Osteosarcoma-targeted Cu and Ce based oxide nanoplatform for NIR II fluorescence/magnetic resonance dual-mode imaging and ros cascade amplification along with immunotherapy.

BACKGROUND: As the lethal bone tumor, osteosarcoma often frequently occurs in children and adolescents with locally destructive and high metastasis. Distinctive kinds of nanoplatform with high therapeutical effect and precise diagnosis for osteosarcoma are urgently required. Multimodal optical imaging and programmed treatment, including synergistic photothermal-chemodynamic therapy (PTT-CDT) elicits immunogenetic cell death (ICD) is a promising strategy that possesses high bio-imaging sensitivity for accurate osteosarcoma delineating as well as appreciable therapeutic efficacy with ignorable side-effects. METHODS AND RESULTS: In this study, mesoporous Cu and Ce based oxide nanoplatform with Arg-Gly-Asp (RGD) anchoring is designed and successfully constructed. After loading with indocyanine green, this nanoplatform can be utilized for precisely targeting and efficaciously ablating against osteosarcoma via PTT boosted CDT and the closely following ICD stimulation both in vitro and in vivo. Besides, it provides off-peak fluorescence bio-imaging in the second window of near-infrared region (NIR II, 1000-1700 nm) and Magnetic resonance signal, serves as the dual-mode contrast agents for osteosarcoma tissue discrimination. CONCLUSION: Tumor targeted Cu&Ce based mesoporous nanoplatform permits efficient osteosarcoma suppression and dual-mode bio-imaging that opens new possibility for effectively diagnosing and inhibiting the clinical malignant osteosarcoma.

Caveolin-mediated cytosolic delivery of spike nanoparticle enhances antitumor immunity of neoantigen vaccine for hepatocellular carcinoma.

Rationale: Although neoantigen-based cancer vaccines have shown promise in various solid tumors, limited immune responses and clinical outcomes have been reported in patients with advanced disease. Cytosolic transport of neoantigen and adjuvant is required for the activation of intracellular Toll-like receptors (TLRs) and cross-presentation to prime neoantigen-specific CD8+T cells but remains a significant challenge. Methods: In this study, we aimed to develop a virus-like silicon vaccine (V-scVLPs) with a unique spike topological structure, capable of efficiently co-delivering a hepatocellular carcinoma (HCC)-specific neoantigen and a TLR9 agonist to dendritic cells (DCs) to induce a robust CD8+T cell response to prevent orthotopic tumor growth. We evaluated the antitumor efficacy of V-scVLPs by examining tumor growth and survival time in animal models, as well as analyzing tumor-infiltrating CD8+T cells and cytokine responses in the tumor microenvironment (TME). To evaluate the synergistic efficacy of V-scVLPs in combination with α-TIM-3 in HCC, we used an orthotopic HCC mouse model, a lung metastasis model, and a tumor rechallenge model after hepatectomy. Results: We found that V-scVLPs can efficiently co-deliver the hepatocellular carcinoma (HCC)-specific neoantigen and the TLR9 agonist to DCs via caveolin-mediated endocytosis. This advanced delivery strategy results in efficient lymph node draining of V-scVLPs to activate lymphoid DC maturation for promoting robust CD8+T cells and central memory T cells responses, which effectively prevents orthotopic HCC tumor growth. However, in the established orthotopic liver tumor models, the inhibitory receptor of TIM-3 was significantly upregulated in tumor-infiltrating CD8+T cells after immunization with V-scVLPs. Blocking the TIM-3 signaling further restored the antitumor activity of V-scVLPs-induced CD8+T cells, reduced the proportion of regulatory T cells, and increased the levels of cytokines to alter the tumor microenvironment to efficiently suppress established orthotopic HCC tumor growth, and inhibit lung metastasis as well as recurrence after hepatectomy. Conclusion: Overall, the developed novel spike nanoparticles with efficient neoantigen and adjuvant intracellular delivery capability holds great promise for future clinical translation to improve HCC immunotherapy.

Amorphous Ultra-Small Fe-Based Nanocluster Engineered and ICG Loaded Organo-Mesoporous Silica for GSH Depletion and Photothermal-Chemodynamic Synergistic Therapy.

