Expression of clMagR/clCry4 protein in mBMSCs provides T2-contrast enhancement of MRI.

Here, we propose for the first time the evaluation of magnetosensitive clMagR/clCry4 as a magnetic resonance imaging (MRI) reporter gene that imparts sensitivity to endogenous contrast in eukaryotic organisms. Using a lentiviral vector, we introduced clMagR/clCry4 into C57BL/6 mice-derived bone marrow mesenchymal stem cells (mBMSCs), which could specifically bind with iron, significantly affected MRI transverse relaxation, and generated readily detectable contrast without adverse effects in vivo. Specifically, clMagR/clCry4 makes mBMSCs beneficial for enhancing the sensitivity of MRI-R2 for iron-bearing granules, in which cells recruit exogenous iron and convert these stores into an MRI-detectable contrast; this is not achievable with control cells. Additionally, Prussian blue staining was performed together with ultrathin cell slices to provide direct evidence of natural iron-bearing granules being detectable on MRI. Hence, it was inferred that the sensitivity of MRI detection should be correlated with clMagR/clCry4 and exogenous iron. Taken together, the clMagR/clCry4 has great potential as an MRI reporter gene. STATEMENT OF SIGNIFICANCE: In this study, we propose the evaluation of magnetosensitive clMagR/clCry4 as an MRI reporter gene, imparting detection sensitivity to eukaryotic mBMSCs for endogenous contrast. At this point, the clMagR and clCry4 were located within the cytoplasm and possibly influence each other. The clMagR/clCry4 makes mBMSCs beneficial for enhancing the sensitivity of MRI-R2 for iron-bearing granules, in which protein could specifically bind with iron and convert these stores into MRI-detectable contrast; this is not achieved by control cells. The viewpoint was speculated that the clMagR/clCry4 and exogenous iron were complementary to each other. Additionally, Prussian blue staining was performed together with TEM observations to provide direct evidence that the iron-bearing granules were sensitive to MRI.

Holmium (III)-doped multifunctional nanotheranostic agent for ultra-high-field magnetic resonance imaging-guided chemo-photothermal tumor therapy.

Ultra-high-field (UHF) MRI has shown great advantages over low-field magnetic resonance imaging (MRI). Despite being the most commonly used MRI contrast agents, gadolinium chelates perform poorly in high magnetic fields, which significantly weakens their T1 intensity. In comparison, the rare element Holmium (Ho)-based nanoparticles (NPs) have demonstrated great potential as T2-weighted MRI contrast agents in UHF MRI due to their extremely short electron relaxation times (∼ 10-13s). In this study, a multifunctional nanotherapeutic probe was designed for UHF MRI-guided chemotherapy and photothermal therapy. The Ho (III)-doped mesoporous polydopamine (Ho-MPDA, HM) nanosphere was loaded with the chemotherapeutic drug mitoxantrone (MTO) and then coated with 4T1 cell membranes to enhance active targeting delivery to breast cancer. The prepared nanotherapeutic probe MTO@HMM@4T1 (HMM@T) exhibited good biocompatibility, high drug-loading capability and great potential as Ho (III)-based UHF MRI contrast agents. Moreover, the biodegradation of HMM@T in response to the intratumor pH and glutathione (GSH) promotes MTO release. Near-infrared (NIR) light irradiation of HM induced photothermal therapy and further enhanced drug release. Consequently, HMM@T effectively acted as an MRI-guided tumor-targeting chemo-photothermal therapy against 4T1 breast cancer. STATEMENT OF SIGNIFICANCE: Ultra-high-field (UHF) MRI has shown great advantages over low-field magnetic resonance imaging (MRI). Although gadolinium chelates are the most commonly used MRI contrast agents in clinical practice, they exhibit a significantly decreased T1 relaxivity at UHF. Holmium exhibits outstanding UHF magnetic resonance capabilities in comparison with gadolinium chelates currently used in clinic. Herein, a theranostic nanodrug (HMM@T) was designed for UHF MRI-guided chemo-photothermal therapy. The nanodrug possessed remarkable UHF T2 MRI properties (r2 = 152.13 mM-1s-1) and high drug loading capability of 18.4 %. The biodegradation of HMM@T NPs under triple stimulations of pH, GSH, and NIR led to an efficient release of MTO in tumor microenvironment. Our results revealed the potential of a novel UHF MRI-guided multifunctional nanosystem in cancer treatment.

Biodegradable germanium nanoparticles as contrast agents for near-infrared-II photoacoustic imaging.

