Histone deacetylase-mediated tumor microenvironment characteristics and synergistic immunotherapy in gastric cancer.

Background: Studies have shown that the expression of histone deacetylases (HDACs) is significantly related to the tumor microenvironment (TME) in gastric cancer. However, the expression of a single molecule or several molecules does not accurately reflect the TME characteristics or guide immunotherapy in gastric cancer. Methods: We constructed an HDAC score (HDS) based on the expression level of HDACs. The single-cell transcriptome was used to analyze the underlying factors contributing to differences in immune infiltration between patients with a high and low HDS. In vitro and in vivo experiments validated the strategy of transforming cold tumors into hot tumors to guide immunotherapy. Results: According to the expression characteristics of HDACs, we constructed an HDS model to characterize the TME. We found that patients with a high HDS had stronger immunogenicity and could benefit more from immunotherapy than those with a low score. The AUC value of the HDS combined with the combined positive score (CPS)for predicting the efficacy of immunotherapy was as high as 0.96. By single-cell and paired bulk transcriptome sequencing analysis, we found that the infiltration levels of CD4+ T cells, CD8+ T cells and NK cells were significantly decreased in the low HDS group, which may be induced by MYH11+ fibroblasts, CD234+ endothelial cells and CCL17+ pDCs via the MIF signaling pathway. Inhibition of the MIF signaling pathway was confirmed to potentially enhance immune infiltration. In addition, our analysis revealed that GPX4 inhibitors might be effective for patients with a low HDS. GPX4 knockout significantly inhibited PD-L1 expression and promoted the infiltration and activation of CD8+ T cells. Conclusion: We constructed an HDS model based on the HDAC expression characteristics of gastric cancer. This model was used to evaluate TME characteristics and predict immunotherapy efficacy. Inhibition of the MIF signaling pathway in the TME and GPX4 expression in tumor cells may be an important strategy for cold tumor synergistic immunotherapy for gastric cancer.

Single Atom Iron-Doped Graphic-Phase C3 N4 Semiconductor Nanosheets for Augmented Sonodynamic Melanoma Therapy Synergy with Endowed Chemodynamic Effect.

Sonodynamic therapy (SDT) is a non-invasive therapeutic modality with high tissue-penetration depth to induce reactive oxygen species (ROS) generation for tumor treatment. However, the clinical translation of SDT is restricted seriously by the lack of high-performance sonosensitizers. Herein, the distinct single atom iron (Fe)-doped graphitic-phase carbon nitride (C3 N4 ) semiconductor nanosheets (Fe-C3 N4 NSs) are designed and engineered as chemoreactive sonosensitizers to effectively separate the electrons (e- ) and holes (h+ ) pairs, achieving high yields of ROS generation against melanoma upon ultrasound (US) activation. Especially, the single atom Fe doping not only substantially elevates the separation efficiency of the e- -h+ pairs involved in SDT, but also can serve as high-performance peroxidase mimetic enzyme to catalyze the Fenton reaction for generating abundant hydroxyl radicals, therefore synergistically augmenting the curative effect mediated by SDT. As verified by density functional theory simulation, the doping of Fe atom significantly promotes the charge redistribution in the C3 N4 -based NSs, which improves their synergistic SDT/chemodynamic activities. Both the in vitro and in vivo assays demonstrate that Fe-C3 N4 NSs feature an outstanding antitumor effect by aggrandizing the sono-chemodynamic effect. This work illustrates a unique single-atom doping strategy for ameliorating the sonosensitizers, and also effectively expands the innovative anticancer-therapeutic applications of semiconductor-based inorganic sonosensitizers.

Single Atom-Doped Nanosonosensitizers for Mutually Optimized Sono/Chemo-Nanodynamic Therapy of Triple Negative Breast Cancer.

