Developing Hypoxia-Sensitive System via Designing Tumor-Targeted Fullerene-Based Photosensitizer for Multimodal Therapy of Deep Tumor.

Photodynamic therapy (PDT) has been approved for clinic. However, powerless efficiency for deep hypoxic tumor therapy remains an enormous challenge for PDT. Herein, a hypoxia-sensitive nanotherapeutic system (FTCD-SRGD) based on fullerene (C70 ) and anoxic activating chemical prodrug tirapazamine (TPZ) is rationally designed for multimodal therapy of deep hypoxic tumors. To enhance the accumulation and achieve specific drug release in tumor, the FTCD-SRGD is modified with cyclo(Arg-Gly-Asp-d-Phe-Lys) (cRGDfK) peptide and disulfide bonds. With the exacerbated hypoxic microenvironment created by C70 consuming O2 for generating reactive oxygen species (ROS), TPZ is activated to produce toxic radical species to ablate deep tumors, which achieves a synergistic treatment of C70 -mediated PDT and hypoxia-enhanced chemotherapy. Additionally, given this hypoxia-sensitive system-induced immunogenic cell death (ICD) activating anticancer cytotoxic T lymphocyte to result in more susceptible tumor to immunotherapy, FTCD-SRGD plus immune checkpoint inhibitor (anti-PD-L1) fully inhibit deep hypoxic tumors by promoting infiltration of effector T cells in tumors. Collectively, it is the first time to develop a multimodal therapy system with fullerene-based hypoxia-sensitive PS for deep tumors. The powerful multimodal nanotherapeutic system for combining hypoxia-enhanced PDT and immunotherapy to massacre deep hypoxic tumors can provide a paradigm to combat the present bottleneck of tumor therapy.

An Antioxidative and Active Shrinkage Hydrogel Integratedly Promotes Re-Epithelization and Skin Constriction for Enhancing Wound Closure.

Delayed re-epithelization and weakened skin contractions are the two primary factors that hinder wound closure in large-scale acute or chronic wounds. However, effective strategies for targeting these two aspects concurrently are still lacking. Herein, an antioxidative active-shrinkage hydrogel (AHF@AS Gel) is constructed that can integratedly promote re-epithelization and skin constriction to accelerate large-scale acute and diabetic chronic wound closure. The AHF@AS Gel is encapsulated by antioxidative amino- and hydroxyl-modified C70 fullerene (AHF) and a thermosensitive active shrinkage hydrogel (AS Gel). Specifically, AHF relieves overactivated inflammation, prevents cellular apoptosis, and promotes fibroblast migration in vitro by reducing excessive reactive oxygen species (ROS). Notably, the AHF@AS Gel achieved ≈2.7-fold and ≈1.7-fold better re-epithelization in acute wounds and chronic diabetic wounds, respectively, significantly contributing to the promotion of wound closure. Using proteomic profiling and mechanistic studies, it is identified that the AHF@AS Gel efficiently promoted the transition of the inflammatory and proliferative phases to the remodeling phase. Notably, it is demonstrated that AS Gel alone activates the mechanosensitive epidermal growth factor receptor/Akt (EGFR/Akt) pathway and promotes cell proliferation. The antioxidative active shrinkage hydrogel offers a comprehensive strategy for acute wound and diabetic chronic wound closure via biochemistry regulation integrating with mechanical forces stimulation.

Self-Cascade Redox Modulator Trilogically Renovates Intestinal Microenvironment for Mitigating Endotoxemia.

