Combined Electrochemical Deposition and Photo-Reduction to Fabricate SERS-Active Silver Substrates: Characterization and Application for Malachite Green Detection in Aquaculture Water.

This research introduces a novel approach using silver (Ag) nanostructures generated through electrochemical deposition and photo-reduction of Ag on fluorine-doped tin oxide glass substrates (denoted as X-Ag-AgyFTO, where 'X' and 'y' represent the type of light source and number of deposited cycles, respectively) for surface-enhanced Raman spectroscopy (SERS). This study used malachite green (MG) as a Raman probe to evaluate the enhancement factors (EFs) in SERS-active substrates under varied fabrication conditions. For the substrates produced via electrochemical deposition, we determined a Raman EF of 6.15 × 104 for the Ag2FTO substrate. In photo-reduction, the impact of reductant concentration, light source, and light exposure duration were examined on X-Ag nanoparticle formation to achieve superior Raman EFs. Under optimal conditions (9.0 mM sodium citrate, 460 nm blue-LED at 10 W for 90 min), the combination of blue-LED-reduced Ag (B-Ag) and an Ag2FTO substrate (denoted as B-Ag-Ag2FTO) exhibited the best Raman EF of 2.79 × 105. This substrate enabled MG detection within a linear range of 0.1 to 1.0 µM (R2 = 0.98) and a detection limit of 0.02 µM. Additionally, the spiked recoveries in aquaculture water samples were between 90.0% and 110.0%, with relative standard deviations between 3.9% and 6.3%, indicating the substrate's potential for fungicide detection in aquaculture.

A Ratiometric Fluorescent Sensor for Penicillin G Based on Color-Tunable Gold-Silver Nanoclusters.

Excessive administration of penicillin G and improper disposal of its residues pose a serious risk to human health; therefore, the development of convenient methods for monitoring penicillin G levels in products is essential. Herein, novel gold-silver nanoclusters (AuAgNCs) were synthesized using chicken egg white and 6-aza-2-thiothymine as dual ligands with strong yellow fluorescence at 509 and 689 nm for the highly selective detection of penicillin G. The AuAgNCs were characterized using transmission electron microscopy, X-ray photoelectron spectroscopy, ultraviolet-visible absorption spectrophotometry, and fluorescence spectrophotometry. Under optimum conditions, the fluorescence intensity decreased linearly with the concentration of penicillin G from 0.2 to 6 µM, with a low detection limit of 18 nM. Real sample analyses indicated that a sensor developed using the AuAgNCs could detect penicillin G in urine and water samples within 10 min, with the recoveries ranging from 99.7 to 104.0%. The particle size of the AuAgNCs increased from 1.80 to 9.06 nm in the presence of penicillin G. We believe the aggregation-induced quenching of the fluorescence of the AuAgNCs was the main mechanism for the detection of penicillin G. These results demonstrate the ability of our sensor for monitoring penicillin G levels in environmental and clinic samples.

Electrochemically synthesized green fluorescent carbon dots for quantitation of hypochlorite and carbendazim.

Green emission carbon dots (CDs) electrochemically prepared from 2,6-pyridinedicarboxylic acid and o-phenyl-enediamine were applied separately for the quantitation of hypochlorite and carbendazim. The characteristic and optical properties of the CDs were studied through fluorescence, UV-vis absorption, X-ray photoelectron spectroscopy, and transmission electron microscopy. The synthesized CDs were mainly 0.8-2.2 nm in size, with an average size of 1.5 nm. The CDs exhibited green luminescence centered at 520 nm when excited by 420 nm light. The green emission of the CDs is quenched after the addition of hypochlorite, mainly through the redox reaction between hypochlorite and hydroxyl groups on the CDs surface. Furthermore, the hypochlorite-induced fluorescence quenched can be prevented in the presence of carbendazim. The sensing approaches exhibit good linear ranges of 1-50 µM and 0.05-5 µM for hypochlorite and carbendazim, respectively, with low detection limits of 0.096 and 0.005 µM, respectively. Practicalities of the luminescent probes were separately validated by the quantitation of the two analytes in real sample matrix with recoveries ranging from 96.3 to 108.9% and the relative standard deviation values below 5.51%. Our results show the potential of the sensitive, selective, and simple CD probe for water and food quality control.

