Bufalin-Loaded Multifunctional Photothermal Nanoparticles Inhibit the Anaerobic Glycolysis by Targeting SRC-3/HIF-1α Pathway for Improved Mild Photothermal Therapy in CRC.

Purpose: Compared with traditional photothermal therapy (PTT, >50°C), mild PTT (≤45°C) is a promising strategy for tumor therapy with fewer adverse effects. Unfortunately, its anti-tumor efficacy is hampered by thermoresistance induced by overexpression of heat shock proteins (HSPs). In our previous study, we found bufalin (BU) is a glycolysis inhibitor that depletes HSPs, which is expected to overcome thermotolerance of tumor cells. In this study, BU-loaded multifunctional nanoparticles (NPs) were developed for enhancing the mild PTT of colorectal cancer (CRC). Methods: Fe3O4 NPs coated with the polydopamine (PDA) shell modified with polyethylene glycol (PEG) and cyclic arginine-glycyl-aspartic peptide (cRGD) for loading BU (Fe3O4@PDA-PEG-cRGD/BU NPs) were developed. The thermal variations in Fe3O4@PDA-PEG-cRGD/BU NPs solution under different conditions were measured. Glycolysis inhibition was evaluated by measuring the glucose uptake, extracellular lactate, and intracellular adenosine triphosphate (ATP) levels. The cellular cytotoxicity of Fe3O4@PDA-PEG-cRGD/BU NPs was analyzed using a cell counting kit-8 assay, Calcein-AM/PI double staining, and flow cytometry in HCT116 cells. The magnetic resonance imaging (MRI) performance and anti-tumor therapeutic efficacy of Fe3O4@PDA-PEG-cRGD/BU NPs were evaluated in HCT116-tumor bearing mice. Results: Fe3O4@PDA-PEG-cRGD/BU NPs had an average diameter of 260.4±3.5 nm, the zeta potential of -23.8±1.6 mV, the drug loading rate of 1.1%, which had good thermal stability, photothermal conversion efficiencies and MRI performance. In addition, the released BU not only killed tumor cells but also interfered with glycolysis by targeting the steroid receptor coactivator 3 (SRC-3)/HIF-1α pathway, preventing intracellular ATP synthesis, and combating HSP-dependent tumor thermoresistance, ultimately strengthening the thermal sensitivity toward mild PTT both in vitro and in vivo. Conclusion: This study provides a highly effective strategy for enhancing the therapeutic effects of mild PTT toward tumors.

Interconnections between urolithiasis and oral health: a cross-sectional and bidirectional Mendelian randomization study.

Introduction: Urolithiasis is one of the most common diseases for urologists and it is a heavy burden for stone formers and society. The theory of the oral-genitourinary axis casts novel light on the pathological process of genitourinary system diseases. Hence, we performed this study to characterize the crosstalk between oral health conditions and urolithiasis to provide evidence for prevention measures and mechanisms of stone formation. Materials and methods: This population-based cross-sectional study included 86,548 Chinese individuals who had undergone a comprehensive examination in 2017. Urolithiasis was diagnosed depending on the results of ultrasonographic imaging. Logistic models were utilized to characterize the association between oral health conditions and urolithiasis. We further applied bidirectional Mendelian randomization to explore the causality between oral health conditions and urolithiasis. Results: We observed that presenting caries indicated a negative correlation with the risk for urolithiasis while presenting gingivitis [OR (95% CI), 2.021 (1.866-2.187)] and impacted tooth [OR (95% CI), 1.312 (1.219-1.411)] shown to be positively associated with urolithiasis. Furthermore, we discovered that genetically predicted gingivitis was associated with a higher risk of urolithiasis [OR (95% CI), 1.174 (1.009-1.366)] and causality from urolithiasis to impacted teeth [OR(95% CI), 1.207 (1.027-1.418)] through bidirectional Mendelian randomization. Conclusion: The results cast new light on the risk factor and pathogenesis of kidney stone formation and could provide novel evidence for the oral-genitourinary axis and the systematic inflammatory network. Our findings could also offer suggestions for tailored clinical prevention strategies against stone diseases.