Sonodynamic therapy (SDT) represents a promising therapeutic modality for treating breast cancer, which relies on the generation of abundant reactive oxygen species (ROS) to induce oxidative stress damage. However, mutant breast cancers, especially triple-negative breast cancer (TNBC), have evolved to acquire specific antioxidant defense functions, significantly limiting the killing efficiency of SDT. Herein, the authors have engineered a distinct single copper atom-doped titanium dioxide (Cu/TiO2 ) nanosonosensitizer with highly catalytic and sonosensitive activities for synergistic chemodynamic and sonodynamic treatment of TNBC. The single-atom Cu is anchored on the most stable Ti vacancies of hollow TiO2 sonosensitizers, which not only substantially improved the catalytic activity of Cu-mediated Fenton-like reaction, but also considerably augmented the sonodynamic efficiency of TiO2 by facilitating the separation of electrons (e- ) and holes (h+ ). Both the in vitro and in vivo studies demonstrate that the engineered single atom-doped nanosonosensitizers effectively achieved the significantly inhibitory effect of TNBC, providing a therapeutic paradigm for non-invasive and safe tumor elimination through the mutual process of sono/chemo-nanodynamic therapy based on multifunctional single-atom nanosonosensitizers.

Ultrasonographic manifestations and misdiagnosis analysis of ovarian leiomyoma.

Objectives: Ovarian leiomyomas (OLs) are rare and account for only 0.5 to 1% of benign ovarian tumors. This study investigated the ultrasonographic manifestations of OL and the potential reasons for misdiagnosis. Methods: Between July 2018 and July 2023, 7 patients diagnosed with OL by surgical pathology and immunohistochemistry were enrolled in this retrospective analysis. Ultrasound (US) examinations were performed before surgery. Clinical characteristics, pathological findings, ultrasonographic manifestations, and treatment were reviewed. Results: The mean age of the 7 patients was 39.0 ± 11.57 years, with a disease course of 0.1 to 24 months. All ovarian leiomyomas were unilateral. Four cases occurred in the right ovary, and three cases occurred in the left ovary. All lesions presented as hypoechogenic, well-circumscribed, round or oval in shape, and regular in morphology. No significant blood flow signal was detected peripheral to or inside the mass in 3 cases (42.8%), and a minimal flow signal was detected peripheral to or inside the mass in 4 cases (58.2%). A total of 7 ultrasonographic images of OL were misdiagnosed: 1 patient was misdiagnosed with subserosal uterine leiomyoma, and 6 patients were misdiagnosed with a tumor in the ovarian thecoma-fibroma group. Conclusion: The imaging manifestation of OL lacks specificity; thus, preoperatively distinguishing OL from other ovarian tumors and subserosal uterine leiomyomas is difficult. Immunohistochemistry may be helpful for the definitive diagnosis of OL. The possibility of ovarian leiomyoma should be considered in patients with uterine leiomyomas coexisting with an adnexal ovarian solid mass.

Right atrial cardiac lipoma with distinctive imaging characteristics. A rare case report and literature review.

Cardiac lipomas are rare primary cardiac tumors that are often only detected incidentally during other examinations. Lipomas of the right atrium are particularly rare. In this report, we describe the case of a patient presenting with a mixed cystic-solid lipoma in the right atrium. The symptoms, imaging findings, and treatment strategies associated with this case are discussed herein. This 65-year-old female patient reported to our hospital due to exertional chest tightness, shortness of breath, and occasional chest pain for over 1 year. She subsequently underwent transthoracic echocardiography and contrast-enhanced ultrasonography, both of which revealed a cystic-solid mass in the right atrium. The transthoracic computed tomography scan showed a dense patchy shadow in the right atrium. The mass was completely excised from the atrial septum, and subsequent histopathological examination confirmed its identity as a lipoma. Surgical resection remains the primary treatment approach for cardiac lipomas, and multimodal imaging is of key importance for the diagnosis and follow-up monitoring of affected patients.

Drug-Loaded Acoustic Nanodroplet for Dual-Imaging Guided Highly Efficient Chemotherapy Against Nasopharyngeal Carcinoma.

