Kidney Injury Causes Accumulation of Renal Sodium That Modulates Renal Lymphatic Dynamics.

Lymphatic vessels are highly responsive to changes in the interstitial environment. Previously, we showed renal lymphatics express the Na-K-2Cl cotransporter. Since interstitial sodium retention is a hallmark of proteinuric injury, we examined whether renal sodium affects NKCC1 expression and the dynamic pumping function of renal lymphatic vessels. Puromycin aminonucleoside (PAN)-injected rats served as a model of proteinuric kidney injury. Sodium 23Na/1H-MRI was used to measure renal sodium and water content in live animals. Renal lymph, which reflects the interstitial composition, was collected, and the sodium analyzed. The contractile dynamics of isolated renal lymphatic vessels were studied in a perfusion chamber. Cultured lymphatic endothelial cells (LECs) were used to assess direct sodium effects on NKCC1. MRI showed elevation in renal sodium and water in PAN. In addition, renal lymph contained higher sodium, although the plasma sodium showed no difference between PAN and controls. High sodium decreased contractility of renal collecting lymphatic vessels. In LECs, high sodium reduced phosphorylated NKCC1 and SPAK, an upstream activating kinase of NKCC1, and eNOS, a downstream effector of lymphatic contractility. The NKCC1 inhibitor furosemide showed a weaker effect on ejection fraction in isolated renal lymphatics of PAN vs controls. High sodium within the renal interstitium following proteinuric injury is associated with impaired renal lymphatic pumping that may, in part, involve the SPAK-NKCC1-eNOS pathway, which may contribute to sodium retention and reduce lymphatic responsiveness to furosemide. We propose that this lymphatic vessel dysfunction is a novel mechanism of impaired interstitial clearance and edema in proteinuric kidney disease.

Renal tubular dilation and fibrosis after unilateral ureter obstruction revealed by relaxometry and spin-lock exchange MRI.

We evaluated the use of quantitative MRI relaxometry, including the dispersion of spin-lock relaxation with different locking fields, for detecting and assessing tubular dilation and fibrosis in a mouse model of unilateral ureter obstruction (UUO). C57BL/6 J and BALB/c mice that exhibit different levels of tubular dilation and renal fibrosis after UUO were subjected to MR imaging at 7 T. Mice were imaged before UUO surgery, and at 5, 10 and 15 days after surgery. We acquired maps of relaxation rates and fit the dispersion of spin-lock relaxation rates R1ρ at different locking fields (frequencies) to a model of exchanging water pools, and assessed the sensitivity of the derived quantities for detecting tubular dilation and fibrosis in kidney. Histological scores for tubular dilation and fibrosis, based on luminal space and positive fibrotic areas in sections, were obtained for comparison. Histology detected extensive tubular dilation and mild to moderate fibrosis in the UUO kidneys, in which enlargement of luminal space, deposition of collagen, and reductions in capillary density were observed in the cortex and outer stripe of the outer medulla. Relaxation rates R1 , R2 and R1ρ clearly decreased in these regions of UUO kidneys longitudinally. While R1 showed the highest detectability to tubular dilation and overall changes in UUO kidneys, Sρ , a parameter derived from R1ρ dispersion data, showed the highest correlation with renal fibrosis in UUO. While relaxation parameters are sensitive to tubular dilation in UUO kidneys, Sρ depends primarily on the average exchange rate between water and other chemically shifted resonances such as hydroxyls and amides, and provides additional specific information for evaluating fibrosis in kidney disease.

Spin-lock relaxation rate dispersion reveals spatiotemporal changes associated with tubulointerstitial fibrosis in murine kidney.