Skin-safe nanophotosensitizers with highly-controlled synthesized polydopamine shell for synergetic chemo-photodynamic therapy.

Although photodynamic therapy (PDT) has been extensively studied as an established modality of cancer treatment, it still suffers from a few clinical limitations, such as skin phototoxicity and tumor hypoxia. To circumvent these hurdles, hollow silica mesoporous nanoparticles (HMSNs) loaded with photosensitizers were employed as the nanoplatform to construct multifunctional nanoparticles (NPs). Specifically, an ultra-uniform polydopamine (PDA) shell was highly controlled grown around HMSNs by photogenerated outwards-diffused 1O2, followed by conjugation of folic acid-poly(ethylene glycol) and chelation of Fe2+ ions. Thanks to the optimal thickness of light-absorbing PDA shell, the multifunctional NPs exhibited not only negligible skin phototoxicity but also efficient 1O2 generation and photothermal (PT)-enhanced •OH generation upon respective photoirradiation. Anti-tumor therapy was then performed on both 4 T1 tumor cells and tumor-bearing mice by the combination of 638 nm PDT and 808 nm PT-enhanced chemodynamic therapy (CDT). As a result, high therapeutic efficacy was achieved compared to single-modality therapy, with a cell inhibitory rate of 86% and tumor growth inhibition of 70.4% respectively. More interestingly, tumor metastasis was effectively inhibited by the synergetic treatment. These results convincingly demonstrate that our multifunctional NPs are very promising skin-safe PDT agents combined with CDT for efficient tumor therapy.

Coil and n-butyl-2-cyanoacrylate migration into the stomach after TIPS for gastroesophageal variceal bleeding: a case report and literature review.

BACKGROUND: Transjugular intrahepatic portosystemic shunt (TIPS) is a well-established therapeutic option for the management of variceal hemorrhage in patients with cirrhosis. The simultaneous migration of the coil and n-butyl-2-cyanoacrylate (NBCA) is an extremely rare but significant complication after TIPS. Because of its rare presentation, there are currently no definitive recommendations for the management of this condition. CASE PRESENTATION: A 46-year-old man with hepatitis B cirrhosis underwent TIPS placement for uncontrolled gastroesophageal varix (GEV) bleeding secondary to portal hypertension in August 2018. During the procedure, large GEVs were embolized using a coil and NBCA. After a year, coil and NBCA migration into the stomach was observed. Attempts to remove the coil using biopsy forceps during esophagogastroduodenoscopy failed. The patient refused further intervention on the coil to prevent further complications and received conservative therapy instead. Close surveillance with endoscopy is recommended for detecting coils and varices. CONCLUSIONS: The present case reports an extremely rare but significant complication after TIPS, which highlights the management and follow-up recommendation for such rare complications. Our experience may provide guidance for the management of future similar cases and stimulate discussion about treatment methods of similar patients.

Effect of ceramic materials on the optical properties of porcelain veneers for tetracycline-stained teeth.