Background: Chemotherapy is an important approach to treating nasopharyngeal carcinoma (NPC). Unfortunately, the lack of selectivity, insufficient tumor accumulation, uneven tumor distribution and severe systemic toxicity lead to the unsatisfactory performance of these drugs. While a more precise drug delivery, on-demand drug release, and deep diffusion of drugs (homogeneous distribution of drugs in the tumor) could improve the application, they remain challenging. Chemotherapeutic drug-loaded acoustic nanodroplet with dual-imaging capacity is expected to solve these problems. Methods: Folate (Fa)-modified and doxorubicin (Dox)-loaded acoustic poly (lactic-co-glycolic acid) (PLGA), low intensity focused ultrasound (LIFU)-responsive perfluoropentane (PFP) and Fe3O4 nanoparticles (designated as Fa-Fe@P-PFP-Dox) were integrated by a double-emulsion method. After the synthesis, the LIFU-triggered acoustic droplet vaporization (ADV) effect, LIFU-triggered drug release, cell targeting capability, in vitro cell-killing effects, biodistribution, PA/MR dual imaging (PA: photoacoustic; MR: magnetic resonance), LIFU-augmented Dox distribution in tumors and chemotherapeutic efficacy of Fa-Fe@P-PFP-Dox were investigated. Results: The distribution of these drug-loaded nanodroplets was clearly monitored via PA/MR dual imaging. Upon LIFU irradiation, PFP within the Fa-Fe@P-PFP-Dox nanodroplets underwent ADV, which led to the release of Dox and promoted the deep penetration of Dox in tumor tissue, eventually achieving highly efficient chemotherapy against NPC. As a result, LIFU-triggered chemotherapy exerted a highly efficient therapeutic effect with a tumor inhibition rate of 74.24 ± 7.95%. Conclusion: Fa-modified and drug-loaded acoustic nanodroplets have been successfully constructed for dual-imaging guided highly efficient chemotherapy against NPC. This novel tumor drug delivery method is expected to provide an efficient, visualized, and precise personalized treatment method for NPC patients with minimal side effects.

Folate-modified erythrocyte membrane nanoparticles loaded with Fe3O4 and artemisinin enhance ferroptosis of tumors by low-intensity focused ultrasound.

To overcome the challenges of the low efficiency of artemisinin (ART) in anticancer therapy due to its poor water solubility and poor bioavailability, we constructed folate (FA)-modified erythrocyte membrane (EM)-camouflaged poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) (PFH/ART@PLGA/Fe3O4-eFA). Specifically, the inner core of these NPs is mainly composed of phase-changeable perfluorohexane (PFH), magnetic Fe3O4 and ART. In vitro experiments showed that the prepared PFH/ART@PLGA/Fe3O4-eFA was readily taken up by 4T1 cancer cells. PFH/ART@PLGA/Fe3O4-eFA was exposed to low-intensity focused ultrasound (LIFU) irradiation to induce PFH phase transition and NPs collapse, which promoted the release of ART and Fe3O4. After LIFU irradiation, the proportion of dead 4T1 cells, the level of reactive oxygen species (ROS) and the concentration of intracellular Fe2+ ions in the PFH/ART@PLGA/Fe3O4-eFA group were much higher than those in the other group, indicating that the synergistic effect between the intracellular Fe2+ ions and the released ART played a critical role in tumor cell ferroptosis by enhancing ROS generation in vitro. We demonstrated that FA-modified EM NPs could enhance the targeting and accumulation of the NPs at the tumor site in vivo. After LIFU irradiation at 3 W/m2 for 7 min, tumor growth was completely suppressed through FA-modified EM NPs collapse and the release of ART and Fe3O4, which exerted synergistic effects in inducing tumor ferroptosis. Because of these characteristics, these NPs are considered as a promising approach for the delivery of drugs with poor water solubility for efficient cancer therapy.

Two-Dimensional MXene-Originated In Situ Nanosonosensitizer Generation for Augmented and Synergistic Sonodynamic Tumor Nanotherapy.

