Microplastics have become emerging contaminants, causing widespread concern about their potential toxic effects. In this study, the uptake and tissue accumulation of polystyrene microplastics (PS-MPs) in zebrafish were detected, and the toxic effects in liver were investigated. The results showed that after 7 days of exposure, 5 μm diameter MPs accumulated in fish gills, liver, and gut, while 20 μm diameter MPs accumulated only in fish gills and gut. Histopathological analysis showed that both 5 μm and 70 nm PS-MPs caused inflammation and lipid accumulation in fish liver. PS-MPs also induced significantly increased activities of superoxide dismutase and catalase, indicating that oxidative stress was induced after treatment with MPs. In addition, metabolomic analysis suggested that exposure to MPs induced alterations of metabolic profiles in fish liver and disturbed the lipid and energy metabolism. These findings provide new insights into the toxic effects of MPs on fish.

Uptake and Accumulation of Polystyrene Microplastics in Zebrafish (Danio rerio) and Toxic Effects in Liver.

Drug molecules with lack of specificity and solubility lead patients to take high doses of the drug to achieve sufficient therapeutic effects. This is a leading cause of adverse drug reactions, particularly for drugs with narrow therapeutic window or cytotoxic chemotherapeutics. To address these problems, there are various functional biocompatible drug carriers available in the market, which can deliver therapeutic agents to the target site in a controlled manner. Among the carriers developed thus far, mesoporous materials emerged as a promising candidate that can deliver a variety of drug molecules in a controllable and sustainable manner. In particular, mesoporous silica nanoparticles are widely used as a delivery reagent because silica possesses favourable chemical properties, thermal stability and biocompatibility. Currently, sol-gel-derived mesoporous silica nanoparticles in soft conditions are of main interest due to simplicity in production and modification and the capacity to maintain function of bioactive agents. The unique mesoporous structure of silica facilitates effective loading of drugs and their subsequent controlled release. The properties of mesopores, including pore size and porosity as well as the surface properties, can be altered depending on additives used to fabricate mesoporous silica nanoparticles. Active surface enables functionalisation to modify surface properties and link therapeutic molecules. The tuneable mesopore structure and modifiable surface of mesoporous silica nanoparticle allow incorporation of various classes of drug molecules and controlled delivery to the target sites. This review aims to present the state of knowledge of currently available drug delivery system and identify properties of an ideal drug carrier for specific application, focusing on mesoporous silica nanoparticles.

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Silica-based mesoporous nanoparticles for controlled drug delivery:

The insufficient blood flow and oxygen supply in solid tumor cause hypoxia, which leads to low sensitivity of tumorous cells and thus causing poor treatment outcome. Here, mesoporous manganese dioxide (mMnO2) with ultrasensitive biodegradability in a tumor microenvironment (TME) is grown on upconversion photodynamic nanoparticles for not only TME-enhanced bioimaging and drug release, but also for relieving tumor hypoxia, thereby markedly improving photodynamic therapy (PDT). In this nanoplatform, mesoporous silica coated upconversion nanoparticles (UCNPs@mSiO2) with covalently loaded chlorin e6 are obtained as near-infrared light mediated PDT agents, and then a mMnO2 shell is grown via a facile ultrasonic way. Because of its unique mesoporous structure, the obtained nanoplatform postmodified with polyethylene glycol can load the chemotherapeutic drug of doxorubicin (DOX). When used for antitumor application, the mMnO2 degrades rapidly within the TME, releasing Mn2+ ions, which couple with trimodal (upconversion luminescence, computed tomography (CT), and magnetic resonance imaging) imaging of UCNPs to perform a selfenhanced imaging. Significantly, the degradation of mMnO2 shell brings an efficient DOX release, and relieve tumor hypoxia by simultaneously inducing decomposition of tumor endogenous H2O2 and reduction of glutathione, thus achieving a highly potent chemo-photodynamic therapy.

Tumor Microenvironment-Responsive Mesoporous MnO2-Coated Upconversion Nanoplatform for Self-Enhanced Tumor Theranostics

Biodegradability of inorganic nanoparticles is one of the most critical issues in their further clinical translations. In this work, a novel “metal ion-doping” approach has been developed to endow inorganic mesoporous silica-based nanoparticles with tumor-sensitive biodegradation and theranostic functions, simply by topological transformation of mesoporous silica to metal-doped composite nanoformulations. “Manganese extraction” sensitive to tumor microenvironment was enabled in manganese-doped hollow mesoporous silica nanoparticles (designated as Mn-HMSNs) to fast promote the disintegration and biodegradation of Mn-HMSNs, further accelerating the breakage of Si–O–Si bonds within the framework. The fast biodegradation of Mn-HMSNs sensitive to mild acidic and reducing microenvironment of tumor resulted in much accelerated anticancer drug releasing and enhanced T1-weighted magnetic resonance imaging of tumor. A high tumor-inhibition effect was simultaneously achieved by anticancer drug delivery mediated by P...