PURPOSE: To develop and evaluate a reliable non-invasive means for assessing the severity and progression of fibrosis in kidneys. We used spin-lock MR imaging with different locking fields to detect and characterize progressive renal fibrosis in an hHB-EGFTg/Tg mouse model. METHODS: Male hHB-EGFTg/Tg mice, a well-established model of progressive fibrosis, and age-matched normal wild type (WT) mice, were imaged at 7T at ages 5-7, 11-13, and 30-40 weeks. Spin-lock relaxation rates R1ρ were measured at different locking fields (frequencies) and the resultant dispersion curves were fit to a model of exchanging water pools. The obtained MRI parameters were evaluated as potential indicators of tubulointerstitial fibrosis in kidney. Histological examinations of renal fibrosis were also carried out post-mortem after MRI. RESULTS: Histology detected extensive fibrosis in the hHB-EGFTg/Tg mice, in which collagen deposition and reductions in capillary density were observed in the fibrotic regions of kidneys. R2 and R1ρ values at different spin-lock powers clearly dropped in the fibrotic region as fibrosis progressed. There was less variation in the asymptotic locking field relaxation rate R1ρ∞ between the groups. The exchange parameter Sρ and the inflection frequency ωinfl changed by larger factors. CONCLUSION: Both Sρ and ωinfl depend primarily on the average exchange rate between water and other chemically shifted resonances such as hydroxyls and amides. Spin-lock relaxation rate dispersion, rather than single measurements of relaxation rates, provides more comprehensive and specific information on spatiotemporal changes associated with tubulointerstitial fibrosis in murine kidney.

Synthesis of brightly PEGylated luminescent magnetic upconversion nanophosphors for deep tissue and dual MRI imaging.

A method is developed to fabricate monodispersed biocompatible Yb/Er or Yb/Tm doped ß-NaGdF4 upconversion phosphors using polyelectrolytes to prevent irreversible particle aggregation during conversion of the precursor, Gd2 O(CO3 )2.H2 O:Yb/Er or Yb/Tm, to ß-NaGdF4 :Yb/Er or Yb/Tm. The polyelectrolyte on the outer surface of nanophosphors also provided an amine tag for PEGylation. This method is also employed to fabricate PEGylated magnetic upconversion phosphors with Fe3 O4 as the core and ß-NaGdF4 as a shell. These magnetic upconversion nanophosphors have relatively high saturation magnetization (7.0 emu g(-1) ) and magnetic susceptibility (1.7 × 10(-2) emu g(-1) Oe(-1) ), providing them with large magnetophoretic mobilities. The magnetic properties for separation and controlled release in flow, their optical properties for cell labeling, deep tissue imaging, and their T1 - and T2 -weighted magnetic resonance imaging (MRI) relaxivities are studied. The magnetic upconversion phosphors display both strong magnetophoresis, dual MRI imaging (r1 = 2.9 mM(-1) s(-1) , r2 = 204 mM(-1) s(-1) ), and bright luminescence under 1 cm chicken breast tissue.

Multifunctional yolk-in-shell nanoparticles for pH-triggered drug release and imaging.

Multifunctional nanoparticles are synthesized for both pH-triggered drug release and imaging with radioluminescence, upconversion luminescent, and magnetic resonance imaging (MRI). The particles have a yolk-in-shell morphology, with a radioluminescent core, an upconverting shell, and a hollow region between the core and shell for loading drugs. They are synthesized by controlled encapsulation of a radioluminescent nanophosphor yolk in a silica shell, partial etching of the yolk in acid, and encapsulation of the silica with an upconverting luminescent shell. Metroxantrone, a chemotherapy drug, was loaded into the hollow space between X-ray phosphor yolk and up-conversion phosphor shell through pores in the shell. To encapsulate the drug and control the release rate, the nanoparticles are coated with pH-responsive biocompatible polyelectrolyte layers of charged hyaluronic acid sodium salt and chitosan. The nanophosphors display bright luminescence under X-ray, blue light (480 nm), and near infrared light (980 nm). They also served as T1 and T2 MRI contrast agents with relaxivities of 3.5 mM(-1) s(-1) (r1 ) and 64 mM(-1) s(-1) (r2 ). These multifunctional nanocapsules have applications in controlled drug delivery and multimodal imaging.