Despite the merits of high tissue-penetrating depth, no ionizing radiation, and low cost, sonodynamic therapy (SDT) still suffers from a low quantum yield of reactive oxygen species (ROS), limited delivery efficiency, and potential toxicity of sonosensitizers. Different from the direct delivery of sonosensitizers into tumor tissue for SDT, this work reports the fabrication of two-dimensional (2D) nanosonosensitizers/nanocatalysts (Ti3C2/CuO2@BSA) for the in situ generation of nanosonosensitizers by responding to the tumor microenvironment, achieving the high-performance and synergistic sonodynamic/chemodynamic tumor therapy. CuO2 nanoparticle integration on 2D Ti3C2 MXene achieved in situ H2O2 generation in an acidic tumor microenvironment for oxidizing Ti3C2 to produce TiO2 nanosonosensitizers, accompanied by the enhanced separation of electrons (e-) and holes (h+) by the carbon matrix after oxidation, further augmenting the SDT efficacy. Ultrasound irradiation during the sonodynamic process also enhanced the Cu-initiated Fenton-like reaction to produce more ROS for synergizing the sonodynamic tumor therapy. The experimental results confirm and demonstrate the synergistic therapeutic effects of chemodynamic and sonodynamic nanotherapy both in vitro and in vivo. The antitumor mechanisms of synergistic chemodynamic and sonodynamic therapies are associated with the upregulation of oxidative phosphorylation, ROS generation, and apoptosis as demonstrated by RNA sequencing. This work thus provides a distinct paradigm of 2D MXene-originated in situ nanosonosensitizer generation for augmented and synergistic sonodynamic tumor nanotherapy.

Cardiac Lymphoma Diagnosed by Multi-Modality Imaging: A Case Report.

A 79-year-old female patient who presented with a cardiac mass detected by conventional echocardiography was ultimately diagnosed with a malignant tumor by myocardial contrast echocardiography. A positron emission tomography/computed tomography examination showed tumors in the right atrium consistent with the findings of the contrast-enhanced ultrasound. Finally, the patient was confirmed by pathology to have cardiac lymphoma. Because no lesions were found elsewhere in the body, primary cardiac lymphoma was diagnosed by combining multi-modal imaging examination and pathological examination. Although conventional echocardiography may identify a cardiac mass, it is difficult to identify whether they are malignant or not. Myocardial contrast echocardiography helps to identify the location, shape, and size of the mass, its relationship with the surrounding tissue, and evaluate its blood supply. Thus, this imaging modality is of great value for identifying the likely etiology of a cardiac mass. Multi-modal imaging is complementary to echocardiography for determining the location of cardiac masses, invasion of surround structures, extra cardiac spread, and determination of whether a mass is likely benign or malignant. Multi-modality imaging provides an important basis for clinical treatment and decision-making.

PLGA+Fe3O4+PFP Nanoparticles Drug-Delivery Demonstrates Potential Anti-Tumor Effects on Tumor Cells.