"Manganese Extraction" Strategy Enables Tumor-Sensitive Biodegradability and Theranostics of Nanoparticles.

In this paper, we demonstrate the tunable T1 and T2 contrast abilities of engineered iron oxide nanoparticles with high performance for liver contrast-enhanced magnetic resonance imaging (MRI) in mice. To enhance the diagnostic accuracy of MRI, large numbers of contrast agents with T1 or T2 contrast ability have been widely explored. The comprehensive investigation of high-performance MRI contrast agents with controllable T1 and T2 contrast abilities is of high importance in the field of molecular imaging. In this study, we synthesized uniform manganese-doped iron oxide (MnIO) nanoparticles with controllable size from 5 to 12 nm and comprehensively investigated their MRI contrast abilities. We revealed that the MRI contrast effects of MnIO nanoparticles are highly size-dependent. By controlling the size of MnIO nanoparticles, we can achieve T1-dominated, T2-dominated, and T1-T2 dual-mode MRI contrast agents with much higher contrast enhancement than the corresponding conventional iron oxide nanoparticles.

Tunable T1 and T2 contrast abilities of manganese-engineered iron oxide nanoparticles through size control

Silica nanoparticles are increasingly used in the biomedical fields due to their excellent solubility, high stability and favorable biocompatibility. However, despite being considered of low genotoxicity, their bio-related adverse effects have attracted particular concern from both the scientific field and the public. In this study, human cervical adenocarcinoma cells (HeLa line) were exposed to 0.01 or 1.0 mg/mL of hydrophilic silica nanoparticles. The H-1 NMR spectroscopy coupled with multivariate statistical analysis were used to characterize the metabolic variations of intracellular metabolites and the compositional changes of the corresponding culture media. At the early stage of silica nanoparticles-exposure, no obvious dose-effect of HeLa cell metabolome was observed, which implied that cellular stress-response regulated the metabolic variations of HeLa cell. Silica nanoparticles induced the increases of lipids including triglyceride, LDL, VLDL and lactate/alanine ratio and the decreases of alanine, ATP, choline, creatine, glycine, glycerol, isoleucine, leucine, phenylalanine, tyrosine, and valine, which involved in membrane modification, catabolism of carbohydrate and protein, and stress-response. Subsequently, a complicated synergistic effect of stress-response and toxicological-effect dominated the biochemical process and metabolic response, which was demonstrated in the reverse changes of some metabolites including acetate, ADP, ATP, choline, creatine, glutamine, glycine, lysine, methionine, phenylalanine and valine between 6 and 48 h post-treatment of silica nanoparticles. The toxicological-effects induced by high-dosage silica nanoparticles could be derived from the elevated levels of ATP and ADP, the utilization of glucose and amino acids and the production of metabolic end-products such as glutamate, glycine, lysine, methionine, phenylalanine, and valine. The results indicated that it is important and necessary to pursue further the physiological responses of silica nanoparticles in animal models and human before their practical use. NMR-based metabolomic analysis helps to understand the biological mechanisms of silica nanoparticles and their metabolic fate, and further, it offers an ideal platform for establishing the bio-safety of existing and new nanomaterials.

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Metabolic responses of HeLa cells to silica nanoparticles by NMR-based metabolomic analyses

Recently, some types of MnO nanoparticle (Mn-NP) with favorable imaging capacity have been developed to improve the biocompatible profile of the existing Mn-based MRI contrast agent Mn-DPDP; however, the overall bio-effects and potential toxicity remain largely unknown. In this study, (1)H NMR-based metabolic profiling, integrated with traditional biochemical analysis and histopathological examinations, was used to investigate the absorption, distribution, metabolism, excretion and toxicity of Mn-NPs as candidates for MRI contrast agent. The metabolic responses in biofluids (plasma and urine) and tissues (liver, spleen, kidney, lung and brain) from rats could be divided into four classes following Mn-NP administration: Mn biodistribution-dependent, time-dependent, dose-dependent and complicated metabolic variations. The variations of these metabolites involved in lipid, energy, amino acid and other nutrient metabolism, which disclosed the metabolic fate and biological effects of Mn-NPs in rats. The changes of metabolic profile implied that the disturbance and impairment of biological functions induced by Mn-NP exposure were correlated with the particle size and the surface chemistry of nanoparticles. Integration of metabonomic technology with traditional methods provides a promising tool to understand the toxicological behavior of biomedical nanomaterials and will result in informed decision-making during drug development.

https://iopscience.iop.org/article/10.1088/0957-4484/24/45/455102/pdf

Understanding the metabolic fate and assessing the biosafety of MnO nanoparticles by metabonomic analysis

