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1.
Cytokine ; 129: 155030, 2020 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-32050144

RESUMO

OBJECTIVE: Our recent genetic-neuroimaging study observed that the rs1799724 polymorphism within the TNFA gene encoding TNF-α selectively affects the anatomy of visual cortex in patients with MDD. In this study, we hypothesized that TNFA is risk factor to MDD, and TNFA rs1799724 polymorphism may be a susceptibility locus for this disorder and its clinical features. METHODS: We enrolled 807 MDD samples and 822 healthy volunteers in Eastern China. There were 104 drug-naïve first episode MDD patients recruited. The Hamilton Rating Scale for Depression -17 (HRSD-17) and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) were performed to evaluate the severity of depressive symptoms and cognitive function, respectively. RESULTS: Patients with MDD have higher levels of TNFA than healthy controls (F = 20.78, P < 0.01). There were no significant differences in genotype or allele distributions of the rs1799724 polymorphism between the MDD and control groups. MDD patients with T/T or T/C genotypes of rs1799724 polymorphism have higher somatic factor and total scores of HAMD than those with C/C genotype. The patients with T/T or T/C genotypes have significantly higher TNFA mRNA levels than those with C/C genotype (F = 4.91, P = 0.029). CONCLUSION: Our findings supported that TNFA may have an important role in the pathophysiology of MDD. Although SNP rs1799724 is not an etiological factor for MDD in Han Chinese, this SNP may be associated with somatic symptom in patients with MDD.

2.
ACS Nano ; 2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-32057223

RESUMO

As one of the major air pollutants, NOX is rather challenging to remove. The main treatment method is catalytic reduction with plenty of reducing agents, which lacks any effective control in an open air environment such as urban spaces. It is necessary to seek a self-powered electrochemical process for environmental treatment. The triboelectric nanogenerator (TENG), a developing technology with various advantages, is widely used in energy and environmental monitoring and cleaning. In this work, a radial-engine-shaped TENG system with five stacked TENGs is designed to synchronously absorb NOX and degrade its main enrichment forms of nitrate and nitrite in aqueous solution. In addition, the system possesses inherent phase differences and outputs continuous direct current after rectification. Moreover, we demonstrated that, driven by artificial wind at a speed of 6 m/s, the NOX generated by a chemical method was effectively degraded by the radial-engine-shaped TENG system.

3.
Steroids ; : 108598, 2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-32068075

RESUMO

Three new oxygenated steroids, sinulasterols A-C (1-3), along with seven known related steroids 4-10, were isolated from the Chinese soft coral Sinularia depressa. The structures of the new compounds were established from extensive spectroscopic data analyses and by comparison of their spectral data with those reported in the literature. Among the new compounds, metabolites 1 and 2 featured on unusual C-18 oxygenated pattern. In the TNF-α bioassay, compound 4 exhibited a potent inhibitory activity (IC50 = 12.1 µM), which was analogous to the positive control dexamethasone (IC50 = 8.7 µM), metabolites 1 and 2 displayed a moderate inhibitory activity (IC50 51.1 µM and 22.7 µM respectively).

5.
Mol Cell ; 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-32017896

RESUMO

U6 snRNA, as an essential component of the catalytic core of the pre-mRNA processing spliceosome, is heavily modified post-transcriptionally, with 2'-O-methylation being most common. The role of these modifications in pre-mRNA splicing as well as their physiological function in mammals have remained largely unclear. Here we report that the La-related protein LARP7 functions as a critical cofactor for 2'-O-methylation of U6 in mouse male germ cells. Mechanistically, LARP7 promotes U6 loading onto box C/D snoRNP, facilitating U6 2'-O-methylation by box C/D snoRNP. Importantly, ablation of LARP7 in the male germline causes defective U6 2'-O-methylation, massive alterations in pre-mRNA splicing, and spermatogenic failure in mice, which can be rescued by ectopic expression of wild-type LARP7 but not an U6-loading-deficient mutant LARP7. Our data uncover a novel role of LARP7 in regulating U6 2'-O-methylation and demonstrate the functional requirement of such modification for splicing fidelity and spermatogenesis in mice.