BACKGROUND Nanoparticles are proven as a potential tool for treating various disorders. However, efficient nanoparticle delivery of anti-tumor drugs is urgently needed for tumor treatment. This study aimed to generate a drug-delivery nanoparticle with higher efficacy and safety. MATERIAL AND METHODS We developed a poly-(lactide-co-glycolide) (PLGA) nanoparticle (FLGA-Fe3O4+PFP) embedded with super-paramagnetic iron oxide (Fe3O4) and perfluoropentane (PFP). Characteristics of FLGA-Fe3O4+PFP nanoparticles were observed using optical microscopy, scanning electron microscopy, and transmission electron microscopy. HNE1 and HepG2 cells were cultured and used for experiments. MTT was used to evaluate cytotoxic effects of FLGA-Fe3O4+PFP nanoparticles on HNE1 and HepG2 cells. Cell engulfment capacity was examined and a cell targeting experiment was conducted to evaluate invasive capability and binding efficiency of PLGA+Fe3O4+PFP nanoparticles, respectively. Biological toxicity of PLGA+Fe3O4+PFP nanoparticles in rats was evaluated by determining CK, LDH, creatinine, and UA levels, and ALT and AST activities. RESULTS PLGA+Fe3O4+PFP nanoparticles demonstrated well-defined spherical and dispersed morphology with smooth surfaces. There were scattered black spots on shells of PLGA+Fe3O4+PFP nanoparticles. PLGA+Fe3O4+PFP nanoparticles did not trigger obvious effects on cell viability of HNE1 and HepG2 cells. HNE1 and HepG2 cells demonstrated higher engulfment capacity for PLGA+ Fe3O4+PFP nanoparticles. PLGA+Fe3O4+PFP nanoparticles demonstrated higher targeting CDDP delivery efficacy and promoted binding efficiency of targeting CDDP with cells. PLGA+Fe3O4+PFP nanoparticles demonstrated no obvious toxic effects on heart, kidney, liver (without effects on CK, LDH, creatinine, UA levels, and ALT and AST activities). CONCLUSIONS PLGA+Fe3O4+PFP nanoparticles were safe, with higher invasive ability and binding efficiency of targeting CDDP with tumor cells. Therefore, PLGA+Fe3O4+PFP nanoparticles demonstrated potential anti-tumor effects after transplantation.

Innate tumor killers in colorectal cancer.

Standard treatment of colorectal cancer (CRC) improves the prognosis of CRC patients, but it is still intractable to control the progression of metastatic CRC. Immune microenvironment and immunotherapies of CRC have received extensive attention in recent years, but present immunotherapies of CRC have mainly focused on T cells and therapeutic response is only observed in a small proportion of patients. Innate immune cells are the first-line of defense in the development of malignancies. Natural killer (NK) cells, NKT cells and γδT cells are three types of innate cells of lymphoid origin and show cytotoxicity against various tumor cells including CRC. Besides, in the development of CRC, they can also be inhibited or express regulatory type, promoting tumor progression. Researches about anti-tumorigenic and pro-tumorigenic mechanisms of these cells are ongoing and regulation of these cells is also being unearthed. Meanwhile, immunotherapies using these cells more or less have shown efficacy in animal models and some of them are under exploration in clinical trials. This review provides an overview of intrinsic properties of NK cell, NKT cell and γδT cell, and summarizes current related promising treatment strategies.

Can Combined Screening of Ultrasound and Elastography Improve Breast Cancer Identification Compared with MRI in Women with Dense Breasts-a Multicenter Prospective Study.

Objectives: To assess the performance of elastography (ES) and ultrasound (US) in predicting the malignancy of breast lesions and to compare their combined diagnostic value with that of magnetic resonance imaging (MRI). Materials and Methods: The study prospectively enrolled 242 female patients with dense breasts treated in 35 heath care facilities in China between November 2018 and October 2019. Based on conventional US and elastography, radiologists classified the degree of suspicion of breast lesions according to the US Breast Imaging Reporting and Data System (BI-RADS) criteria. The diagnostic value was compared between US BI-RADS and MRI BI-RADS, with pathological results used as the reference standard. Results: The results demonstrated that irregular tumor shape, a nonparallel growth orientation, indistinct margins, angular contours, microcalcifications, color Doppler flow and ES score on US imaging were significantly related to breast cancer in dense breasts (P=0.001; P=0.001; P=0.008; P<0.001; P=0.019; P=0.008; P=0.002, respectively). The sensitivity, specificity, PPV, NPV, accuracy and AUC of US BI-RADS category were 94.7%, 90.7%, 95.8%, 88.0%, 93.4% and 0.93 (95%CI, 0.88-0.97), respectively, while those of MRI BI-RADS category were 98.2%, 57.5%, 84.3%, 83.3%, 86.0% and 0.78 (95%CI, 0.71-0.85), respectively. MRI BI-RADS showed a significantly higher sensitivity than US BI-RADS (98.2% vs 94.7%, P=0.043), whereas US BI-RADS showed significantly higher specificity (90.7% vs 57.5%, P<0.001). US BI-RADS showed better diagnostic efficiency in differentiating nodules in dense breasts than MRI BI-RADS (AUC 0.93 vs 0.78, P<0.001). Conclusion: By combining the use of ES and conventional US, US BI-RADS had better diagnostic efficiency in differentiating nodules in dense breasts than MRI. For the diagnosis of malignant tumors in patients with dense breasts, MRI and US BI-RADS can be used as supplemental diagnostic tools to detect lesions, with US BI-RADS considered the preferred adjunctive resource.