Proposed A2C2S2-VASc score for predicting atrial fibrillation development in patients with atrial flutter.

AIMS: The clinical outcome and threshold of oral anticoagulation differs between patients with solitary atrial flutter (AFL) and those with AFL developing atrial fibrillation (AF) (AFL-DAF). We therefore investigated previously unevaluated predictors of AF development in patients with AFL, and also the predictive values of risk scores in predicting the occurrence of AF and ischaemic stroke. METHODS AND RESULTS: Participants were those diagnosed with AFL between 1 January 2001 and 31 December 2013. Patients were classified into solitary AFL and AFL-DAF groups during follow-up. Finally, 4101 patients with solitary AFL and 4101 patients with AFL-DAF were included after 1:1 propensity score matching with CHA2DS2-VASc scores and their components, AFL diagnosis year and other comorbidities. The group difference in the prevalence of ischaemic stroke/transient ischaemic attack (TIA) and congestive heart failure (CHF) was substantial, that of vascular disease was moderate, and that of diabetes and hypertension was negligible. Therefore, we reweighted the component of heart failure as 2 (the same with stroke/TIA) and vascular disease as 1 in the proposed A2C2S2-VASc score. The proposed A2C2S2-VASc and CHA2DS2-VASC scores showed patients with AFL who had higher delta scores and follow-up scores had higher risk of AF development. The delta score outperformed the follow-up score in both scoring systems in predicting ischaemic stroke. CONCLUSION: This study showed that new-onset CHF, stroke/TIA and vascular disease were predictors of AF development in patients with AFL. The dynamic score and changes in both CHA2DS2-VASC and the proposed A2C2S2-VASc score could predict the development of AF and ischaemic stroke.

Female sex as a risk factor for ischaemic stroke varies with age in patients with atrial fibrillation.

OBJECTIVES: Female sex is an inconsistent ischaemic stroke risk factor in patients with atrial fibrillation (AF). We hypothesised that the ischaemic stroke risk varies with age among women compared with men. METHODS: We retrieved the patients with newly diagnosed AF during 2001-2013 from Taiwan's National Health Insurance Research Database. Patients with missing information, age <20 years, history of valvular heart disease and surgery, rheumatic heart disease, hyperthyroidism or anticoagulation and/or antiplatelet use were excluded. Propensity score matching (PSM) included patient comorbidities, medications and index date stratified by age and sex groups. Primary outcome was defined as ischaemic stroke at follow-up. RESULTS: After exclusion criteria, 87 369 men and 71 853 women remained for analysis (aged 73.1±14.4 years). After 1:1 PSM, we included 59 583 men (aged 73.5±13.7 years) and 59 583 women (aged 73.4±13.8 years) for analysis. We also stratified patients by age. The ischaemic stroke risk varied with age in women compared with men: lower in the ≤55 years (subdistribution HR (SHR)=0.75, 95% CI 0.62 to 0.90) and 56-65 years (SHR=0.87, 95% CI 0.78 to 0.98) groups, neutral in the 66-75 years group (SHR=1.01, 95% CI 0.94 to 1.08) and adverse in the >75 years group (SHR=1.14, 95% CI 1.09 to 1.19). CONCLUSIONS: The female/male ischaemic stroke risk ratio varied with age. Only women aged >75 years had a higher risk, whereas women aged <65 years had a lower risk compared with men. These findings challenge the 'sex category' component of the CHA2DS2-VASc score, used to make decision regarding anticoagulation treatment in AF patients.

Cell-Templated Silica Microparticles with Supported Lipid Bilayers as Artificial Antigen-Presenting Cells for T Cell Activation.