6.
J Biol Chem ; 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32019868

RESUMO

Pseudomonas aeruginosa uses a type III secretion system (T3SS) to inject cytotoxic effector proteins into host cells. The promiscuous nucleotidyl cyclase, exoenzyme Y (ExoY), is one of the most common effectors found in clinical P. aeruginosa isolates. Recent studies have revealed that the nucleotidyl cyclase activity of ExoY is stimulated by actin filaments (F-actin), and that ExoY alters actin cytoskeleton dynamics in vitro, via an unknown mechanism.The actin cytoskeleton plays an important role in numerous key biological processes and is targeted by many pathogens to gain competitive advantages. We utilized total internal reflection fluorescence microscopy, bulk actin assays, and EM to investigate how ExoY impacts actin dynamics. We found that ExoY can directly bundle actin filaments with high affinity, comparable to eukaryotic F-actin bundling proteins such as fimbrin. Of note, ExoY enzymatic activity was not required for F-actin bundling. Bundling is known to require multiple actin binding sites, yet small angle X-ray scattering (SAXS) experiments revealed that ExoY is a monomer in solution and previous data suggested that ExoY possesses only one actin binding site. We therefore hypothesized that ExoY oligomerizes in response to F-actin binding and have used the ExoY structure to construct a dimer-based structural model for the ExoY-F-actin complex. Subsequent mutational analyses suggested that the ExoY oligomerization interface plays a crucial role in mediating F-actin bundling. Our results indicate that ExoY represents a new class of actin binding proteins that modulate the actin cytoskeleton both directly, via F-actin bundling, and indirectly, via actin-activated nucleotidyl cyclase activity.

7.
Sensors (Basel) ; 20(3)2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32033499

RESUMO

Wi-Fi based positioning has great potential for use in indoor environments because Wi-Fi signals are near-ubiquitous in many indoor environments. With a Reference Fingerprint Map (RFM), fingerprint matching can be adopted for positioning. Much assisting information can be adopted for increasing the accuracy of Wi-Fi based positioning. One of the most adopted pieces of assisting information is the Pedestrian Dead Reckoning (PDR) information derived from inertial measurements. This is widely adopted because the inertial measurements can be acquired through a Commercial Off The Shelf (COTS) smartphone. To integrate the information of Wi-Fi fingerprinting and PDR information, many methods have adopted filters, such as Kalman filters and particle filters. A new methodology for integration of Wi-Fi fingerprinting and PDR is proposed using graph optimization in this paper. For the Wi-Fi based fingerprinting part, our method adopts the state-of-art hierarchical structure and the Penalized Logarithmic Gaussian Distance (PLGD) metric. In the integration part, a simple extended Kalman filter (EKF) is first used for integration of Wi-Fi fingerprinting and PDR results. Then, the tracking results are adopted as initial values for the optimization block, where Wi-Fi fingerprinting and PDR results are adopted to form an concentrated cost function (CCF). The CCF can be minimized with the aim of finding the optimal poses of the user with better tracking results. With both real-scenario experiments and simulations, we show that the proposed method performs better than classical Kalman filter based and particle filter based methods with both less average and maximum positioning error. Additionally, the proposed method is more robust to outliers in both Wi-Fi based and PDR based results, which is commonly seen in practical situations.

8.
J Thorac Oncol ; 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32036071

RESUMO

BACKGROUND: Programmed death receptor-1 (PD-1) inhibitors have shown efficacy in first line treatment of non-small cell lung cancer (NSCLC), however, evidence of PD-1 inhibitor as neoadjuvant treatment is limited. This is a phase 1b study to evaluate the safety and outcome of PD-1 inhibitor in neoadjuvant setting. METHODS: Treatment-naïve patients with resectable NSCLC (stage IA-IIIB) received two cycles of sintilimab (200 mg, intravenously, day 1/22). Surgery was performed between day 29-43. PET-CT was obtained at baseline and prior to surgery. Primary endpoint was safety. Efficacy endpoints included rate of major pathologic response (MPR) and objective response rate (ORR). PD-L1 expression was also evaluated. (Registration Number: ChiCTR-OIC-17013726). RESULTS: Forty patients enrolled, all of whom received 2 doses of sintilimab, and 37 underwent radical resection. Twenty-one (52.5%) patients experienced neoadjuvant treatment-related adverse events (TRAEs). Four (10.0%) patients experienced grade 3-4 neoadjuvant TRAEs, and one patient had grade 5 TRAE. Eight patients achieved radiological partial response, resulting in an ORR of 20.0%. Among 37 patients, 15 (40.5%) achieved MPR, including 6 (16.2%) with a pathologic complete response in primary tumor and 3 (8.1%) in lymph nodes as well. Squamouse cell NSCLC exhibited superior response compared to adenocarcinoma (MPR: 48.4% VS. 0%). Decrease of maximum standardized uptake values (SUVmax) after sintilimab treatment correlated with pathological remission (p<0.00001). Baseline PD-L1 expression of stromal cells instead of tumor cells was correlated with pathological regression (p=0.0471). CONCLUSION: Neoadjuvant sintilimab was tolerable for NSCLC patients and 40.5% MPR rate is encouraging. The decrease of SUVmax after sintilimab might predict pathologic response.