Therapeutic mesopore construction on 2D Nb2C MXenes for targeted and enhanced chemo-photothermal cancer therapy in NIR-II biowindow.

Two-dimensional (2D) MXenes have emerged as a promising planar theranostic nanoplatform for versatile biomedical applications; but their in vivo behavior and performance has been severely influenced and hindered by a lack of necessary surface chemistry for adequate surface engineering. To solve this critical issue, this work employs versatile sol-gel chemistry for the construction of a unique "therapeutic mesopore" layer onto the surface of 2D niobium carbide (Nb2C) MXene. Methods: The in situ self-assembled mesopore-making agent (cetanecyltrimethylammonium chloride, in this case) was kept within the mesopores for efficient chemotherapy. The abundant surface saline chemistry of mesoporous silica-coated Nb2C MXene was further adopted for stepwise surface engineering including PEGylation and conjugation with cyclic arginine-glycine-aspartic pentapeptide c(RGDyC) for targeted tumor accumulation. Results: 2D Nb2C MXenes were chosen based on their photothermal conversion capability (28.6%) in the near infrared (NIR)-II biowindow (1064 nm) for enhanced photothermal hyperthermia. Systematic in vitro and in vivo assessments demonstrate targeted and enhanced chemotherapy and photothermal hyperthermia of cancer (U87 cancer cell line and corresponding tumor xenograft; inhibition efficiency: 92.37%) in the NIR-II biowindow by these mesopore-coated 2D Nb2C MXenes. Conclusion: This work not only significantly broadens the biomedical applications of 2D Nb2C MXene for enhanced cancer therapy, but also provides an efficient strategy for surface engineering of 2D MXenes to satisfy versatile application requirements.

Oxygen-Deficient Black Titania for Synergistic/Enhanced Sonodynamic and Photoinduced Cancer Therapy at Near Infrared-II Biowindow.

The conventional inorganic semiconductors are not suitable for in vivo therapeutic nanomedicine because of the lack of an adequate and safe irradiation source to activate them. This work reports on the rational design of titania (TiO2)-based semiconductors for enhanced and synergistic sono-/photoinduced tumor eradication by creating an oxygen-deficient TiO2- x layer onto the surface of TiO2 nanocrystals, which can create a crystalline-disordered core/shell structure (TiO2@TiO2- x) with black color. As found in the lessons from traditional photocatalysis, such an oxygen-deficient TiO2- x layer with abundant oxygen defects facilitates and enhances the separation of electrons (e-) and holes (h+) from the energy-band structure upon external ultrasound irradiation, which can significantly improve the efficacy of sono-triggered sonocatalytic tumor therapy. Such an oxygen-deficient TiO2- x layer can also endow black titania nanoparticles with high photothermal-conversion efficiency (39.8%) at the NIR-II biowindow (1064 nm) for enhanced photothermal hyperthermia. Both in vitro cell level and systematic in vivo tumor-bearing mice xenograft evaluations have demonstrated the high synergistic efficacy of combined and enhanced sonodynamic therapy and photothermal ablation as assisted by oxygen-deficient black titania, which has achieved complete tumor eradication with high therapeutic biosafety and without obvious reoccurrence. This work not only provides the paradigm of high therapeutic efficacy of a combined sono-/photoinduced tumor-treatment protocol but also significantly broadens the nanomedical applications of semiconductor-based nanoplatforms by rational design of their nanostructures and control of their physiochemical properties.