Dual-modality photothermal optical coherence tomography and magnetic-resonance imaging of carbon nanotubes.

We demonstrate polyethylene-glycol-coated single-walled carbon nanotubes (CNTs) as contrast agents for both photothermal optical coherence tomography (OCT) and magnetic-resonance imaging (MRI). Photothermal OCT was accomplished with a spectral domain OCT system with an amplitude-modulated 750 nm pump beam using 10 mW of power, and T(2) MRI was achieved with a 4.7 T animal system. Photothermal OCT and T(2) MRI achieved sensitivities of nanomolar concentrations to CNTs dispersed in amine-terminated polyethylene glycol, thus establishing the potential for dual-modality molecular imaging with CNTs.

Effects of intracellular organelles on the apparent diffusion coefficient of water molecules in cultured human embryonic kidney cells.

The apparent diffusion coefficient (ADC) of water in tissues is dependent on the size and spacing of structures in the cellular environment and has been used to characterize pathological changes in stroke and cancer. However, the factors that affect ADC values remain incompletely understood. Measurements of ADC are usually made using relatively long diffusion times; so they reflect the integrated effects of cellular structures over a broad range of spatial scales. We used temporal diffusion spectroscopy to study diffusion in packed cultured human embryonic kidney cells over a range of effective diffusion times following microtubule and actin/cytoskeleton depolymerization and disassembly of the Golgi complex. While Golgi disruption did not change ADC, depolymerization of the microtubule and the actin filament networks caused small decreases in ADC at short diffusion times only. Temporal diffusion spectroscopy provided a novel way to assess intracellular influences on the diffusion properties of tissue water.

Influence of cell cycle phase on apparent diffusion coefficient in synchronized cells detected using temporal diffusion spectroscopy.

The relationship between the apparent diffusion coefficient of tissue water measured by MR methods and the physiological status of cells is of particular relevance for better understanding and interpretation of diffusion-weighted MRI. In addition, there is considerable interest in developing diffusion-dependent imaging methods capable of providing novel information on tissue microstructure, including intracellular changes. To this end, both the conventional pulsed gradient spin-echo methods and the oscillating gradient spin-echo method, which probes diffusion over very short distance (<

Characterization of tissue structure at varying length scales using temporal diffusion spectroscopy.

The concepts, theoretical behavior and experimental applications of temporal diffusion spectroscopy are reviewed and illustrated. Temporal diffusion spectra are obtained using oscillating-gradient waveforms in diffusion-weighted measurements, and represent the manner in which various spectral components of molecular velocity correlations vary in different geometrical structures that restrict or hinder free movements. Measurements made at different gradient frequencies reveal information on the scale of restrictions or hindrances to free diffusion, and the shape of a spectrum reveals the relative contributions of spatial restrictions at different distance scales. Such spectra differ from other so-called diffusion spectra which depict spatial frequencies and are defined at a fixed diffusion time. Experimentally, oscillating gradients at moderate frequency are more feasible for exploring restrictions at very short distances which, in tissues, correspond to structures smaller than cells. We describe the underlying concepts of temporal diffusion spectra and provide analytical expressions for the behavior of the diffusion coefficient as a function of gradient frequency in simple geometries with different dimensions. Diffusion in more complex model media that mimic tissues has been simulated using numerical methods. Experimental measurements of diffusion spectra have been obtained in suspensions of particles and cells, as well as in vivo in intact animals. An observation of particular interest is the increased contrast and heterogeneity observed in tumors using oscillating gradients at moderate frequency compared with conventional pulse gradient methods, and the potential for detecting changes in tumors early in their response to treatment. Computer simulations suggest that diffusion spectral measurements may be sensitive to intracellular structures, such as nuclear size, and that changes in tissue diffusion properties may be measured before there are changes in cell density.

Translocator Protein PET Imaging in a Preclinical Prostate Cancer Model.