9.
Environ Pollut ; 260: 114045, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-32045968

RESUMO

The increasing release of metallic nanoparticles (NPs) or their sulfidized forms into soils have raised concerns about their potential risks to soil ecosystems. Hence, there is a need for novel strategies to remediate metallic NPs pollution in soils. In this study, to explore the feasibility of using earthworm Eisenia fetida to manage soils contaminated with metallic NPs, we simultaneously investigated the chronic soil toxicities of ZnO NPs and ZnS NPs to E. fetida, and the effects of E. fetida on Zn extractability in soils amended with ZnO NPs and ZnS NPs. After a 28 d exposure, survival rate and weight loss of earthworms were not impacted by either ZnO NPs or ZnS NPs at a concentration of 400 mg Zn per kg soil. Further, while ZnO NPs activated earthworm antioxidative system, ZnS NPs resulted in significant alleviation of oxidative damage in earthworm. The presence of earthworms significantly decreased the bioavailability of Zn in ZnO NPs contaminated soil, whereas significantly increased the bioavailability of Zn in ZnS NPs contaminated soil. These findings implied that the earthworm E. fetida could play an important role in altering the mobilization of metals originating from metallic NPs in soils, which may further aid in the development of a method for the treatment of metallic NPs pollution in soils.

10.
Bioorg Med Chem ; : 115344, 2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-32051094

RESUMO

Proprotein convertase (PC) subtilisin kexin type 9 (PCSK9) inhibits the clearance of low density lipoprotein (LDL) cholesterol from plasma by directly interacting with the LDL receptor (LDLR). As the interaction promotes elevated plasma LDL cholesterol levels and a predisposition to cardiovascular disease (CVD), it has attracted much interest as a therapeutic target. While anti-PCSK9 monoclonal antibodies have been successful in the treatment of hypercholesteremia by decreasing CVD risk, their high cost and a requirement for injection have prohibited widespread use. The advent of an orally bioavailable small molecule inhibitor of the PCSK9-LDLR interaction is an attractive alternative, however efforts have been tempered as the binding interface is unfavourable for binding by small organic molecules. Despite its challenging nature, we report herein the discovery of compound 3f as a small molecule inhibitor of PCSK9. The kinase inhibitor nilotinib emerged from a computational screen that was applied to identify compounds that may bind to a cryptic groove within PCSK9 and proximal to the LDLR-binding interface. A subsequent in vitro PCSK9-LDLR binding assay established that nilotinib was a bona fide but modest inhibitor of the interaction (IC50 = 9.8 µM). Through multiple rounds of medicinal chemistry, 3f emerged as a lead-like molecule by demonstrating disruption of the PCSK9-LDLR interaction at nanomolar levels in vitro (IC50 = 537 nM) with no inhibitory activity (IC50 > 10 µM) against a small panel of kinases. Compound 3f restored LDL uptake by liver cells at sub-micromolar levels and demonstrated excellent bioavailability when delivered subcutaneously in mice. Most significantly, compound 3f lowered total cholesterol levels in the plasma of wild-type mice, thereby providing proof-of-concept that the notion of a small molecule inhibitor against PCSK9 is therapeutically viable.