Endotoxemia is a life-threatening multiple organ failure disease caused by bacterial endotoxin infection. Unfortunately, current single-target therapy strategies have failed to prevent the progression of endotoxemia. Here, we reported that alanine fullerene redox modulator (AFRM) remodeled the intestinal microenvironment for multiple targets endotoxemia mitigation by suppressing inflammatory macrophages, inhibiting macrophage pyroptosis, and repairing epithelial cell barrier integrity. Specifically, AFRM exhibited broad-spectrum and self-cascade redox regulation properties with superoxide dismutase (SOD)-like enzyme, peroxidase (POD)-like enzyme activity, and hydroxyl radical (•OH) scavenging ability. Guided by proteomics, we demonstrated that AFRM regulated macrophage redox homeostasis and down-regulated LPS/TLR4/NF-κB and MAPK/ERK signaling pathways to suppress inflammatory hyperactivation. Of note, AFRM could attenuate inflammation-induced macrophage pyroptosis via inhibiting the activation of gasdermin D (GSDMD). In addition, our results revealed that AFRM could restore extracellular matrix and cell-tight junction proteins and protect the epithelial cell barrier integrity by regulating extracellular redox homeostasis. Consequently, AFRM inhibited systemic inflammation and potentiated intestinal epithelial barrier damage repair during endotoxemia in mice. Together, our work suggested that fullerene based self-cascade redox modulator has the potential in the management of endotoxemia through synergistically remodeling the inflammation and epithelial barriers in the intestinal microenvironment.

Recovering intestinal redox homeostasis to resolve systemic inflammation for preventing remote myocardial injury by oral fullerenes.

The unbalanced immune state is the dominant feature of myocardial injury. However, the complicated pathology of cardiovascular diseases and the unique structure of cardiac tissue lead to challenges for effective immunoregulation therapy. Here, we exploited oral fullerene nanoscavenger (OFNS) to maintain intestinal redox homeostasis to resolve systemic inflammation for effectively preventing distal myocardial injury through bidirectional communication along the heart-gut immune axis. Observably, OFNS regulated redox microenvironment to repair cellular injury and reduce inflammation in vitro. Subsequently, OFNS prevented myocardial injury by regulating intestinal redox homeostasis and recovering epithelium barrier integrity in vivo. Based on the profiles of transcriptomics and proteomics, we demonstrated that OFNS balanced intestinal and systemic immune homeostasis for remote cardioprotection. Of note, we applied this principle to intervene myocardial infarction in mice and mini-pigs. These findings highlight that locally addressing intestinal redox to inhibit systemic inflammation could be a potent strategy for resolving remote tissue injury.

Oral Immunotherapy Reshapes Intestinal Immunosuppression via Metabolic Reprogramming to Enhance Systemic Anti-Tumor Immunity.

Tumor immunotherapy offers a new paradigm to treat cancer; however, the existing regimens are accompanied by the dilemma of insufficient therapeutic outcomes and off-target adverse effects. The intestinal immune system contains a bulk of immune cells, which can be important contributors to the maintenance of systemic immune homeostasis. However, manipulating intestinal immunity to achieve systemic anti-tumor immunity is extremely challenging. Here, an oral immunotherapy strategy is reported using immune-enhancing fullerenes (IEF) that can reinvigorate anti-tumor immunity via immune cell-metabolic reprogramming of intestinal immune cells. Findings show that IEF can remodel anti-inflammatory macrophages into tumor-killing macrophages by regulating the energy metabolism pathway from oxidative phosphorylation (OXPHOS) to glycolysis. Consequently, IEF can reprogram the immunosuppressive intestinal immunity and enhance sys temic immunity in vivo, thereby boosting anti-tumor immunity and converting "cold" tumors into "hot" tumors. Oral immunotherapy strategy, modulating autoimmune cells in the intestine and achieving systemic anti-tumor immunity, can ensure safe and efficient tumor immunotherapy.

Oral [60]fullerene reduces neuroinflammation to alleviate Parkinson's disease via regulating gut microbiome.