Biomaterial properties that modulate T cell activation, growth, and differentiation are of significant interest in the field of cellular immunotherapy manufacturing. In this work, a new platform technology that allows for the modulation of various activation particle design parameters important for polyclonal T cell activation is presented. Artificial antigen presenting cells (aAPCs) are successfully created using supported lipid bilayers on various cell-templated silica microparticles with defined membrane fluidity and stimulating antibody density. This panel of aAPCs is used to probe the importance of activation particle shape, size, membrane fluidity, and stimulation antibody density on T cell outgrowth and differentiation. All aAPC formulations are able to stimulate T cell growth, and preferentially promote CD8+ T cell growth over CD4+ T cell growth when compared to commercially available pendant antibody-conjugated particles. T cells cultured with HeLa- and red blood cell-templated aAPCs have a less-differentiated and less-exhausted phenotype than those cultured with spherical aAPCs with matched membrane coatings when cultured for 14 days. These results support continued exploration of silica-supported lipid bilayers as an aAPC platform.

Establishing the effects of mesoporous silica nanoparticle properties on in vivo disposition using imaging-based pharmacokinetics.

The progress of nanoparticle (NP)-based drug delivery has been hindered by an inability to establish structure-activity relationships in vivo. Here, using stable, monosized, radiolabeled, mesoporous silica nanoparticles (MSNs), we apply an integrated SPECT/CT imaging and mathematical modeling approach to understand the combined effects of MSN size, surface chemistry and routes of administration on biodistribution and clearance kinetics in healthy rats. We show that increased particle size from ~32- to ~142-nm results in a monotonic decrease in systemic bioavailability, irrespective of route of administration, with corresponding accumulation in liver and spleen. Cationic MSNs with surface exposed amines (PEI) have reduced circulation, compared to MSNs of identical size and charge but with shielded amines (QA), due to rapid sequestration into liver and spleen. However, QA show greater total excretion than PEI and their size-matched neutral counterparts (TMS). Overall, we provide important predictive functional correlations to support the rational design of nanomedicines.

Understanding the Connection between Nanoparticle Uptake and Cancer Treatment Efficacy using Mathematical Modeling.

Nanoparticles have shown great promise in improving cancer treatment efficacy while reducing toxicity and treatment side effects. Predicting the treatment outcome for nanoparticle systems by measuring nanoparticle biodistribution has been challenging due to the commonly unmatched, heterogeneous distribution of nanoparticles relative to free drug distribution. We here present a proof-of-concept study that uses mathematical modeling together with experimentation to address this challenge. Individual mice with 4T1 breast cancer were treated with either nanoparticle-delivered or free doxorubicin, with results demonstrating improved cancer kill efficacy of doxorubicin loaded nanoparticles in comparison to free doxorubicin. We then developed a mathematical theory to render model predictions from measured nanoparticle biodistribution, as determined using graphite furnace atomic absorption. Model analysis finds that treatment efficacy increased exponentially with increased nanoparticle accumulation within the tumor, emphasizing the significance of developing new ways to optimize the delivery efficiency of nanoparticles to the tumor microenvironment.

Cost drivers for breast, lung, and colorectal cancer care in a commercially insured population over a 6-month episode: an economic analysis from a health plan perspective.