11.
Curr Alzheimer Res ; 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32053075

RESUMO

Studies have suggested that cognitive impairment in Alzheimer's disease (AD) is associated with dendritic spine loss, especially in the hippocampus. Fluoxetine (FLX) has been shown to improve cognition in the early stage of AD and to be associated with diminishing synapse degeneration in the hippocampus. However, little is known about whether FLX affects the pathogenesis of AD in the middle- to-late stage and whether its effects are correlated with the amelioration of hippocampal dendritic dysfunction. Previously, it has been observed that FLX improves the spatial learning ability of middleaged APP/PS1 mice. In the present study, we further characterized the impact of FLX on dendritic spines in the hippocampus of middle-aged APP/PS1 mice. It has been found that the numbers of dendritic spines in dentate gyrus (DG), CA1 and CA2/3 of hippocampus were significantly increased by FLX. Meanwhile, FLX effectively attenuated hyperphosphorylation of tau at Ser396 and elevated protein levels of postsynaptic density 95 (PSD-95) and synapsin-1 (SYN-1) in the hippocampus. These results indicated that the enhanced learning ability observed in FLX-treated middle-aged APP/PS1 mice might be associated with remarkable mitigation of hippocampal dendritic spine pathology by FLX and suggested that FLX might be explored as a new strategy for therapy of AD in the middle-to-late stage.

12.
Int J Med Sci ; 17(2): 182-190, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32038102

RESUMO

Background: Fatty acid-binding protein 1 (FABP1) (also known as liver-type fatty acid-binding protein or LFABP) is a protein that is mainly expressed in the liver, and is associated with hepatocyte injury in acute transplant rejection. Reduced levels of FABP1 in mice livers have been shown to be effective against nonalcoholic fatty liver disease (NAFLD). In this study, we investigated the association between plasma FABP1 levels and NAFLD in patients with type 2 diabetes mellitus (T2DM). Methods: We enrolled 267 T2DM patients. Clinical and biochemical parameters were measured. The severity of NAFLD was assessed by ultrasound. FABP1 levels were determined using by enzyme-linked immunosorbent assays. Results: FABP1 levels were higher in patients with overt NAFLD, defined as more than a moderate degree of fatty liver compared to those without NAFLD. Age- and sex-adjusted analysis of FABP1 showed positive associations with body mass index (BMI), waist circumference, homeostasis model assessment estimate of ß-cell function, creatinine, and fatty liver index, but showed negative associations with albumin and estimated glomerular filtration rate (eGFR). The odds ratio (OR) for the risk of overt NAFLD with increasing levels of sex-specific FABP1 was significantly increased (OR 2.63 [95% CI 1.30-5.73] vs. 4.94 [2.25-11.48]). The OR in the second and third tertiles of FABP1 remained significant after adjustments for BMI, triglycerides, high-density lipoprotein cholesterol, HbA1C, homeostasis model assessment estimate of insulin resistance, white blood cell count, hepatic enzymes, and eGFR. Conclusion: Our results indicate that FABP1 may play a role in the pathogenesis of NAFLD in patients with T2DM.

13.
J Hematol Oncol ; 13(1): 11, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32024555

RESUMO

BACKGROUND: Aberrant AKT activation contributes to cancer stem cell (CSC) traits in hepatocellular carcinoma (HCC). We previously reported that CD73 activated AKT signaling via the Rap1/P110ß cascade. Here, we further explored the roles of CD73 in regulating CSC characteristics of HCC. METHODS: CD73 expression modulations were conducted by lentiviral transfections. CD73+ fractions were purified by magnetic-based sorting, and fluorescent-activated cell sorting was used to assess differentiation potentials. A sphere-forming assay was performed to evaluate CSC traits in vitro, subcutaneous NOD/SCID mice models were generated to assess in vivo CSC features, and colony formation assays assessed drug resistance capacities. Stemness-associated gene expression was also determined, and underlying mechanisms were investigated by evaluating immunoprecipitation and ubiquitylation. RESULTS: We found CD73 expression was positively associated with sphere-forming capacity and elevated in HCC spheroids. CD73 knockdown hindered sphere formation, Lenvatinib resistance, and stemness-associated gene expression, while CD73 overexpression achieved the opposite effects. Moreover, CD73 knockdown significantly inhibited the in vivo tumor propagation capacity. Notably, we found that CD73+ cells exhibited substantially stronger CSC traits than their CD73- counterparts. Mechanistically, CD73 exerted its pro-stemness activity through dual AKT-dependent mechanisms: activating SOX9 transcription via c-Myc, and preventing SOX9 degradation by inhibiting glycogen synthase kinase 3ß. Clinically, the combined analysis of CD73 and SOX9 achieved a more accurate prediction of prognosis. CONCLUSIONS: Collectively, CD73 plays a critical role in sustaining CSCs traits by upregulating SOX9 expression and enhancing its protein stability. Targeting CD73 might be a promising strategy to eradicate CSCs and reverse Lenvatinib resistance in HCC.

