Design of an imaging magnetic microsphere based on photopolymerization for magnetic hyperthermia in tumor therapy.

Magnetic hyperthermia therapy has been widely used in the nonsurgical treatment of patients with advanced stage cancers that cannot be treated by surgery. It is minimally invasive, precise, and highly efficient and has a good curative effect. In this paper, a magnetic microsphere with Fe3O4 was prepared for thermal therapy and imaging based on a photoinitiated suspension polymerization method from biallelic monomers. The preparation method clearly minimized the degradative chain transfer of allyl polymerization reactions. The microspheres were characterized by microscope observation, spectral analysis, thermal analysis, and magnetic testing. The magnetothermal effect was detected by an infrared thermal imager in vitro and in vivo under a high-frequency alternating magnetic field (AMF). The antitumor effect was verified by testing the viability of H22 cells and observing a tumor-bearing mouse model under high-frequency AMF. Biocompatibility was evaluated by cell viability assay, tissue section observation, and blood biochemical analysis. The imaging capacity was tested by X-ray, MRI, and CT imaging experiments. The results show that the product has good dispersibility, thermal stability, superparamagnetism, and biocompatibility. Under the action of an AMF, the magnetic hyperthermia effect in tumor-bearing mice was better, and an antitumor effect could be achieved.

Nicotinamide Adenine Dinucleotide Precursor Suppresses Hepatocellular Cancer Progression in Mice.

Targeting Nicotinamide adenine dinucleotide (NAD) metabolism has emerged as a promising anti-cancer strategy; we aimed to explore the health benefits of boosting NAD levels with nicotinamide riboside (NR) on hepatocellular carcinoma (HCC). We established three in vivo tumor models, including subcutaneous transplantation tumor model in both Balb/c nude mice (xenograft), C57BL/6J mice (allograft), and hematogenous metastatic neoplasm in nude mice. NR (400 mg/kg bw) was supplied daily in gavage. In-situ tumor growth or noninvasive bioluminescence were measured to evaluate the effect of NR on the HCC process. HepG2 cells were treated with transforming growth factor-ß (TGF-ß) in the absence/presence of NR in vitro. We found that NR supplementation alleviated malignancy-induced weight loss and metastasis to lung in nude mice in both subcutaneous xenograft and hematogenous metastasis models. NR supplementation decreased metastasis to the bone and liver in the hematogenous metastasis model. NR supplementation also significantly decreased the size of allografted tumors and extended the survival time in C57BL/6J mice. In vitro experiments showed that NR intervention inhibited the migration and invasion of HepG2 cells triggered by TGF-ß. In summary, our results supply evidence that boosting NAD levels by supplementing NR alleviates HCC progression and metastasis, which may serve as an effective treatment for the suppression of HCC progression.

One-step photocatalytic synthesis of Fe3O4@polydiallyl isophthalate magnetic microspheres for magnetocaloric tumor ablation and its potential for tracing on MRI and CT.

Allyl monomers that were previously considered to be difficult to polymerize are applied, and Fe3O4@polydiallyl isophthalate (Fe3O4@PDAIP) magnetic were synthesized by one-step photopolymerization. The skeleton of the microspheres is made of diallyl isophthalate (DAIP). We obtained the microspheres using the photo-click technique in a soft template with Nano-Fe3O4 evenly disseminated in hydrophobic DAIP by cation-π and polar interaction. The obtained Fe3O4@PDAIP magnetic microspheres can achieve tumor cell necrosis temperatures (41-52 °C) in an alternating magnetic field due to their inherent magnetic response. The results of in vitro CT and MR imaging indicate that the microspheres might be monitored accurately in vivo. Then the structural characteristics of the microspheres were confirmed by morphological analysis and physicochemical property analysis. Experiments in vitro and in vivo revealed that the microspheres had an anti-tumor effect and their biocompatibility satisfies the standards. The stability experiment proves that the microspheres have the potential for long-term effectiveness in vivo. It demonstrates the promise of Fe3O4@PDAIP magnetic microspheres in clinical applications.

Deficient DNASE1L3 facilitates neutrophil extracellular traps-induced invasion via cyclic GMP-AMP synthase and the non-canonical NF-κB pathway in diabetic hepatocellular carcinoma.