Neuroinflammation is considered to drive the pathogenic process of neuronal degeneration in Parkinson's disease (PD). However, effective anti-neuroinflammation therapeutics for PD still remain dissatisfactory. Here we explore a robust therapeutic strategy for PD using anti-neuroinflammatory fullerenes. Methods: Oral fullerene was prepared by a ball-milling method. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model was used to investigate the therapeutic effects and mechanisms of it. The gut microenvironment was evaluated by 16S rRNA gene sequencing, gas chromatography-mass spectrometry, quantitative polymerase chain reaction (Q-PCR), and western blot (WB). The neuroinflammation and neurodegeneration were evaluated by pathological analysis, Elisa kits, transmission electron microscopy, Q-PCR, WB and so on. Toxicity was assessed by weight, blood test and hematoxylin-eosin (HE) staining. Results: Oral fullerene therapeutic system that dissolved [60]fullerene into olive oil (abbreviated as OFO) was dexterously designed, which could reduce neuroinflammation via regulating the diversity of gut microbiome, increasing the contents of short chain fatty acids (SCFAs) and recovering the integrity of gut barrier. Accordingly, the reduction of neuroinflammation prevented dopaminergic neuronal degeneration. And thus, OFO significantly ameliorated motor deficits and fundamentally reversed dopamine (DA) loss in MPTP-induced PD mice. Of note, OFO exhibited low toxicity towards the living body. Conclusion: Our findings suggest that OFO is a safe-to-use, easy-to-apply, and prospective candidate for PD treatment in clinic, opening a therapeutic window for neuroinflammation-triggered neurodegeneration.

Inhibiting redox-mediated endothelial migration by gadofullerenes for inducing tumor vascular normalization and improving chemotherapy.

Tumor vascular normalization (TVN) reverses abnormal tumor vasculatures, which could boost anti-cancer efficiency and especially increase drug intratumoral delivery. Endothelial cells play a vital role in angiogenesis, yet continuous modulating endothelial cell migration to improve TVN is ingenious but challenging. Here we propose a potential strategy for TVN based on inhibiting endothelial migration using antioxidative fullerene nanoparticles (FNPs). We demonstrate that FNPs inhibit cell migration upon their anti-oxidation effects in vitro. The optimized alanine-modified gadofullerene (GFA) exhibits superior TVN ability and inhibits tumor growth in vivo. Mechanically, facilitated with the protein microarray, we confirm that GFA could suppress the focal adhesion pathway to restrain endothelial migration. Subsequently, remarkable anti-tumor efficacy of chemotherapy synergy was obtained, which benefited from a more normalized vascular network by GFA. Together, our study introduces the potential of FNPs as promising TVN boosters to consider in cancer nanomedicine design.

Metal-Free Peroxidase-Mimetic Nanocatalysts for Chemodynamic Vascular-Disrupting Cancer Therapy.

Metal ion-facilitated chemodynamic therapy (CDT) is an emerging method for treating cancer. However, its potential is hindered by its low catalytic performance in weakly acidic tumor microenvironments (TMEs) and the severe toxicity of free metal ions. A new approach to tumor therapy, chemodynamic vascular disruption (CVD), is introduced using metal-free, peroxidase (POD)-mimetic multihydroxylated [70] fullerene (MHF) nanocatalysts. The research shows that MHF contains C···O active sites, as demonstrated by density functional theory (DFT) calculations, and converts H2 O2 into ∙OH across a pH range of 6.0-10.0. The generation of ∙OH and the dismantling of tumor blood vessels are observed in real-time using mouse dorsal skin-fold chamber (DSFC) models. Applying proteomics, it is discovered that the CVD mechanism involves the nanocatalytic MHF enhancing H2 O2 decomposition in the TME, producing ∙OH. This damages tumor vascular endothelial junction proteins, causing vascular leakage and subsequently cutting off the vascular supply to the tumor cells. This method deviates from the traditional CDT that targets tumor cells. Instead, the proficient MHF nanocatalysts aim to directly disrupt the tumor vasculature, enhancing anti-tumor efficiency without triggering harmful toxicity. The proposed CVD therapeutic strategy enhances the application of gentle carbon nanocatalysts in cancer therapy, offering new perspectives on nanocatalytic medicine.

Efficiently normalizing leukopoiesis by gadofullerene nanoparticles to ameliorate radiation-triggered myelosuppression.