14.
Artigo em Inglês | MEDLINE | ID: mdl-32043180

RESUMO

PURPOSE: Investigate whether 18F-FDG PET-CT has the potential to predict the major pathologic response (MPR) to neoadjuvant sintilimab in resectable NSCLC patients, and the potential of sifting patients who probably benefit from immunotherapy. METHODS: Treatment-naive patients with resectable NSCLC (stage IA-IIIB) received two cycles of sintilimab (200 mg, intravenously, day 1 and 22). Surgery was performed between day 29 and 43. PET-CT was obtained at baseline and prior to surgery. The following lean body mass-corrected metabolic parameters were calculated by PET VCAR: SULmax, SULpeak, MTV, TLG, ΔSULmax%, ΔSULpeak%, ΔMTV%, ΔTLG%. PET responses were classified using PERCIST. The above metabolic information on FDG-PET was correlated with the surgical pathology. (Registration Number: ChiCTR-OIC-17013726). RESULTS: Thirty-six patients received 2 doses of sintilimab, all of whom underwent PET-CT twice and had radical resection (35) or biopsy (1). MPR occurred in 13 of 36 resected tumors (36.1%, 13/36). The degree of pathological regression was positively correlated with SULmax (p = 0.036) of scan-1, and was negatively correlated with all metabolic parameters of scan-2, and the percentage changes of the metabolic parameters after neoadjuvant therapy (p < 0.05). According to PERCIST, 13 patients (36.1%, 13/36) showed partial metabolic response (PMR), 21 (58.3%, 21/36) had stable metabolic disease, and 2 (5.6%, 2/36) had progressive metabolic disease (PMD). There was a significant correlation between the pathological response and the PET responses which were classified using PERCIST. All (100.0%) the PMR (ΔSULpeak% < - 30.0%) tumors showed MPR. CONCLUSIONS: 18F-FDG PET-CT can predict MPR to neoadjuvant sintilimab in resectable non-small cell lung cancer.

15.
Chem Commun (Camb) ; 56(10): 1497-1500, 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-31915758

RESUMO

The direct photocatalyzed para-selective CAr-H difluoroalkylation of aromatic aldehyde derivatives has been accomplished using a newly explored catalytic system. In addition, when using para-substituted benzaldehydes as substrates, ortho-selective CAr-H difluoroalkylation was also accomplished. It is worth noting that all the above site-selectivity is opposite to traditional Friedel-Crafts reactions of aromatic aldehydes. The preliminary mechanistic investigations indicate that an electrophilic difluoroalkyl radical is involved in the catalytic cycle.

16.
Appl Microbiol Biotechnol ; 104(4): 1695-1705, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31900559

RESUMO

The interspecies communication roles of γ-butyrolactones (GBLs) have been described for a long time but are still poorly understood. Herein, we analyzed more than 1000 Streptomyces strains and noticed a big quantitative gap between the strains with GBL biosynthetic genes and the strains with GBL receptor genes, which implies the wide-spread of GBLs as interspecies signals in Streptomyces and their great potential in the activation of silent natural product gene clusters. Streptomyces albidoflavus J1074, which has one GBL receptor gene but no GBL biosynthetic gene, was chosen as a target to study the possible interspecies communication roles of GBLs. At first, the GBL biosynthetic genes from Streptomyces coelicolor M145 were expressed in S. albidoflavus J1074, which enabled the S. albidoflavus strains to synthesize Streptomyces coelicolor butanolides (SCBs) and activated the production of paulomycins. Further studies showed that this activation process requires the participation of the GBL receptor gene XNR_4681. The results suggest that the expression of exogenous GBL biosynthetic genes can modulate the metabolisms of GBL non-producing strains, and this regulation role might be meaningful for silent gene cluster activation in Streptomyces. At final, we synthesized racemic-SCB2 and tried to simplify the activation process by adding SCB2 directly to S. albidoflavus J1074, which unfortunately failed to induce paulomycin production.