AIMS: In the absence of clinical data, accurate identification of cost drivers is needed for economic comparison in an alternate payment model. From a health plan perspective using claims data in a commercial population, the objective was to identify and quantify the effects of cost drivers in economic models of breast, lung, and colorectal cancer costs over a 6-month episode following initial chemotherapy. RESEARCH DESIGN AND METHODS: This study analyzed claims data from 9,748 Cigna beneficiaries with diagnosis of breast, lung, and colorectal cancer following initial chemotherapy from January 1, 2014 to December 31, 2015. We used multivariable regression models to quantify the impact of key factors on cost during the initial 6-month cancer care episode. RESULTS: Metastasis, facility provider affiliation, episode risk group (ERG) risk score, and radiation were cost drivers for all three types of cancer (breast, lung, and colorectal). In addition, younger age (p < .0001) and human epidermal growth factor receptor-2 oncogene overexpression (HER2+)-directed therapy (p < .0001) were associated with higher costs in breast cancer. Younger age (p < .0001) and female gender (p < .0001) were also associated with higher costs in colorectal cancer. Metastasis was also associated with 50% more hospital admissions and increased hospital length of stay (p < .001) in all three cancers over the 6-month episode duration. Chemotherapy and supportive drug therapies accounted for the highest proportion (48%) of total medical costs among beneficiaries observed. CONCLUSIONS: Value-based reimbursement models in oncology should appropriately account for key cost drivers. Although claims-based methodologies may be further augmented with clinical data, this study recommends adjusting for the factors identified in these models to predict costs in breast, lung, and colorectal cancers.

Predictors of Left Ventricle Remodeling: Combined Plasma B-type Natriuretic Peptide Decreasing Ratio and Peak Creatine Kinase-MB.

Background: Previous studies reported that patients who had an acute myocardial infarction (AMI) have found that measuring B-type natriuretic peptide (BNP) during the subacute phase of left ventricular (LV) remodeling can predict the possible course of LV remodeling. This study assessed the use of serial BNP serum levels combined with early creatine kinase-MB (CK-MB) to predict the development of significant LV remodeling in AMI patients. Methods: Nighty-seven patients with new onset AMI were assessed using serial echocardiographic studies and serial measurements of BNP levels, both performed on day-2 (BNP1), day-7 (BNP2), day-90 (BNP3), and day-180 (BNP4) after admission. LV remodeling was defined as >20% increase in biplane LV end-diastolic volume on day-180 compared to baseline (day-2). Results: Patients were divided into LV remodeling [LVR(+)] and non LV remodeling [LVR(-)] groups. No first-week BNP level was found to predict remodeling. However, the two groups had significantly different day-90 BNP level (208.1 ± 263.7 pg/ml vs. 82.4 ± 153.7 pg/ml, P = 0.039) and significantly different 3-month BNP decrease ratios ( R BNP13) (14.4 ± 92.2% vs. 69.4 ± 25.9%, P < 0.001). The appropriate cut-off value for R BNP13 was 53.2% (AUC = 0.764, P < 0.001). Early peak CK-MB (cut-off 48.2 ng/ml; AUC = 0.672; P = 0.014) was another independent predictor of remodeling. Additionally, combining peak CK-MB and R BNP13 offered an excellent discrimination for half-year remodeling when assessed by ROC curve (AUC = 0.818, P < 0.001). Conclusion: R BNP13 is a significant independent predictor of 6-month LV remodeling. The early peak CK-MB additionally offered an incremental power to the predictions derived from serial BNP examinations.

Two-Dimensional Speckle Tracking Echocardiography Predict Left Ventricular Remodeling after Acute Myocardial Infarction in Patients with Preserved Ejection Fraction.

OBJECTIVES: Left ventricular remodeling after acute myocardial infarction increases cardiovascular events and mortality. But few study was done in patients with preserved ejection fraction (EF > 40%). We investigate whether the strain and strain rate by 2D speckle tracking echocardiography could predict left ventricular remodeling after acute myocardial infarction in this cohort. METHODS: The 83 patients (average age 60.7 ± 12.3 y, 75 [90.4%] male) with new-onset acute myocardial infarction receiving echocardiography immediately, and 6 months after admission were grouped by the presence or absence of left ventricular remodeling. Strain and strain rate including longitudinal, circumferential, and radial direction were calculated. The average of strain and strain rate of which segmental longitudinal strains > - 15% were defined as the injury longitudinal strain (InjLS). RESULTS: Left ventricular remodeling occurred in 24 of 83 patients (28.9%). In univariate logistic regression analyses, gender, peak CK-MB, log BNP, use of statin before discharge, wall motion score index, and InjLS were significantly associated with left ventricular remodeling (p < 0.05). In multivariate analysis using the forward stepwise method, gender, CK-MB, and InjLS were independent predictors. The hazard ratio for InjLS was 1.48 (p = 0.04). Receiver operating characteristic curve (ROC) analyses showed the area under the curve (AUC) of InjLS was largest (AUC = 0.75, cut-off value = -11.7%, sensitivity = 81%, specificity = 71%, p < 0.01). In ST-segment elevation myocardial infarction subgroup, InjLS was the only predictor according to ROC analysis (AUC = 0.79, p < 0.01, cut-off value = -11.4%, sensitivity = 88%, specificity = 77%) and multivariate logistic regression analysis (hazard ratio = 1.88, 95% CI: 1.22-2.88, p < 0.01). CONCLUSIONS: InjLS was an excellent predictor for left ventricular remodeling after acute myocardial infarction in patient with preserved ejection fraction.