Myelosuppression is a predominant side-effect of radiotherapy, which manifests as the lower activity of blood cell precursors in bone marrow. Though progress in anti-myelosuppression has been made by the application of growth factors e.g., the granulocyte colony-stimulating factor (G-CSF), the side-effects (e.g., bone-pain, liver injury, and lung toxicity) limit their applications in clinic. Herein, we developed a strategy of efficiently normalizing leukopoiesis using gadofullerene nanoparticles (GFNPs) against myelosuppression triggered by radiation. Specifically, GFNPs with high radical-scavenging abilities elevated the generation of leukocytes and alleviated the bone marrow's pathological state under myelosuppression. Notably, GFNPs potentiated the differentiation, development, and maturation of leukocytes (neutrophils, lymphocytes) in radiation bearing mice even better than what G-CSF did. In addition, GFNPs had little toxicity towards the main organs including the heart, liver, spleen, lung, and kidney. This work provides an in-depth understanding of how advanced nanomaterials mitigate myelosuppression by regulating leukopoiesis.

Efficiently Inhibiting Systemic Inflammatory Cascades by Fullerenes for Retarding HFD-Fueled Atherosclerosis.

Atherosclerosis accounts for major mortality of cardiac-cerebral vascular diseases worldwide. Pathologically, persistent inflammation dominates the progression of atherosclerosis, which can be accelerated by a high-fat diet (HFD), possibly through triggering local intestinal oxidative stress and ensuing gut barrier dysfunction. Current pharmacotherapy has been disappointing, ascribed to limited therapeutic efficacy and undesirable side effects. Hence it is compelling to explore novel efficient anti-atherosclerotic drugs with minimal toxicity. Herein, two fullerene-based therapies with exceptional antioxidant capacity, in the form of water-soluble injectable fullerene nanoparticles (IFNPs) and oral fullerene tablets (OFTs), are demonstrated to retard HFD-fueled atherosclerosis in ApoE-/- mice with favorable biosafety. Especially, OFTs afford robust anti-atherosclerotic therapeutic even against advanced plaques, besides stabilizing plaques with less lipid deposition and improved collagen expression. Specifically, it is identified that OFTs can ameliorate HFD-induced dysregulated intestinal redox homeostasis and restore gut barrier integrity, thereby restraining the translocation of luminal lipopolysaccharide (LPS) into the bloodstream. Furthermore, significantly reduced circulating LPS after OFTs treatment contributes to down-regulated LPS/TLR4/NF-κB signaling in aortic focal, which further mitigates local inflammation and disease development. Overall, this study confirms the universal anti-atherosclerotic effect of fullerenes and provides a novel therapeutic mechanism via modulating intestinal barrier to attenuate atherosclerosis.

Oral nano-antioxidants improve sleep by restoring intestinal barrier integrity and preventing systemic inflammation.

Sleep deprivation (SD) is a severe public health threat that can cause systemic inflammation and nerve damage. Few effective and side-effect-free drugs are available to address SD. However, the bidirectional communications between the brain and gut provide new strategies for anti-SD therapeutics. Here we explored oral delivery of fullerene nano-antioxidants (FNAO) in the SD model to improve sleep by regulating abnormal intestinal barrier and systemic inflammation via the brain-gut axis. SD caused excessive reactive oxygen species (ROS) production and hyperactive inflammatory responses in the intestines of zebrafish and mouse models, leading to disturbed sleep patterns and reduced brain nerve activity. Of note, based on the property of the conjugated π bond of the C60 structure to absorb unpaired electrons, oral FNAO efficiently reduced the excessive ROS in the intestines, maintained redox homeostasis and intestinal barrier integrity, and ameliorated intestinal and systemic inflammation, resulting in superior sleep improvement. Our findings suggest that maintaining intestinal homeostasis may be a promising avenue for SD-related nerve injury therapy.

Oral fullerene tablets for colorectal cancer therapy based on modulation of tumor inflammatory microenvironments.

