiation, making it suitable candidate for time-lapse and long-term bioimaging application. Moreover, Bth-Mito could specifically localize in mitochondrial. Furthermore, in vivo imaging studies on nude mice have revealed that Bth-Mito could be used as optical imaging probe for in vivo imaging. Histological assessment of tissues treated with Bth-Mito also further confirmed the low toxicity and good biocompatibility of Bth-Mito.

A photostable cationic fluorophore for long-term bioimaging.

Fluorophores for efficient long-term bioimaging are of great importance to fully understand the cellular and molecular processes of disease. In this study, a bright and photostable cationic fluorophore (PPB) was successfully developed as a long-term tracer. The PPB displayed advanced properties such as high fluorescence efficiency, large Stokes shift, low cytotoxicity, and good biocompatibility. Moreover, the PPB exhibited comparable photostability to the commercial cell tracker Qtracker 585. More importantly, the PPB can trace HeLa cells as long as 16 passages in vitro and monitor tumor growth for 27 days in vivo. These remarkable features endow the PPB as an ideal fluorescent probe for long-term bioimaging applications.