PURPOSE: The identification and targeting of biomarkers specific to prostate cancer (PCa) could improve its detection. Given the high expression of translocator protein (TSPO) in PCa, we investigated the use of [18F]VUIIS1008 (a novel TSPO-targeting radioligand) coupled with positron emission tomography (PET) to identify PCa in mice and to characterize their TSPO uptake. PROCEDURES: Ptenpc-/-, Trp53pc-/- prostate cancer-bearing mice (n = 9, 4-6 months old) were imaged in a 7T MRI scanner for lesion localization. Within 24 h, the mice were imaged using a microPET scanner for 60 min in dynamic mode following a retro-orbital injection of ~ 18 MBq [18F]VUIIS1008. Following imaging, tumors were harvested and stained with a TSPO antibody. Regions of interest (ROIs) were drawn around the tumor and muscle (hind limb) in the PET images. Time-activity curves (TACs) were recorded over the duration of the scan for each ROI. The mean activity concentrations between 40 and 60 min post radiotracer administration between tumor and muscle were compared. RESULTS: Tumor presence was confirmed by visual inspection of the MR images. The uptake of [18F]VUIIS1008 in the tumors was significantly higher (p < 0.05) than that in the muscle, where the percent injected dose per unit volume for tumor was 7.1 ± 1.6 % ID/ml and that of muscle was < 1 % ID/ml. In addition, positive TSPO expression was observed in tumor tissue analysis. CONCLUSIONS: The foregoing preliminary data suggest that TSPO may be a useful biomarker of PCa. Therefore, using TSPO-targeting PET ligands, such as [18F]VUIIS1008, may improve PCa detectability and characterization.

Combined In Silico and In Vitro Approach Predicts Low Wall Shear Stress Regions in a Hemofilter that Correlate with Thrombus Formation In Vivo.

A major challenge in developing blood-contacting medical devices is mitigating thrombogenicity of an intravascular device. Thrombi may interfere with device function or embolize from the device to occlude distant vascular beds with catastrophic consequences. Chemical interactions between plasma proteins and bioengineered surface occur at the nanometer scale; however, continuum models of blood predict local shear stresses that lead to platelet activation or aggregation and thrombosis. Here, an iterative approach to blood flow path design incorporating in silico, in vitro, and in vivo experiments predicted the occurrence and location of thrombi in an implantable hemofilter. Low wall shear stress (WSS) regions identified by computational fluid dynamics (CFD) predicted clot formation in vivo. Revised designs based on CFD demonstrated superior performance, illustrating the importance of a multipronged approach for a successful design process.

Integrated molecular imaging reveals tissue heterogeneity driving host-pathogen interactions.

Diseases are characterized by distinct changes in tissue molecular distribution. Molecular analysis of intact tissues traditionally requires preexisting knowledge of, and reagents for, the targets of interest. Conversely, label-free discovery of disease-associated tissue analytes requires destructive processing for downstream identification platforms. Tissue-based analyses therefore sacrifice discovery to gain spatial distribution of known targets or sacrifice tissue architecture for discovery of unknown targets. To overcome these obstacles, we developed a multimodality imaging platform for discovery-based molecular histology. We apply this platform to a model of disseminated infection triggered by the pathogen Staphylococcus aureus, leading to the discovery of infection-associated alterations in the distribution and abundance of proteins and elements in tissue in mice. These data provide an unbiased, three-dimensional analysis of how disease affects the molecular architecture of complex tissues, enable culture-free diagnosis of infection through imaging-based detection of bacterial and host analytes, and reveal molecular heterogeneity at the host-pathogen interface.

EPHA2 Blockade Overcomes Acquired Resistance to EGFR Kinase Inhibitors in Lung Cancer.