Intracellular oxidative amplification can effectively destroy tumor cells. Additionally, Fe-mediated Fenton reaction often converts cytoplasm H2 O2 to generate extensive hypertoxic hydroxyl radical (• OH), leading to irreversible mitochondrion damage for tumor celleradication, which is widely famous as tumor chemodynamic therapy (CDT). Unfortunately, intracellular overexpressed glutathione (GSH) always efficiently scavenges • OH, resulting in the significantly reduced CDT effect. To overcome this shortcoming and improve the oxidative stress in cytoplasm, Fe3 O4 ultrasmall nanoparticle encapsulated and ICG loaded organo-mesoporous silica nanovehicles (omSN@Fe-ICG) are constructed to perform both photothermal and GSH depletion to enhance the Fenton-like CDT, by realizing intracellular oxidative stress amplification. After this nanoagents are internalized, the tetrasulfide bonds in the dendritic mesoporous framework can be decomposed with GSH to amplify the toxic ROS neration by selectively converting H2 O2 to hydroxyl radicals through the released Fe-based nanogranules. Furthermore, the NIR laser-induced hyperthermia can further improve the Fenton reaction rate that simultaneously destroyed the mitochondria. As a result, the GSH depletion and photothermal assisted CDT can remarkably improve the tumor eradication efficacy.

Mesoporous Polydopamine-Based Nanovehicles as a Versatile Drug Loading Platform to Enable Tumor-Sufficient Synergistic Therapy.

The combination of photothermal therapy and chemotherapy are developing as a promising clinical strategy but it urgently needs the high exploration of intelligent multifunctional drug delivery nanovectors. In this paper, we used a versatile method to construct mesoporous polydopamine nanovehicles (MPDA) with the dendritic mesopores loaded with a clinical chemotherapeutic drug, Doxorubicin (MPDA@DOX). The monodisperse nanoagents are spherical with a size of ∼160 nm and pore size of approximately 10 nm. MPDA could efficiently delivery DOX with π-π stacking interaction and acts as the potent photothermal agents. Importantly, MPDA@DOX are preferentially internalized by cancerous cells, then bursting drug release and local hyperthermia generation were observed in conditions representative of the cytoplasm in tumor cells that highly synergistic cell killing effect were found under 808 nm laser irradiation. The fluorescent imaging results of human breast tumor bearing murine model evidenced that MPDA delivery platform have excellent tumor precise targeting effect and in vivo tumor ablation experiment further revealed that MPDA@DOX showed markedly eradicated tumor growth capability under laser exposure. Therefore, this work provided a fascinating strategy based on biocompatible MPDA based drug delivery system for malignant tumors eradication via synergistic therapy.

A Novel Yolk-Shell Fe3O4@ Mesoporous Carbon Nanoparticle as an Effective Tumor-Targeting Nanocarrier for Improvement of Chemotherapy and Photothermal Therapy.

Owing to their good stability and high photothermal conversion efficiency, the development of carbon-based nanoparticles has been intensively investigated, while the limitation of unsatisfactory cellular internalization impedes their further clinical application. Herein, we report a novel strategy for fabrication of Fe3O4 yolk-shell mesoporous carbon nanocarriers (Fe3O4@hmC) with monodispersity and uniform size, which presented significantly higher cell membrane adsorption and cellular uptake properties in comparison with common solid silica-supported mesoporous carbon nanoparticles with core-shell structure. Moreover, the MRI performance of this novel Fe-based nanoparticle could facilitate precise tumor diagnosis. More importantly, after DOX loading (Fe3O4@hmC-DOX), owing to synergistic effect of chemo-phototherapy, this therapeutic agent exhibited predominant tumor cell ablation capability under 808 nm NIR laser irradiation, both in vitro and in vivo. Our work has laid a solid foundation for therapeutics with hollowed carbon shell for solid tumor diagnosis and therapy in clinical trials.

What and where in the auditory systems of sighted and early blind individuals: Evidence from representational similarity analysis.