Mesoporous Silica Nanoparticle-Supported Lipid Bilayers (Protocells) for Active Targeting and Delivery to Individual Leukemia Cells.

Many nanocarrier cancer therapeutics currently under development, as well as those used in the clinical setting, rely upon the enhanced permeability and retention (EPR) effect to passively accumulate in the tumor microenvironment and kill cancer cells. In leukemia, where leukemogenic stem cells and their progeny circulate within the peripheral blood or bone marrow, the EPR effect may not be operative. Thus, for leukemia therapeutics, it is essential to target and bind individual circulating cells. Here, we investigate mesoporous silica nanoparticle (MSN)-supported lipid bilayers (protocells), an emerging class of nanocarriers, and establish the synthesis conditions and lipid bilayer composition needed to achieve highly monodisperse protocells that remain stable in complex media as assessed in vitro by dynamic light scattering and cryo-electron microscopy and ex ovo by direct imaging within a chick chorioallantoic membrane (CAM) model. We show that for vesicle fusion conditions where the lipid surface area exceeds the external surface area of the MSN and the ionic strength exceeds 20 mM, we form monosized protocells (polydispersity index <0.1) on MSN cores with varying size, shape, and pore size, whose conformal zwitterionic supported lipid bilayer confers excellent stability as judged by circulation in the CAM and minimal opsonization in vivo in a mouse model. Having established protocell formulations that are stable colloids, we further modified them with anti-EGFR antibodies as targeting agents and reverified their monodispersity and stability. Then, using intravital imaging in the CAM, we directly observed in real time the progression of selective targeting of individual leukemia cells (using the established REH leukemia cell line transduced with EGFR) and delivery of a model cargo. Overall, we have established the effectiveness of the protocell platform for individual cell targeting and delivery needed for leukemia and other disseminated disease.

Integrated nanotechnology platform for tumor-targeted multimodal imaging and therapeutic cargo release.

A major challenge of targeted molecular imaging and drug delivery in cancer is establishing a functional combination of ligand-directed cargo with a triggered release system. Here we develop a hydrogel-based nanotechnology platform that integrates tumor targeting, photon-to-heat conversion, and triggered drug delivery within a single nanostructure to enable multimodal imaging and controlled release of therapeutic cargo. In proof-of-concept experiments, we show a broad range of ligand peptide-based applications with phage particles, heat-sensitive liposomes, or mesoporous silica nanoparticles that self-assemble into a hydrogel for tumor-targeted drug delivery. Because nanoparticles pack densely within the nanocarrier, their surface plasmon resonance shifts to near-infrared, thereby enabling a laser-mediated photothermal mechanism of cargo release. We demonstrate both noninvasive imaging and targeted drug delivery in preclinical mouse models of breast and prostate cancer. Finally, we applied mathematical modeling to predict and confirm tumor targeting and drug delivery. These results are meaningful steps toward the design and initial translation of an enabling nanotechnology platform with potential for broad clinical applications.

Synthetic fossilization of soft biological tissues and their shape-preserving transformation into silica or electron-conductive replicas.