Despite the success of treating EGFR-mutant lung cancer patients with EGFR tyrosine kinase inhibitors (TKI), all patients eventually acquire resistance to these therapies. Although various resistance mechanisms have been described, there are currently no FDA-approved therapies that target alternative mechanisms to treat lung tumors with acquired resistance to first-line EGFR TKI agents. Here we found that EPHA2 is overexpressed in EGFR TKI-resistant tumor cells. Loss of EPHA2 reduced the viability of erlotinib-resistant tumor cells harboring EGFR(T790M) mutations in vitro and inhibited tumor growth and progression in an inducible EGFR(L858R+T790M)-mutant lung cancer model in vivo. Targeting EPHA2 in erlotinib-resistant cells decreased S6K1-mediated phosphorylation of cell death agonist BAD, resulting in reduced tumor cell proliferation and increased apoptosis. Furthermore, pharmacologic inhibition of EPHA2 by the small-molecule inhibitor ALW-II-41-27 decreased both survival and proliferation of erlotinib-resistant tumor cells and inhibited tumor growth in vivo. ALW-II-41-27 was also effective in decreasing viability of cells with acquired resistance to the third-generation EGFR TKI AZD9291. Collectively, these data define a role for EPHA2 in the maintenance of cell survival of TKI-resistant, EGFR-mutant lung cancer and indicate that EPHA2 may serve as a useful therapeutic target in TKI-resistant tumors.

Evaluation of the pathologic characteristics of excitotoxic spinal cord injury with MR imaging.

BACKGROUND AND PURPOSE: Although high-resolution MR imaging is a valuable diagnostic tool, in vivo MR imaging has not yet been compared with in vitro MR imaging and histologic techniques following experimental spinal cord injury (SCI). The goal of the present study was to evaluate the feasibility of using in vivo MR imaging, in vitro MR imaging, and histologic techniques to study pathologic changes associated with excitotoxic SCI at a single time point. These results are important for future research using in vivo MR imaging to study the temporal profile of pathologic changes following SCI. METHODS: Rats received intraspinal injections of quisqualic acid at the T12-L2 spinal level. In vivo T1- and T2-weighted and dynamic contrast-enhanced MR images were collected 17-24 days postinjury. Once completed, spinal cords were removed and in vitro MR microscopy and histologic assessment were performed. MR images were collected using 4.7-T (in vivo) and 14.1-T magnets (in vitro). RESULTS: Pathologic changes--including hemorrhage, neuronal loss, cavities, and central canal expansion--were visible in T2-weighted in vivo MR images. Evaluation of the blood-spinal cord barrier after injury with contrast agent enhancement showed no disruption at the time points evaluated. In vitro MR images and histologic evaluation confirmed pathologic details observed in vivo. CONCLUSION: Results show that high-resolution in vivo MR imaging has the potential to be used in studying the progression of pathologic changes at multiple time points following SCI. This strategy may provide a way of studying structure-function relationships between therapeutic interventions and different pathologic characteristics of the injured spinal cord.

Iron-Loaded Magnetic Nanocapsules for pH-Triggered Drug Release and MRI Imaging.

Magnetic nanocapsules were synthesized for controlled drug release, magnetically assisted delivery, and MRI imaging. These magnetic nanocapsules, consisting of a stable iron nanocore and a mesoporous silica shell, were synthesized by controlled encapsulation of ellipsoidal hematite in silica, partial etching of the hematite core in acid, and reduction of the core by hydrogen. The iron core provided a high saturation magnetization and was stable against oxidation for at least 6 months in air and 1 month in aqueous solution. The hollow space between the iron core and mesoporous silica shell was used to load anticancer drug and a T1-weighted MRI contrast agent (Gd-DTPA). These multifunctional monodispersed magnetic "nanoeyes" were coated by multiple polyelectrolyte layers of biocompatible poly-l-lysine and sodium alginate to control the drug release as a function of pH. We studied pH-controlled release, magnetic hysteresis curves, and T1/T2 MRI contrast of the magnetic nanoeyes. They also served as MRI contrast agents with relaxivities of 8.6 mM-1 s-1 (r1) and 285 mM-1 s-1 (r2).