Separated ventral and dorsal streams in auditory system have been proposed to process sound identification and localization respectively. Despite the popularity of the dual-pathway model, it remains controversial how much independence two neural pathways enjoy and whether visual experiences can influence the distinct cortical organizational scheme. In this study, representational similarity analysis (RSA) was used to explore the functional roles of distinct cortical regions that lay within either the ventral or dorsal auditory streams of sighted and early blind (EB) participants. We found functionally segregated auditory networks in both sighted and EB groups where anterior superior temporal gyrus (aSTG) and inferior frontal junction (IFJ) were more related to the sound identification, while posterior superior temporal gyrus (pSTG) and inferior parietal lobe (IPL) preferred the sound localization. The findings indicated visual experiences may not have an influence on this functional dissociation and the cortex of the human brain may be organized as task-specific and modality-independent strategies. Meanwhile, partial overlap of spatial and non-spatial auditory information processing was observed, illustrating the existence of interaction between the two auditory streams. Furthermore, we investigated the effect of visual experiences on the neural bases of auditory perception and observed the cortical reorganization in EB participants in whom middle occipital gyrus was recruited to process auditory information. Our findings examined the distinct cortical networks that abstractly encoded sound identification and localization, and confirmed the existence of interaction from the multivariate perspective. Furthermore, the results suggested visual experience might not impact the functional specialization of auditory regions.

Revealing the differences of the representations of sounds from different directions in the human brain using functional connectivity.

Many studies have focused on the processing mechanism of sound directions in the human brain, however, as far as we know, it remains unclear whether the representations of sounds from different directions are different. In the present study, 28 subjects were scanned while listening to sounds from different directions. We used the whole-brain functional connectivity (FC) analysis to explore which brain regions had significant changes. Our results revealed that sounds from different directions affected the FC in the widely distributed regions. Importantly, all regions showed significant differences in FC between the central and eccentric directions, while few regions showed a difference between the left and right directions. These findings revealed the differences in the representations of sounds from different directions.

Cross-modal representations in early visual and auditory cortices revealed by multi-voxel pattern analysis.

Primary sensory cortices can respond not only to their defined sensory modality but also to cross-modal information. In addition to the observed cross-modal phenomenon, it is valuable to research further whether cross-modal information can be valuable for categorizing stimuli and what effect other factors, such as experience and imagination, may have on cross-modal processing. In this study, we researched cross-modal information processing in the early visual cortex (EVC, including the visual area 1, 2, and 3 (V1, V2, and V3)) and auditory cortex (primary (A1) and secondary (A2) auditory cortex). Images and sound clips were presented to participants separately in two experiments in which participants' imagination and expectations were restricted by an orthogonal fixation task and the data were collected by functional magnetic resonance imaging (fMRI). We successfully decoded categories of the cross-modal stimuli in the ROIs except for V1 by multi-voxel pattern analysis (MVPA). It was further shown that familiar sounds had the advantage of classification accuracies in V2 and V3 when compared with unfamiliar sounds. The results of the cross-classification analysis showed that there was no significant similarity between the activity patterns induced by different stimulus modalities. Even though the cross-modal representation is robust when considering the restriction of top-down expectations and mental imagery in our experiments, the sound experience showed effects on cross-modal representation in V2 and V3. In addition, primary sensory cortices may receive information from different modalities in different ways, so the activity patterns between two modalities were not similar enough to complete the cross-classification successfully.

Decoding sound categories based on whole-brain functional connectivity patterns.

2Sound decoding is important for patients with sensory loss, such as the blind. Previous studies on sound categorization were conducted by estimating brain activity using univariate analysis or voxel-wise multivariate decoding methods and suggested some regions were sensitive to auditory categories. It is proposed that feedback connections between brain areas may facilitate auditory object selection. Therefore, it is important to explore whether functional connectivity among regions can be used to decode sound category. In this study, we constructed whole-brain functional connectivity patterns when subjects perceived four different sound categories and combined them with multivariate pattern classification analysis for sound decoding. The categorical discriminative networks and regions were determined based on the weight maps. Results showed that a high accuracy in multi-category classification was obtained based on the whole-brain functional connectivity patterns and the results were verified by different preprocessing parameters. Insight into the category discriminative functional networks showed that contributive connections crossed the left and right brain, and ranged from primary regions to high-level cognitive regions, which provide new evidence for the distributed representation of auditory object. Further analysis of brain regions in the discriminative networks showed that superior temporal gyrus and Heschl's gyrus significantly contributed to discriminating sound categories. Together, the findings reveal that functional connectivity based multivariate classification method provides rich information for auditory category decoding. The successful decoding results implicate the interactive properties of the distributed brain areas in auditory sound representation.

An investigation of the neural association between auditory imagery and perception of complex sounds.