18.
Radiology ; : 191470, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31934830

RESUMO

Background Early stage hepatocellular carcinoma (HCC) is the ideal candidate for resection in patients with preserved liver function; however, cancer will recur in half of these patients and no reliable prognostic tool has been established. Purpose To investigate the effectiveness of radiomic features in predicting tumor recurrence after resection of early stage HCC. Materials and Methods In total, 295 patients (median age, 58 years; interquartile range, 50-65 years; 221 men) who underwent contrast material-enhanced CT and curative resection for early stage HCC that met the Milan criteria between February 2009 and December 2016 were retrospectively recruited from three independent institutions. Follow-up consisted of serum α-fetoprotein level, liver function tests, and dynamic imaging examinations every 3 months during the first 2 years and then every 6 months thereafter. In the development cohort of 177 patients from institution 1, recurrence-related radiomic features were computationally extracted from the tumor and its periphery and a radiomics signature was built with least absolute shrinkage and selection operator regression. Two models, one integrating preoperative and one integrating pre- and postoperative variables, were created by using multivariable Cox regression analysis. An independent external cohort of 118 patients from institutions 2 and 3 was used to validate the proposed models. Results The preoperative model integrated radiomics signature with serum α-fetoprotein level and tumor number; the postoperative model incorporated microvascular invasion and satellite nodules into the above-mentioned predictors. In both study cohorts, two radiomics-based models provided better predictive performance (concordance index ≥0.77, P < .05 for all), lower prediction error (integrated Brier score ≤0.14), and larger net benefits, as determined by means of decision curve analysis, than rival models without radiomics and widely adopted staging systems. The radiomics-based models gave three risk strata with high, intermediate, or low risk of recurrence and distinct profiles of recurrent tumor number. Conclusion The proposed radiomics models with pre- and postresection features helped predict tumor recurrence for early stage hepatocellular carcinoma. © RSNA, 2020 Online supplemental material is available for this article.

19.
Biomaterials ; 235: 119783, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31981762

RESUMO

Glioblastoma (GBM) is one of the most malignant tumors with poor prognosis and outcomes. Although smaller particle size can lead to higher blood-brain barrier (BBB)-permeability of the nanomaterials, most of the reported BBB-crossable nanomaterials for targeted GBM therapy are larger than 24 nm. To realize theranostics of GBM, co-loading of therapeutic and diagnostic agents on the same nanomaterials further results in larger particle size. In this study, we developed a kind of novel BBB-transportable nanomaterials smaller than 14 nm for high-efficiency theranostics of GBM (i.e., high contrast magnetic resonance imaging (MRI) and radiosensitization of GBM). Typically, poly(acrylic acid) (PAA) stabilized extremely small gadolinium oxide nanoparticles with modification of reductive bovine serum albumin (ES-GON-rBSA) was synthesized in water phase, resulting in excellent water-dispersibility. RGD dimer (RGD2, Glu-{Cyclo[Arg-Gly-Asp-(D-Phe)-Lys]}2) and lactoferrin (LF) were then conjugated to the ES-GON-rBSA to obtain composite nanoparticle ES-GON-rBSA-LF-RGD2 with extraordinary relaxivities (r1 = 60.8 mM-1 s-1, r2/r1 = 1.1). The maximum signal enhancement (ΔSNR) for T1-weighted MRI of tumors reached up to 423 ± 42% at 12 h post-injection of ES-GON-rBSA-LF-RGD2, which is much higher than commercial Gd-chelates (<80%). ES-GON-rBSA-LF-RGD2 exhibited high biocompatibility and can transport across the in vitro BBB model and the in vivo BBB of mice due to its small particle size (dh = 13.4 nm) and LF receptor mediated transcytosis. Orthotopic GBM studies reinforce that ES-GON-rBSA3-LF-RGD2 can accumulate in the orthotopic GBM and enhance the radiation therapy of GBM as an effective radiosensitizing agent.

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