Assessing reproducibility of diffusion-weighted magnetic resonance imaging studies in a murine model of HER2+ breast cancer.

BACKGROUND AND PURPOSE: The use of diffusion-weighted magnetic resonance imaging (DW-MRI) as a surrogate biomarker of response in preclinical studies is increasing. However, before a biomarker can be reliably employed to assess treatment response, the reproducibility of the technique must be established. There is a paucity of literature that quantifies the reproducibility of DW-MRI in preclinical studies; thus, the purpose of this study was to investigate DW-MRI reproducibility in a murine model of HER2+ breast cancer. MATERIALS AND METHODS: Test-Retest DW-MRI scans separated by approximately six hours were acquired from eleven athymic female mice with HER2+ xenografts using a pulsed gradient spin echo diffusion-weighted sequence with three b values [150, 500, and 800s/mm(2)]. Reproducibility was assessed for the mean apparent diffusion coefficient (ADC) from tumor and muscle tissue regions. RESULTS: The threshold to reflect a change in tumor physiology in a cohort of mice is defined by the 95% confidence interval (CI), which was±0.0972×10(-3)mm(2)/s (±11.8%) for mean tumor ADC. The repeatability coefficient defines this threshold for an individual mouse, which was±0.273×10(-3)mm(2)/s. The 95% CI and repeatability coefficient for mean ADC of muscle tissue were±0.0949×10(-3)mm(2)/s (±8.30%) and±0.266×10(-3)mm(2)/s, respectively. CONCLUSIONS: Mean ADC of tumors is reproducible and appropriate for detecting treatment-induced changes on both an individual and mouse cohort basis.

Genetic and pharmacologic inhibition of EPHA2 promotes apoptosis in NSCLC.

Genome-wide analyses determined previously that the receptor tyrosine kinase (RTK) EPHA2 is commonly overexpressed in non-small cell lung cancers (NSCLCs). EPHA2 overexpression is associated with poor clinical outcomes; therefore, EPHA2 may represent a promising therapeutic target for patients with NSCLC. In support of this hypothesis, here we have shown that targeted disruption of EphA2 in a murine model of aggressive Kras-mutant NSCLC impairs tumor growth. Knockdown of EPHA2 in human NSCLC cell lines reduced cell growth and viability, confirming the epithelial cell autonomous requirements for EPHA2 in NSCLCs. Targeting EPHA2 in NSCLCs decreased S6K1-mediated phosphorylation of cell death agonist BAD and induced apoptosis. Induction of EPHA2 knockdown within established NSCLC tumors in a subcutaneous murine model reduced tumor volume and induced tumor cell death. Furthermore, an ATP-competitive EPHA2 RTK inhibitor, ALW-II-41-27, reduced the number of viable NSCLC cells in a time-dependent and dose-dependent manner in vitro and induced tumor regression in human NSCLC xenografts in vivo. Collectively, these data demonstrate a role for EPHA2 in the maintenance and progression of NSCLCs and provide evidence that ALW-II-41-27 effectively inhibits EPHA2-mediated tumor growth in preclinical models of NSCLC.

Monitoring pH-triggered drug release from radioluminescent nanocapsules with X-ray excited optical luminescence.