Structural preservation of complex biological systems from the subcellular to whole organism level in robust forms, enabling dissection and imaging while preserving 3D context, represents an enduring grand challenge in biology. Here we report a simple immersion method for structurally preserving intact organisms via conformal stabilization within silica. This self-limiting process, which we refer to as silica bioreplication, occurs by condensation of water-soluble silicic acid proximally to biomolecular interfaces throughout the organism. Conformal nanoscopic silicification of all biomolecular features imparts structural rigidity enabling the preservation of shape and nano-to-macroscale dimensional features upon drying to form a biocomposite and further high temperature oxidative calcination to form silica replicas or reductive pyrolysis to form electrically conductive carbon replicas of complete organisms. The simplicity and generalizability of this approach should facilitate efforts in biological preservation and analysis and could enable the development of new classes of biomimetic composite materials.

Porous ice phases with VI and distorted VII structures constrained in nanoporous silica.

High-pressure compression of water contained in nanoporous silica allowed fabrication of novel porous ice phases as a function of pressure. The starting liquid nanoporous H2O transformed to ice VI and VII at 1.7 and 2.5 GPa, respectively, which are 0.6 and 0.4 GPa higher than commonly accepted pressures for bulk H2O. The continuous increase of pressure drives the formation of a tetragonally distorted VII structure with the space group I4mm, rather than a cubic Pn3m phase in bulk ice. The enhanced incompressibility of the tetragonal ice is related to the unique nanoporous configuration, and the distortion ratio c/a gradually increases with increasing pressure. The structural changes and enhanced thermodynamic stability may be interpreted by the two-dimensional distribution of silanol groups on the porous silica surfaces and the associated anisotropic interactions with H2O at the interfaces.

One-pot synthesis of fluorescent BSA-Ce/Au nanoclusters as ratiometric pH probes.

A facile, one-pot synthetic approach has been developed for the preparation of BSA-Ce/Au NCs. The fluorescence intensities of BSA-Ce/Au NCs at 410 and 650 nm are pH dependent and independent, respectively. The fluorescence intensity ratio (I410/I650) is linear against pH values from 6.0 to 9.0. These stable and biocompatible BSA-Ce/Au NCs have been used as ratiometric probes for monitoring local pH values inside HeLa cells.

Two-wave nanotherapy to target the stroma and optimize gemcitabine delivery to a human pancreatic cancer model in mice.

Pancreatic ductal adenocarcinoma (PDAC) elicits a dense stromal response that blocks vascular access because of pericyte coverage of vascular fenestrations. In this way, the PDAC stroma contributes to chemotherapy resistance in addition to causing other problems. In order to improve the delivery of gemcitabine, a first-line chemotherapeutic agent, a PEGylated drug-carrying liposome was developed, using a transmembrane ammonium sulfate gradient to encapsulate the protonated drug up to 20% w/w. However, because the liposome was precluded from entering the xenograft site due to the stromal interference, we developed a first-wave nanocarrier that decreases pericyte coverage of the vasculature through interference in the pericyte recruiting TGF-ß signaling pathway. This was accomplished using a polyethyleneimine (PEI)/polyethylene glycol (PEG)-coated mesoporous silica nanoparticle (MSNP) for molecular complexation to a small molecule TGF-ß inhibitor, LY364947. LY364947 contains a nitrogen atom that attaches, through H-bonding, to PEI amines with a high rate of efficiency. The copolymer coating also facilitates systemic biodistribution and retention at the tumor site. Because of the high loading capacity and pH-dependent LY364947 release from the MSNPs, we achieved rapid entry of IV-injected liposomes and MSNPs at the PDAC tumor site. This two-wave approach provided effective shrinkage of the tumor xenografts beyond 25 days, compared to the treatment with free drug or gemcitabine-loaded liposomes only. Not only does this approach overcome stromal resistance to drug delivery in PDAC, but it also introduces the concept of using a stepwise engineered approach to address a range of biological impediments that interfere in nanocancer therapy in a spectrum of cancers.