The development and progression of colorectal cancer (CRC) are highly dependent on the long-term inflammatory microenvironment with immune dysregulation in the colorectum. However, effective therapeutics are limited to targeting CRC. Here, we developed oral fullerene tablets (OFTs) that can act directly on the colorectal site by oral administration and reduce the inflammatory state at the tumor site for effective CRC therapy. In detail, OFTs scavenged reactive oxygen species (ROS), restrained the mutation of the wild-type P53, inhibited the activation of the inflammatory pathway nuclear factor-κB (NF-κB) and the signal transducer and activator of transcription 3 (STAT3) in the colorectum of CRC mice. Subsequently, OFTs could greatly reduce the infiltration of pro-inflammatory M1 macrophages and neutrophils at the tumor site, restoring the inflammatory microenvironment and immune homeostasis in the colorectal region, and ultimately achieving the inhibition of CRC. In addition, there were no significant toxic side effects of the long-term administration of OFTs. Our work provides an effective oral therapeutic strategy for CRC therapy by modulating the colorectal tumor inflammatory microenvironment and sheds light on the route for oral nano-materials in the clinical treatment of CRC.

Amphiphilic Aminated Derivatives of [60]Fullerene as Potent Inhibitors of Tumor Growth and Metastasis.

Malignant proliferation and metastasis are the hallmarks of cancer cells. Aminated [70]fullerene exhibits notable antineoplastic effects, promoting it a candidate for multi-targeted cancer drugs. It is an urgent need to reveal the structure-activity relationship for antineoplastic aminated fullerenes. Herein, three amphiphilic derivatives of [60]fullerene with clarified molecular structures are synthesized: TAPC-4, TAPC-3, and TCPC-4. TAPC-4 inhibits the proliferation of diverse tumor cells via G0/G1 cell cycle arrest, reverses the epithelial-mesenchymal transition, and abrogates the high mobility of tumor cells. TAPC-4 can be excreted from the organism and achieves an in vivo inhibition index of 75.5% in tumor proliferation and 87.5% in metastatic melanoma with a wide safety margin. Molecular dynamics simulations reveal that the amphiphilic molecular structure and the ending amino groups promote the targeting of TAPC-4 to heat shock protein Hsp90-beta, vimentin, and myosin heavy chain 9 (MYH9), probably resulting in the alteration of cyclin D1 translation, vimentin expression, and MYH9 location, respectively. This work initially emphasizes the dominant role of the amphiphilic structure and the terminal amino moieties in the antineoplastic effects of aminated fullerenes, providing fundamental support for their anti-tumor drug development.

Functionalized gadofullerene ameliorates impaired glycolipid metabolism in type 2 diabetic mice.

The soaring global prevalence of diabetes makes it urgent to explore new drugs with high efficacy and safety. Nanomaterial-derived bioactive agents are emerging as one of the most promising candidates for biomedical application. In the present study, we investigated the anti-diabetic effects of a functionalized gadofullerene (GF) using obese db/db and non-obese mouse model of type 2 diabete mellitus (MKR) mouse type 2 diabetes mellitus (T2DM) models. In both mouse models, the diabetic phenotypes, including hyperglycemia, impaired glucose tolerance, and insulin sensitivity, were ameliorated after two or four weeks of intraperitoneal administration of GF. GF lowered blood glucose levels in a dose-dependent manner. Importantly, the restored blood glucose levels could persist ten days after withdrawal of GF treatment. The hepatic AKT/GSK3ß/FoxO1 pathway is shown to be the main target of GF for rebalancing gluconeogenesis and glycogen synthesis in vivo and in vitro. Furthermore, GF treatment significantly reduced weight gain of db/db mice with reduced hepatic fat storage by the inhibition of de novo lipogenesis through mTOR/S6K/SREBP1 pathway. Our data provide compelling evidence to support the promising application of GF for the treatment of T2DM.

A gadofullerene based liver-specific MRI contrast agent for an early diagnosis of orthotopic hepatocellular carcinoma.