OBJECTIVES: To analyze the chromatic properties and translucency of porcelain veneers made from different ceramic materials against the background of tetracycline-stained teeth. METHODS: Porcelain specimens (A1, A3, B2, B4) measuring 0.50 mm in thickness were prepared by heat-press casting and layering. The L*, a*, and b* values of the specimens against simulated tetracycline tooth and black-and-white backgrounds were measured by a spectrophotometer, and color differences ΔE001 between specimens on simulated tetracycline backgrounds and the backgrounds themselves and ΔE002 between specimens on simulated tetracycline backgrounds and the white background were calculated. The translucent parameter (TP) was also evaluated. RESULTS: The ΔE001 of feldspathic specimens (IPS d.SIGN) with the opaque layer was significantly greater than that of glass ceramic specimens (IPS e.max Press LT), and the ΔE001 of group B4 was consistently greater than those of the other color groups (P<0.05). The ΔE002 values of all feldspathic specimens with the opaque layer were less than 1.25, and the ΔE002 values of the glass ceramic specimens were greater than 2.23. However, no significant difference was observed among the different color groups (P>0.05). The TP values of feldspathic specimens with the opaque layer were significantly lower than those of glass ceramic specimens(P<0.05), but no significant difference was observed among different color groups (P>0.05). CONCLUSIONS: When changing the color of tetracycline-stained teeth, 0.50 mm-thick IPS d.SIGN feldspathic veneers with an opaque layer provide better chromatic properties than IPS e.max Press LT glass ceramic veneers. However, the translucency of feldspathic veneers is generally poorer than that of glass ceramic veneers.

High pressure laminates reinforced with electrospun cellulose acetate nanofibers.

In the work, the non-woven cellulose acetate (CA) nanofiber mats were prepared via electrospinning, and CA nanofiber were incorporated into the core layer of the high-pressure laminates (HPLs). When the concentration of CA was 16 wt%, SEM images demonstrated that the morphology of the CA nanofiber mat was the best, with an average diameter of 654±246 nm. When CA nanofiber mats were incorporated into the core layer of HPLs, the mechanical properties of the resulted HPLs composites were significantly improved. Specifically, the tensile strength and elongation at break of the nanofiber mats reinforced HPLs composites increased remarkably to 40.8 ±1.1 MPa and 27.9 ± 0.9 %, respectively, which were nearly 6 times and 4.4 times higher than those of the pure HPLs. Furthermore, the incorporation of the CA nanofiber mats also significantly improved the flame retardancy of the HPLs, which was revealed from the thermogravimetric analysis (TGA) results.

Gelling and bile acid binding properties of gelatin-alginate gels with interpenetrating polymer networks by double cross-linking.

Interpenetrating polymer network (IPN) is an effective method to improve functional properties of hydrogels by forming cross-linking networks. In this study, the gelatin-alginate gels formed by the combination of enzymatic and ionic cross-linking were called IPN gels. Meanwhile, the gels with the treatment of only transglutaminase (TG) or Ca2+ were named as G-semi-IPN and A-semi-IPN, respectively. The formation of semi-IPN and IPN was confirmed by studies on rheology, thermodynamics and micro-morphology. The results showed that the IPN gels had improved gelling properties and structural stability. The functional properties of different gelatin-alginate gels were also investigated. It was firstly found that the IPN gels could enhance mechanical properties, decrease swelling capacity and had better bile acid binding capacity. These results of gelatin-alginate gels provide references and novel prospects of IPN for the application in the field of food industry.

Precise design and synthesis of an AIE fluorophore with near-infrared emission for cellular bioimaging.

Organic fluorophores emerge as important stains for bioimaging and biosensing, especially for fluorophores with aggregation-induced emission characters. However, the development of organic fluorophores with efficient AIE properties expand to far-red and/or near-infrared is still a great challenge. Herein, we precisely design and synthesize a novel D-π-A type of near-infrared AIE fluorophore (TPE-PTZ-R) by introducing phenothiazine (PTZ) to modify the typical AIE unit (tetraphenylethylene, TPE). TPE-PTZ-R displays good optical properties including a large Stokes shift and typical AIE properties. We next fabricate the uniform and stable AIE nanoparticles by loading Pluronic F127 and apply it in cellular bioimaging with high uptake efficiency, low cytotoxicity and good photostability.

Molecularly Selective Regulation of Delivery Fluxes by Employing Supramolecular Interactions in Layer-by-Layer Films.