Objective: Diabetic hepatocellular carcinoma (HCC) patients have high mortality and metastasis rates. Diabetic conditions promote neutrophil extracellular traps (NETs) generation, which mediates HCC metastasis and invasion. However, whether and how diabetes-induced NETs trigger HCC invasion is largely unknown. Here, we aimed to observe the effects of diabetes-induced NETs on HCC invasion and investigate mechanisms relevant to a DNA sensor cyclic GMP-AMP synthase (cGAS). Methods: Serum from diabetic patients and healthy individuals was collected. Human neutrophil-derived NETs were isolated for stimulating HCC cell invasion. Data from the SEER and TCGA databases were used for bioinformatics analysis. In HCC cells and allograft models, NETs-triggered invasion was observed. Results: Diabetic HCC patients had poorer survival than non-diabetic ones. Either diabetic serum or extracted NETs caused HCC invasion. Induction of diabetes or NETosis elicited HCC allograft invasion in nude mice. HCC cell invasion was attenuated by the treatment with DNase1. In TCGA_LIHC, an extracellular DNase DNASE1L3 was downregulated in tumor tissues, while function terms (the endocytic vesicle membrane, the NF-κB pathway and extracellular matrix disassembly) were enriched. DNASE1L3 knockdown in LO2 hepatocytes or H22 cell-derived allografts facilitated HCC invasion in NETotic or diabetic nude mice. Moreover, exposure of HCC cells to NETs upregulated cGAS and the non-canonical NF-κB pathway and induced expression of metastasis genes (MMP9 and SPP1). Both cGAS inhibitor and NF-κB RELB knockdown diminished HCC invasion caused by NETs DNA. Also, cGAS inhibitor was able to retard translocation of NF-κB RELB. Conclusion: Defective DNASE1L3 aggravates NETs DNA-triggered HCC invasion on diabetic conditions via cGAS and the non-canonical NF-κB pathway.

Metabolic Reprogramming of Sulfur in Hepatocellular Carcinoma and Sulfane Sulfur-Triggered Anti-Cancer Strategy.

Metabolic reprogramming is a cancer hallmark. Although the reprogramming of central carbon has been well documented, the role of sulfur metabolism has been largely overlooked. Additionally, the effects of sulfur are sometimes contradictory in tumorigenesis. In this study, we aimed to investigate the gene expression profile in hepatocellular carcinoma (HCC) and the effects of reactive sulfur species (RSS) on HCC tumor cells. Furthermore, the cell imaging technology was applied to discover some potential anti-cancer compounds. Gene Set Enrichment Analysis (GSEA) of Gene Expression Omnibus (GEO) dataset (GSE102083) revealed that sulfur amino acid-related metabolism and vitamin B6 binding activity in HCC tissues were downregulated. Calculation of the interaction network identified nine hub genes, among which eight were validated by differential expression and survival analysis in the TCGA_LIHC cohort, and two (CSE and CBS) had the highest enrichment degree. The metabolomics analysis suggested that the hub genes were associated with RSS metabolism including H2S, H2S2, cystine, cysteine, homocysteine, cystathionine, and methionine. The cell viability assay demonstrated that H2S2 had significant anti-cancer effects in HCC SNU398 tumor cells. The cell imaging assay showed that treatment with H2S2 remarkably increased intracellular sulfane sulfur content. On this basis, the anti-cancer activity of some other sulfane sulfur compounds, such as DATS and DADS, was further verified. Lastly, according to the fact that HCC tumor cells preferentially take in cystine due to high expression of SLC7A11 (a cystine/glutamate transporter), persulfided cysteine precursor (PSCP) was tested for its sulfane sulfur release capability and found to selectively inhibit HCC tumor cell viability. Collectively, this study uncovered sulfur metabolism in HCC was reprogrammed, and provided a potential therapeutic strategy for HCC by donating sulfane sulfur.

Synthesis and assessment of drug-eluting microspheres for transcatheter arterial chemoembolization.

Transcatheter arterial chemoembolization (TACE) is well known as an effective treatment for inoperable hepatocellular carcinoma (HCC). In this study, a novel embolic agent of ion-exchange poly(hydroxyethyl methacrylate-acrylic acid) microspheres (HAMs) was successfully synthesized by the inverse suspension polymerization method. Then, HAMs were assessed for their activity as an embolic agent by investigating morphology, particle size, water retention capability, elasticity and viscoelasticity, microcatheter/catheter deliverability, cytotoxicity, renal arterial embolization to rabbits and histopathological examinations. The ability of drug loading and drug eluting of HAMs was also investigated by using doxorubicin (Dox) as the model drug. HAMs showed to be feasible and effective for vascular embolization and to be as a drug vehicle for loading positively charged molecules and potential use in the clinical interventional chemoembolization therapy. STATEMENT OF SIGNIFICANCE: A novel embolic agent of ion-exchange poly(hydroxyethyl methacrylate-acrylic acid) microspheres (HAMs) was successfully synthesized by the inverse suspension polymerization method and was used as a drug vehicle to load positively charged molecules by ion absorption. Then, a series of assessments including physicochemical properties, mechanical properties, drug-loading capability, and embolic efficacy were performed. Surface and cross-section morphology and pore size of fully hydrated HAMs were first investigated by Phenom ProX SEM, which intuitively disclosed the "honeycomb" network morphology. HAMs also showed to be feasible and effective for vascular occlusion and have potential use in clinical interventional embolization therapy.