Hepatocellular carcinoma has become one of the most prevalent cancers, with a high mortality rate. Accurate diagnosis at an earlier stage is regarded as an effective measure to reduce the disease-related mortality of liver cancer. Magnetic resonance imaging (MRI) as a non-invasive checking mode has become a powerful tool in medical diagnosis. However, MRI contrast agents for liver-specific imaging either have some side effects or the imaging effect is not ideal. Thus, development of more efficient and security MRI contrast agents for the early diagnosis of hepatocellular carcinoma is urgent. Herein, a kind of water-soluble gadofullerene nanoparticle (GFNP) with high efficiency and security has been successfully used to achieve in situ liver cancer imaging. By comparing GFNPs with different functional groups, Gd@C82 modified by a hydroxyl group (GF-OH) presents the highest contrast efficiency both in vitro and in vivo. Notably, the smallest tumor with a diameter of only 0.5 mm could be clearly observed by GF-OH using MRI. Moreover, the imaging window of GF-OH is more than 3-6 hours. In addition, GF-OH can be mostly excreted from the living body and causes no serious toxicity. These results demonstrate that GF-OH is a safe, efficient MRI contrast agent for the diagnosis of early orthotopic hepatocellular carcinoma.

Cellular Uptake, Organelle Enrichment, and In Vitro Antioxidation of Fullerene Derivatives, Mediated by Surface Charge.

Hydrophilic fullerene derivatives get notable performance in various biological applications, especially in cancer therapy and antioxidation. The biological behaviors of functional fullerenes are much dependent on their surface physicochemical properties. The excellent reactive oxygen species-scavenging capabilities of functional fullerenes promote their outstanding performances in inhibiting pathological symptoms associated with oxidative stress, including neurodegenerative diseases, cardiovascular diseases, acute and chronic kidney disease, and diabetes. Herein, fullerene derivatives with reversed surface charges in aqueous solutions are prepared: cationic C60-EDA and anionic C60-(EDA-EA). Under the driving force of membrane potential (negative inside) in the cell and mitochondria, C60-EDA is much rapidly taken in by cells and transported into mitochondria compared with C60-(EDA-EA) that is enriched in lysosomes. With high cellular uptake and mitochondrial enrichment, C60-EDA exhibits stronger antioxidation capabilities in vitro than C60-(EDA-EA), indicating its better performance in the therapy of oxidation-induced diseases. It is revealed that the cellular uptake rate, subcellular location, and intracellular antioxidation behavior of fullerene derivatives are primarily mediated by their surface charges, providing new strategies for the design of fullerene drugs and their biological applications.

Aminated Fullerene Abrogates Cancer Cell Migration by Directly Targeting Myosin Heavy Chain 9.

Functional fullerene derivatives exhibit fantastic inhibitory capabilities against cancer survival and metastasis, but the absence of clarified biological molecular targets and ambiguous regulation mechanisms set barriers for their clinical transformation. Cancer metastasis is the primary cause of mortality and initiated with increased cell migration, making cell motility regulation a high-value therapeutic target in precision medicine. Herein, a critical molecular target of the aminated fullerene derivative (C70-EDA), myosin heavy chain 9 (MYH9), was initially identified by a pull-down assay and MS screening. MYH9 is a cytoplasm-located protein and is responsible for cell motility and epithelial-mesenchymal transition regulation. Omics data from large-scale clinical samples reveals that MYH9 gets overexpressed in various cancers and correlates with unfavorable prognosis, indicating that it is a potential antineoplastic target. It is unveiled that C70-EDA binds to the C-terminal of MYH9, triggering the transport of MYH9 from the cytoplasm to the cell edge, blocking the MYH9-involved cell mobility, and inhibiting the metastasis-associated EMT process. This work provides a precise biological target and new strategies for fullerene applications in cancer therapy.

Gadofullerene inhibits the degradation of apolipoprotein B100 and boosts triglyceride transport for reversing hepatic steatosis.