Re-examining the size/charge paradigm: differing in vivo characteristics of size- and charge-matched mesoporous silica nanoparticles.

The combination of nanoparticle (NP) size, charge, and surface chemistry (e.g., extent of modification with polyethylene glycol (PEG)) is accepted as a key determinant of NP/cellular interactions. However, the influence of spatial arrangement and accessibility of the charged molecules on the NP surface vis-à-vis the average surface charge (zeta (ζ) potential) is incompletely understood. Here we demonstrate that two types of mesoporous silica nanoparticles (MSNP) that are matched in terms of primary and hydrodynamic particle size, shape, pore structure, colloidal stability, and ζ potential, but differ in surface chemistry, viz. the spatial arrangement and relative exposure of surface amines, have profoundly different interactions with cells and tissues when evaluated in vitro and in vivo. While both particles are ∼50 nm in diameter, PEGylated, and positively charged (ζ = +40 mV), PEG-PEI (MSNPs modified with exposed polyamines), but not PEG-NMe3(+) (MSNP modified with distributed, obstructed amines) rapidly bind serum proteins, diverse cells types in vitro, and endothelial and white blood cells in vivo (ex ovo chick embryo model). This finding helps elucidate the relative role of surface exposure of charged molecules vs ζ potential in otherwise physicochemically matched MSNP and highlights protein corona neutrality as an important design consideration when synthesizing cationic NPs for biological applications.

Effects of Mesoporous Silica Coating and Post-Synthetic Treatment on the Transverse Relaxivity of Iron Oxide Nanoparticles.

Mesoporous silica nanoparticles have the capacity to load and deliver therapeutic cargo and incorporate imaging modalities, making them prominent candidates for theranostic devices. One of the most widespread imaging agents utilized in this and other theranostic platforms is nanoscale superparamagnetic iron oxide. Although several core-shell magnetic mesoporous silica nanoparticles presented in the literature have provided high T2 contrast in vitro and in vivo, there is ambiguity surrounding which parameters lead to enhanced contrast. Additionally, there is a need to understand the behavior of these imaging agents over time in biologically relevant environments. Herein, we present a systematic analysis of how the transverse relaxivity (r2) of magnetic mesoporous silica nanoparticles is influenced by nanoparticle diameter, iron oxide nanoparticle core synthesis, and the use of a hydrothermal treatment. This work demonstrates that samples which did not undergo a hydrothermal treatment experienced a drop in r2 (75% of original r2 within 8 days of water storage), while samples with hydrothermal treatment maintained roughly the same r2 for over 30 days in water. Our results suggest that iron oxide oxidation is the cause of the r2 loss, and this oxidation can be prevented both during synthesis and storage by the use of deoxygenated conditions during nanoparticle synthesis. The hydrothermal treatment also provides colloidal stability, even in acidic and highly salted solutions, and a resistance against acid degradation of the iron oxide nanoparticle core. The results of this study show the promise of multifunctional mesoporous silica nanoparticles but will also likely inspire further investigation into multiples types of theranostic devices, taking into consideration their behavior over time and in relevant biological environments.

High payload Gd(iii) encapsulated in hollow silica nanospheres for high resolution magnetic resonance imaging.

For clear MR imaging of blood vessels, a long blood circulation time of effective T1 contrast agents is necessary. Nanoparticulate MR contrast agents are much more effective owing to their enhanced relaxivity, a result of reduced tumbling rates, and large payloads of active magnetic species. PEGylated yolk-shell silica nanospheres containing high payloads of Gd(iii) with cross-linking ligands are synthesized and evaluated as a blood-pool magnetic resonance contrast agent. The hydrophilic PEG coating and the microporous silica shell allow water exchange while keeping the multi-nuclear Gd species from leaching out. These Gd(iii)-containing yolk-shell silica nanoparticles with PEGylated surfaces give excellent resolution and contrast in magnetic resonance angiography images of vasculature in rat brains.