The molecularly selective regulation of molecular fluxes in a biomaterial that delivers multiple chemical species simultaneously is still beyond the reach of materials scientists. A delivery material was developed by means of the layer-by-layer (LbL) technique. This material discriminatively regulates the delivery flux of bioactive small molecules, as represented by a peptide containing the RGD fragment and the chemotherapy drug doxorubicin (DOX). Molecularly selective flux regulations in LbL films are realized through fast, reversible supramolecular interactions between cyclodextrin and its guests. The mechanism underlining the delivery strategy is that supramolecular interactions promote molecular loading and slow down diffusion-dependent release. In a preliminary survey of materials parameters, a maximum difference in cell viability between healthy human bronchial epithelial cells and cancer cells (A549) was realized.

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.

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.

Feasibility study of high-temperature thermoseed inductive hyperthermia in melanoma treatment.

Current treatment modalities for melanoma do not offer satisfactory efficacy. We have developed a new, minimally invasive hyperthermia technology based on radio-frequency hyperthermia. Herein, we investigated the feasibility of using a nickel-copper thermoseed for inductive hyperthermia at a relatively high temperature (46-55 ˚C). In vitro, the thermoseed showed good thermal effects and effective killing of B16/F10 melanoma cells. Temperatures of 53.1 ± 0.5 ˚C were achieved for a single thermoseed and 56.5 ± 0.5 ˚C for two in parallel (spacing 5 mm). No B16/F10 melanoma cells survived with heating time longer than 20 min in the parallel thermoseed group. Magnetic fields or thermoseeds alone did not affect the survival rate of B16/F10 cells (P>0.05). In vivo, B16/F10 melanoma cells were subcutaneously injected into the right axilla of C57BL/6 mice. After the tumors grew to ~11-13 mm, two thermoseeds (spacing 5 mm) were implanted into the tumors and the mice were subjected to an alternating magnetic field (100-250 kHz, 15 kA/m) to induce hyperthermia. The temperature at the center of the tumor reached 46 ˚C at 5 min and plateaued at 50 ˚C. Thermoseed treatment produced large necrotic areas, inhibited tumor growth in 60% (6 of 10) of animals and prolonged survival time (P<0.05). Thus, with further optimization and testing, high-temperature thermoseed inductive hyperthermia may have therapeutic potential for melanoma.

[A method of showing thermal effect of iron oxide nanoparticles in alternating magnetic field].

BACKGROUND & OBJECTIVE: Ferromagnet has thermal effect in alternating magnetic field (AMF). Magnetically mediating hyperthermia is to localize magnetic substance within tumor tissue under AMF to promote the targeting ability and heat distribution of hyperthermia. This study was to develop a new method of showing the thermal effect of iron oxide Fe3O4 nanoparticles in AMF in vitro. METHODS: Melted polyethelene glycol (PEG) was dropped on a slide to form crystal monolayer after cooling, and was covered with a bipartite blood coverslip. Certain amount of Fe3O4 powder (average diameter, 10 nm) was added in the gap of the blood coverslip to form a strip wandering on the slide with the width of 0.5-1.0 mm. This apparatus, named analog vessel bed, was then alternated in a 4.6 mT AMF at 100-250 kHz for 15 min. The changes of PEG crystal images were observed under micropolariscope. The thermal range of the heated Fe3O4 powder was affirmed according to melting status and melting point value of PEG crystal. RESULTS: In AMF, 5 mg of Fe3O4 could rise the temperature to above 45 degrees C-50 degrees C, which exceeded the required hyperthermic temperature 43 degree C; 15 mg of Fe3O4 could rise the temperature to no more than 59 degrees C-61 degrees C; while 25 mg of Fe3O4 could be heated up to 59 degrees C-61 degrees C. The PEG melting area was enlarged with the increasing Fe3O4 quantity or decreasing PEG melting point. CONCLUSION: The analog vessel bed apparatus could display the thermal effect of Fe3O4 nanoparticles in AMF, and would be helpful for further studies on effect of magnetically mediated hyperthermia on cancer cells.