One of the greatest challenges in cancer therapy is to develop methods to deliver chemotherapy agents to tumor cells while reducing systemic toxicity to noncancerous cells. A promising approach to localizing drug release is to employ drug-loaded nanoparticles with coatings that release the drugs only in the presence of specific triggers found in the target cells such as pH, enzymes, or light. However, many parameters affect the nanoparticle distribution and drug release rate, and it is difficult to quantify drug release in situ. In this work, we show proof-of-principle for a "smart" radioluminescent nanocapsule with an X-ray excited optical luminescence (XEOL) spectrum that changes during release of the optically absorbing chemotherapy drug, doxorubicin. XEOL provides an almost background-free luminescent signal for measuring drug release from particles irradiated by a narrow X-ray beam. We study in vitro pH-triggered release rates of doxorubicin from nanocapsules coated with a pH-responsive polyelectrolyte multilayer using HPLC and XEOL spectroscopy. The doxorubicin was loaded to over 5% by weight and released from the capsule with a time constant in vitro of ∼36 days at pH 7.4 and 21 h at pH 5.0, respectively. The Gd2O2S:Eu nanocapsules are also paramagnetic at room temperature with similar magnetic susceptibility and similarly good MRI T2 relaxivities to Gd2O3, but the sulfur increases the radioluminescence intensity and shifts the spectrum. Empty nanocapsules did not affect cell viability up to concentrations of at least 250 µg/mL. These empty nanocapsules accumulated in a mouse liver and spleen following tail vein injection and could be observed in vivo using XEOL. The particles are synthesized with a versatile template synthesis technique which allows for control of particle size and shape. The XEOL analysis technique opens the door to noninvasive quantification of drug release as a function of nanoparticle size, shape, surface chemistry, and tissue type.

Iron deficiency accelerates Helicobacter pylori-induced carcinogenesis in rodents and humans.

Gastric adenocarcinoma is strongly associated with Helicobacter pylori infection; however, most infected persons never develop this malignancy. H. pylori strains harboring the cag pathogenicity island (cag+), which encodes CagA and a type IV secretion system (T4SS), induce more severe disease outcomes. H. pylori infection is also associated with iron deficiency, which similarly augments gastric cancer risk. To define the influence of iron deficiency on microbial virulence in gastric carcinogenesis, Mongolian gerbils were maintained on iron-depleted diets and infected with an oncogenic H. pylori cag+ strain. Iron depletion accelerated the development of H. pylori-induced premalignant and malignant lesions in a cagA-dependent manner. H. pylori strains harvested from iron-depleted gerbils or grown under iron-limiting conditions exhibited enhanced virulence and induction of inflammatory factors. Further, in a human population at high risk for gastric cancer, H. pylori strains isolated from patients with the lowest ferritin levels induced more robust proinflammatory responses compared with strains isolated from patients with the highest ferritin levels, irrespective of histologic status. These data demonstrate that iron deficiency enhances H. pylori virulence and represents a measurable biomarker to identify populations of infected persons at high risk for gastric cancer.

Magnetic and optical properties of multifunctional core-shell radioluminescence nanoparticles.

When X-rays irradiate radioluminescence nanoparticles, they generate visible and near infrared light that can penetrate through centimeters of tissue. X-ray luminescence tomography (XLT) maps the location of these radioluminescent contrast agents at high resolution by scanning a narrow X-ray beam through the tissue sample and collecting the luminescence at every position. Adding magnetic functionality to these radioluminescent particles would enable them to be guided, oriented, and heated using external magnetic fields, while their location and spectrum could be imaged with XLT and complementary magnetic resonance imaging. In this work, multifunctional monodispersed magnetic radioluminescent nanoparticles were developed as potential drug delivery carriers and radioluminescence imaging agents. The particles consisted of a spindle-shaped magnetic γ-Fe2O3 core and a radioluminescent europium-doped gadolinium oxide shell. Particles with solid iron oxide cores displayed saturation magnetizations consistent with their ~13% core volume, however, the iron oxide quenched their luminescence. In order to increase the luminescence, we partially etched the iron oxide core in oxalic acid while preserving the radioluminescent shell. The core size was controlled by the etching time which in turn affected the particles' luminescence and magnetic properties. Particles with intermediate core sizes displayed both strong magnetophoresis and luminescence properties. They also served as MRI contrast agents with relaxivities of up to 58 mM-1s-1 (r2) and 120 mM-1s-1 (r2*). These particles offer promising multimodal MRI/fluorescence/X-ray luminescence contrast agents. Our core-shell synthesis technique offers a flexible method to control particle size, shape, and composition for a wide range of biological applications of magnetic/luminescent nanoparticles.