Two-Dimensional Tantalum Carbide (MXenes) Composite Nanosheets for Multiple Imaging-Guided Photothermal Tumor Ablation.

MXenes, an emerging family of graphene-analogues two-dimensional (2D) materials, have attracted continuous and tremendous attention in many application fields because of their intrinsic physiochemical properties and high performance in versatile applications. In this work, we report on the construction of tantalum carbide (Ta4C3) MXene-based composite nanosheets for multiple imaging-guided photothermal tumor ablation, which has been achieved by rational choice of the composition of MXenes and their surface functionalization. A redox reaction was activated on the surface of tantalum carbide (Ta4C3) MXene for in situ growth of manganese oxide nanoparticles (MnOx/Ta4C3) based on the reducing surface of the nanosheets. The tantalum components of MnOx/Ta4C3 acted as the high-performance contrast agents for contrast-enhanced computed tomography, and the integrated MnOx component functionalized as the tumor microenvironment-responsive contrast agents for T1-weighted magnetic resonance imaging. The photothermal-conversion performance of MnOx/Ta4C3 composite nanosheets not only has achieved contrast-enhanced photoacoustic imaging, but also realized the significant tumor-growth suppression by photothermal hyperthermia. This work broadens the biomedical applications of MXenes, not only by the fabrication of family members of biocompatible MXenes, but also by the development of functionalization strategies of MXenes for cancer-theranostic applications.

Construction of Silica-Based Micro/Nanoplatforms for Ultrasound Theranostic Biomedicine.

Ultrasound (US)-based biomedicine has been extensively explored for its applications in both diagnostic imaging and disease therapy. The fast development of theranostic nanomedicine significantly promotes the development of US-based biomedicine. This progress report summarizes and discusses the recent developments of rational design and fabrication of silica-based micro/nanoparticles for versatile US-based biomedical applications. The synthetic strategies and surface-engineering approaches of silica-based micro/nanoparticles are initially discussed, followed by detailed introduction on their US-based theranostic applications. They have been extensively explored in contrast-enhanced US imaging, US-based multi-modality imaging, synergistic high-intensity focused US (HIFU) ablation, sonosensitizer-enhanced sonodynamic therapy (SDT), as well as US-triggered chemotherapy. Their biological effects and biosafety have been briefly discussed to guarantee further clinical translation. Based on the high biocompatibility, versatile composition/structure and high performance in US-based theranostic biomedicine, these silica-based theranostic agents are expected to pave a new way for achieving efficient US-based theranostics of disease by taking the specific advantages of material science, nanotechnology and US-based biomedicine.

Material chemistry of graphene oxide-based nanocomposites for theranostic nanomedicine.

The promising biomedical applications of graphene oxide (GO) have quickly catalyzed a generation of various GO-based functional composites with desirable nanostructures and composites to satisfy the specific biomedical applications of GO-based nanosystems. This comprehensive review summarizes and discusses the very recent developments in rational design, chemical fabrication and versatile biomedical applications of GO-based functional composites, including metal oxide-GO, metal-GO, fluorescent nanoparticles-GO, silica-GO, polymer-GO and other specific GO-based composite nanosystems. The integration of multi-components with GO is also discussed. Their versatile theranostic applications include diagnostic imaging-guided therapy (photothermal therapy, photodynamic therapy and chemotherapy), biosensing-based tumor detection, and synergistic therapy. The biocompatibility and biosafety of these promising GO-based nanocomposites are also briefly mentioned. Finally, the unresolved critical issues and challenges facing the design/fabrication/application of these unique GO-based functional nanocomposites are proposed to further promote their clinical translation. The unique multi-composition, nanostructure and unique theranostic performance of GO-based composites are highly expected to pave a new way for the development of highly efficient theranostic protocols/approaches for precise personalized biomedicine to benefit human health.

EGFP gene transfection into the synovial joint tissues of rats with rheumatoid arthritis by ultrasound-mediated microbubble destruction.