Hepatic steatosis is a widespread metabolic disease characterized by excessive accumulation of triglyceride (TG) in liver. So far, effective approved drugs for hepatic steatosis are still in development, and removing the unnecessary TG from the hepatocytes is an enormous challenge. Here, we explore a promising anti-hepatic steatosis strategy by boosting hepatocellular TG transport using ß-alanine-modified gadofullerene (GF-Ala) nanoparticles. We confirm that GF-Ala could reverse hepatic steatosis in oleic acid-induced hepatocytes, fructose-induced mice, and obesity-associated transgenic ob/ob mice. Observably, GF-Ala improves hepatomegaly and hepatic lipid accumulation, reduces lipid peroxidation, and repairs abnormal mitochondria. Of note, we demonstrate that GF-Ala markedly inhibits the posttranslational degradation of apolipoprotein B100 (ApoB100) and boosts hepatocellular TG transport based on their superior antioxidant property. Together, we conclude that GF-Ala could potently ameliorate hepatic TG transport and maintain hepatic metabolic homeostasis without apparent toxicity, being beneficial for treatments of hepatic steatosis and other fatty liver diseases.

Amino acid modified gadofullerene protects against insulin resistance induced by oxidative stress in 3T3-L1 adipocytes.

Reactive oxygen species (ROS) have been shown to be involved in the development of insulin resistance; thus, antioxidant therapy is a promising strategy in the treatment of insulin resistance related diseases. In this study, we synthesized a high-efficiency ROS scavenger, an amino acid derivative of Gd@C82 (GF-Ala), and evaluated its effects on ROS-mediated insulin resistance in 3T3-L1 adipocytes. The exposure of adipocytes to H2O2 (generated by glucose oxidase) resulted in an elevated level of ROS, a reduced content of GSH and an increase in JNK activation, concomitantly with a decrease in insulin-stimulated PI3K, Akt and p70S6K activation and cellular glucose uptake. The pre-treatment of cells with GF-Ala suppressed H2O2-induced abnormalities in the cellular redox state and insulin signalling pathway and attenuated insulin resistance in a dose-dependent manner. Altogether, gadofullerene has potential therapeutic prospects in the prevention and treatment of insulin resistance related diseases.

Gadofullerene nanoparticles for robust treatment of aplastic anemia induced by chemotherapy drugs.

Aplastic anemia (AA) is characterized as hypoplasia of bone marrow hematopoietic cells and hematopenia of peripheral blood cells. Though the supplement of exogenous erythropoietin (EPO) has been clinically approved for AA treatment, the side-effects hinder its further application. Here a robust treatment for AA induced by chemotherapy drugs is explored using gadofullerene nanoparticles (GFNPs). Methods: The gadofullerene were modified with hydrogen peroxide under alkaline conditions to become the water-soluble nanoparticles (GFNPs). The physicochemical properties, in vitro chemical construction, stability, hydroxyl radical scavenging ability, in vitro cytotoxicity, antioxidant activity, in vivo treatment efficacy, therapeutic mechanism and biological distribution, metabolism, toxicity of GFNPs were examined. Results: GFNPs with great stability and high-efficiency antioxidant activity could observably increase the number of red blood cells (RBC) in the peripheral blood of AA mice and relieve the abnormal pathological state of bone marrow. The erythropoiesis mainly includes hemopoietic stem cells (HSCs) differentiation, erythrocyte development in bone marrow and erythrocyte maturation in peripheral blood. The positive control-EPO promotes erythropoiesis by regulating HSCs differentiation and erythrocyte development in bone marrow. Different from the anti-AA mechanism of EPO, GFNPs have little impact on both the differentiation of HSCs and the myeloid erythrocyte development, but notably improve the erythrocyte maturation. Besides, GFNPs can notably decrease the excessive reactive oxygen species (ROS) and inhibit apoptosis of hemocytes in blood. In addition, GFNPs are mostly excreted from the living body and cause no serious toxicity. Conclusion: Our work provides an insight into the advanced nanoparticles to powerfully treat AA through ameliorating the erythrocyte maturation during erythropoiesis.