Many hepatocellular carcinoma (HCC) patients suffer from late stages when diagnosed, leading to dismal prospects for cure. Improving the diagnosis and treatment of HCC remains a challenge. In this work, NMR-based metabolomic techniques were used to investigate the metabolic alterations of HCC patients from different pathological backgrounds. Metabolic improvement of clinical surgical treatments or transcatheter arterial chemoembolization (TACE) for recurrent or metastatic HCC was also evaluated. HCC was characterized by enhanced lipid metabolism and high consumption in response to liver injury. Expectedly, higher consumption of glucose and lactate production in TACE group confirmed that recurrent or metastatic HCC is more active in citric acid cycle and oxidative phosphorylation. However, TACE or surgical treatments did not immediately improve the metabolic profiles of HCC patients. Combining multivariate statistical analyses with univariate t-test, a series of characteristic metabolites were identified and served as biomarkers for discrimination of HCC patients in different pathological backgrounds. The relative metabolic pathway analyses help to get insight into the underlying biochemical mechanism and extend clinical relevance. Furthermore, algorithm of support vector classification was used to identify HCC and control subjects, and diagnostic sensitivity and specificity reached to 100% and 81.08% respectively by receiver operating characteristic analysis. It is concluded that NMR-based metabolomic analysis of plasma can provide a powerful approach to discover diagnostic and therapeutic biomarkers, and subsequently contribute to clinical disease management.

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Plasma metabolomic analysis of human hepatocellular carcinoma: Diagnostic and therapeutic study.

MnO-embedded iron oxide nanoparticles (MnIO-NPs) can be treated as potential dual-modal contrast agents. However, their overall bio-effects and potential toxicity remain unknown. In this study, the metabolic effects of MnIO-NPs (dosed at 1 and 5 mg Fe/kg) on Sprague–Dawley rats were investigated using metabonomic analysis, histopathological examination, and conventional biochemical analysis. The histological changes included a focal inflammation in the liver at high-dose and a slightly enlarged area of splenic white pulp after 48 h post-dose. Blood biochemical analysis showed that albumin, globulins, aspartate aminotransferase, lactate dehydrogenase, blood urea nitrogen, and glucose changed distinctly compared to the control. The metabonomic analysis of body fluids (serum and urine) and tissues (liver, kidney, and spleen) indicated that MnIO-NPs induced metabolic perturbation in rats including energy, nucleotides, amino acids and phospholipid metabolisms. Besides, the variations of supportive nutrients: valine, leucine, isoleucine, nicotinamide adenine dinucleotide (phosphate), and nicotinamide, and the conjugation substrates: glycine, taurine, glutamine, glutathione, and methyl donors (formate, sarcosine, dimethylglycine, choline, and betaine) were involved in detoxification reaction of MnIO-NPs. The obtained information would provide identifiable ground for the candidate selection and optimization.

NMR-based metabonomic analysis of MnO-embedded iron oxide nanoparticles as potential dual-modal contrast agents

Background Core-shell-structured nanoparticles (NPs) have attracted much scientific attention due to their promising potential in biomedical fields in recent years. However, their underlying mechanisms of action and potential adverse effects following administration remain unknown. Methods In the present study, a 1H nuclear magnetic resonance-based metabonomic strategy was applied to investigate the metabolic consequences in rats following the intravenous administration of parent NPs of core-shell-structured nanoparticles, Fe3O4@SiO2-NH2 (Fe@Si) NPs. Results Alterations reflected in plasma and urinary metabonomes indicated that Fe@Si NPs induced metabolic perturbation in choline, ketone-body, and amino-acid metabolism besides the common metabolic disorders in tricarboxylic acid cycle, lipids, and glycogen metabolism often induced by the exogenous agents. Additionally, intestinal flora metabolism and the urea cycle were also influenced by Fe@Si NP exposure. Time-dependent biological effects revealed obvious metabolic regression, dose-dependent biological effects implied different biochemical mechanisms between low- and high-dose Fe@Si NPs, and size-dependent biological effects provided potential windows for size optimization. Conclusion Nuclear magnetic resonance-based metabonomic analysis helps in understanding the biological mechanisms of Fe@Si NPs, provides an identifiable ground for the selection of view windows, and further serves the clinical translation of Fe@Si NP-derived and -modified bioprobes or bioagents.

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Jinquan Li

Papers

Metabolic responses of HeLa cells to silica nanoparticles by NMR-based metabolomic analyses

Understanding the metabolic fate and assessing the biosafety of MnO nanoparticles by metabonomic analysis

Plasma metabolomic analysis of human hepatocellular carcinoma: Diagnostic and therapeutic study.

NMR-based metabonomic analysis of MnO-embedded iron oxide nanoparticles as potential dual-modal contrast agents

Biological responses to core–shell-structured Fe 3 O 4 @SiO 2 -NH 2 nanoparticles in rats by a nuclear magnetic resonance-based metabonomic strategy