The aim of the present study was to explore the feasibility of enhancing green fluorescent protein (EGFP) gene transfection into the synovial joint tissues of rats with rheumatoid arthritis (RA) by ultrasound-mediated microbubble destruction. An optimal SonoVue dose was determined using 40 normal rats categorized into five groups according to the various doses of microbubbles used. At 1 week after ultrasound irradiation, the rats were sacrificed. Damage to the joint synovial tissues was observed with hematoxylin and eosin histopathological staining under a microscope. A further 44 normal rats were used to establish a rat model of RA, and were then categorized into four groups: EGFP, ultrasound + EGFP, microbubbles + EGFP and ultrasound + microbubbles + EGFP. The last group was irradiated with ultrasound for 10 min following the injection of 300 µl SonoVue and 10 µg EGFP into the joint cavity. Rats were sacrificed after 3 days and synovial tissue was collected from the knee joints for observation of EGFP with fluorescence microscopy and analysis by quantitative polymerase chain reaction. EGFP expression was observed in the synovial tissues of all groups. However, high EGFP expression levels were observed in the ultrasound + microbubbles + EGFP group. No statistically significant differences (P>0.05) were observed in the EGFP expression levels between the EGFP, ultrasound + EGFP and microbubbles + EGFP groups. However, EGFP expression levels in the EGFP, ultrasound + EGFP and microbubbles + EGFP groups significantly differed (P<0.05) from that in the ultrasound + microbubbles + EGFP group. Therefore, ultrasound-mediated microbubble destruction improved EGFP transfection efficiency into the joint synovial tissues of rats with RA.

Evaluation of renal ischemia-reperfusion injury in rabbits using microbubbles targeted to activated neutrophils.

OBJECTIVE: The objective of this study was to noninvasively evaluate the severity of renal ischemia-reperfusion (I-R) injury in rabbits with microbubbles targeted to activated neutrophils [phosphatidylserine-conjugated surfactant perfluoropropane-filled microbubbles (SPMB-PS)]. METHODS: Microbubbles targeted to activated neutrophils (SPMB-PS) were prepared by conjugating phosphatidylserine (PS) to self-assembling surfactant perfluoropropane-filled microbubbles (SPMB). Flow cytometry was performed to assess the presence of PS in SPMB. A renal I-R injury model was established in 18 rabbits for contrast-enhanced ultrasonography. Examination of ultrasonography with SPMB-PS and SPMB was performed on 12 rabbits before and after I-R injury. The time-intensity curve (TIC) was generated from a selected region of interest. Another six rabbits with renal I-R injury underwent contrast-enhanced ultrasonography for 15 min after intravenous injection of SPMB-PS. The renal tissues were immediately excised for immunohistochemical staining and myeloperoxidase (MPO) activity analysis. The correlation between MPO activity and echo intensity (VI) was analyzed. RESULTS: Flow cytometry demonstrated that PS was located on the surface of SPMB. TIC showed that the time at which the maximum VI was reached and the time needed for the microbubbles to wash out were the same in the normal kidneys injected with SPMB-PS or SPMB, while there was an obvious delay in emptying time with SPMB-PS compared with SPMB after I-R injury. Fifteen minutes after the injection of SPMB-PS and SPMB, VI was not remarkably different (P>.05) in the normal kidneys, while it was significantly higher (P<.01) in the I-R-injured kidneys. There was a strong correlation between MPO activity and VI 15 min after the injection of SPMB-PS (r=.933, P<.01). Immunohistochemistry showed that most of the inflammatory cells in the I-R-injured kidneys were neutrophils. CONCLUSION: A delayed emptying phenomenon was observed during contrast-enhanced ultrasonography in the I-R-injured kidneys, with SPMB-PS targeted to activated neutrophils. Therefore, contrast-enhanced ultrasonography with SPMB-PS may noninvasively evaluate the severity of ischemia-reperfusion injury to the kidneys.