Neuroimaging studies have demonstrated that mental imagery and perception share similar neural substrates, however, there are still ambiguities according to different auditory imagery content. In addition, there is still a lack of information regarding the underlying neural correlation between the two modalities. In the present study, we adopted functional magnetic resonance imaging to explore the neural representation during imagery and perception of actual sounds in our surroundings. Univariate analysis was used to assess the differences between the modalities of average activation intensity, and stronger imagery activation was found in sensorimotor regions but weaker activation in auditory association cortices. Additionally, multi-voxel pattern analysis with a support vector machine classifier was implemented to decode environmental sounds within- or cross-modality. Significant above-chance accuracies were found in all overlapping regions in the classification of within-modality, while successful cross-modality classification only was found in sensorimotor regions. Both univariate and multivariate analyses found distinct representation between auditory imagery and perception in the overlapping regions, including superior temporal gyrus and inferior frontal sulcus as well as the precentral cortex and pre-supplementary motor area. Our results confirm the overlapping activation regions between auditory imagery and perception reported by previous studies and suggest that activation regions showed dissociable representation pattern in imagery and perception of sound categories.

[Effects of Tongbi capsule on joint lesions in rabbits with rheumatoid arthritis].

The purpose of this experiment is to observe the effects of Tongbi capsule on joint lesions in rabbit with rheumatoid arthritis induced by ovalbumin and explore the mechanism in order to provide reference for clinical application of Tongbi capsule. Rheumatoid arthritis in rabbits was induced by subcutaneous injection of emulsions of ovalbumin and Freund's complete adjuvant and intra articular injection of ovalbumin. After successful modeling, 30 New Zealand rabbits with arthritis were randomly divided into model control group, the high, medium and low dose groups of Tongbi capsule (90, 45, 22.5 mg·kg⁻¹) and prednisone group (5 mg·kg⁻¹). Another six normal rabbits were used as normal control group. After 24 hours of modeling, the rabbits in Tongbi capsule groups received intragastric (i.g.) administrations of Tongbi capsule at 90, 45, 22.5 mg·kg⁻¹·d⁻¹, and the rabbits of prednisone group received i.g. administrations of prednisone at 5 mg·kg⁻¹·d⁻¹ for 2 weeks. The rabbits in normal and model groups received the same volume of distilled water at the same time. The swelling degree of rabbit knee joint and local skin temperature were observed daily. After two weeks of administration, pathological changes of rabbit knee joint were examined by magnetic resonance imaging (MRI); the morphological changes of articular cartilage and synovial membrane were observed by microscope; and the contents of interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-α) in serum were detected by enzyme linked immunosorbent assay (ELISA).The results showed that 24 h after modeling, the knee joints of the rabbits were swollen, with red or dark redlocal skin, and fever, elevated local skin temperature and increased diameters of knee joints. Two weeks after modeling, the swelling of rabbit knee joints was obvious in model group; the joint cavities were filled with purulent fluid; joint synovial membranes were obviously thickened, and even joint cavities were fibrotic and cartilage surfaces showed slight defect; the surface of articular cartilage was obvious fibrosis; synovial epithelial cell proliferation was obvious and accompanied by extensive inflammatory cell infiltration; the levels of IL-1 and TNF-α were significantly higher as compared with those seen in model rabbits (P<0.05, P<0.01). After 1 and 2 weeks of administration, knee joint diameters and local skin temperatures were smaller or lower than thosein model group (P<0.05, P<0.01); The lesions of joint cartilage and synovial of all rabbits in each group were less than those in model group; IL-1 and TNF-α levels in serum were also lower than those in model group (P<0.05, P<0.01). The results reveal that high and medium doses of Tongbi capsule can suppress rheumatoid arthritis induced by ovalbumin in rabbits, reduce joint swelling, inhibit synovial epithelial and fiber hyperplasia and inflammatory cell infiltration, and alleviate articular cartilage damage. The mechanism may be associated with decreasing IL-1 and TNF-α levels in serum.

[Protective effect of pueraria flavonoid on the cerebral ischemic reperfusion injury in rats].

OBJECTIVE: To research the protective effect of pueraria flavonoid on the cerebral ischemic reperfusion injury. METHOD: Using the middle cerebral artery occlusion model (MCAO) in rats, we investigated the influence of pueraria flavonoid on the brain water content, the infarct volume, the activities of SOD, and the content of MDA. RESULT: Pueraria Flavonoid could obviously reduce the brain water content and the infract volume in MCAO, increase the activities of SOD, and decrease the content of MDA in the cerebral ischemia- reinfusion model of rats. CONCLUSION: Pueraria has the function of scavenging free radicals and the protective effect on ischemic brain tissue.