Photoacoustic (PA) imaging using contrast agents with strong near-infrared-II (NIR-II, 1000-1700 nm) absorption enables deep penetration into biological tissue. Besides, biocompatibility and biodegradability are essential for clinical translation. Herein, we developed biocompatible and biodegradable germanium nanoparticles (GeNPs) with high photothermal stability as well as strong and broad absorption for NIR-II PA imaging. We first demonstrate the excellent biocompatibility of the GeNPs through experiments, including the zebrafish embryo survival rates, nude mouse body weight curves, and histological images of the major organs. Then, comprehensive PA imaging demonstrations are presented to showcase the versatile imaging capabilities and excellent biodegradability, including in vitro PA imaging which can bypass blood absorption, in vivo dual-wavelength PA imaging which can clearly distinguish the injected GeNPs from the background blood vessels, in vivo and ex vivo PA imaging with deep penetration, in vivo time-lapse PA imaging of a mouse ear for observing biodegradation, ex vivo time-lapse PA imaging of the major organs of a mouse model for observing the biodistribution after intravenous injection, and notably in vivo dual-modality fluorescence and PA imaging of osteosarcoma tumors. The in vivo biodegradation of GeNPs is observed not only in the normal tissue but also in the tumor, making the GeNPs a promising candidate for clinical NIR-II PA imaging applications.

Redox ferrocenylseleno compounds modulate longitudinal and transverse relaxation times of FNPs-Gd MRI contrast agents for multimodal imaging and photo-Fenton therapy.

Developing a feasible way to feature longitudinal (T1) and transverse (T2) relaxation performance of contrast agents for magnetic resonance imaging (MRI) is important in cancer diagnosis and therapy. Improved accessibility to water molecule is essential for accelerating the relaxation rate of water protons around the contrast agents. Ferrocenyl compounds have reversible redox property for modulating the hydrophobicity/hydrophilicity of assemblies. Thus, they could be the candidates that can change water accessibility to the contrast agent surface. Herein, we incorporated ferrocenylseleno compound (FcSe) with Gd3+-based paramagnetic UCNPs, to obtain FNPs-Gd nanocomposites using T1-T2 MR/UCL trimodal imaging and simultaneous photo-Fenton therapy. When the surface of NaGdF4:Yb,Tm UNCPs was ligated by FcSe, the hydrogen bonding between hydrophilic selenium and surrounding water molecules accelerated their proton exchange to initially endow FNPs-Gd with high r1 relaxivity. Then, hydrogen nuclei from FcSe disrupted the homogeneity of the magnetic field around the water molecules. This facilitated T2 relaxation and resulted in enhanced r2 relaxivity. Notably, upon the near-infrared light-promoted Fenton-like reaction in the tumor microenvironment, hydrophobic ferrocene(II) of FcSe was oxidized into hydrophilic ferrocenium(III), which further increased the relaxation rate of water protons to obtain r1 = 1.90±0.12 mM-1 s-1 and r2 = 12.80±0.60 mM-1 s-1. With an ideal relaxivity ratio (r2/r1) of 6.74, FNPs-Gd exhibited high contrast potential of T1-T2 dual-mode MRI in vitro and in vivo. This work confirms that ferrocene and selenium are effective boosters that enhance the T1-T2 relaxivities of MRI contrast agents, which could provide a new strategy for multimodal imaging-guided photo-Fenton therapy of tumors. STATEMENT OF SIGNIFICANCE: T1-T2 dual-mode MRI nanoplatform with tumor-microenvironment-responsive features has been an attractive prospect. Herein, we designed redox ferrocenylseleno compound (FcSe) modified paramagnetic Gd3+-based UCNPs, to modulate T1-T2 relaxation time for multimodal imaging and H2O2-responsive photo-Fenton therapy. Selenium-hydrogen bond of FcSe with surrounding water molecules facilitated water accessibility for fast T1 relaxation. Hydrogen nucleus in FcSe perturbed the phase coherence of water molecules in an inhomogeneous magnetic field and thus accelerated T2 relaxation. In tumor microenvironment, FcSe was oxidized into hydrophilic ferrocenium via NIR light-promoted Fenton-like reaction which further increased both T1 and T2 relaxation rates; Meanwhile, the released toxic •OH performed on-demand cancer therapy. This work confirms that FcSe is an effective redox mediate for multimodal imaging-guided cancer therapy.

Multifunctional Nanosnowflakes for T1-T2 Double-Contrast Enhanced MRI and PAI Guided Oxygen Self-Supplementing Effective Anti-Tumor Therapy.

Introduction: Accurate tumor diagnosis is essential to achieve the ideal therapeutic effect. However, it is difficult to accurately diagnose cancer using a single imaging method because of the technical limitations. Multimodal imaging plays an increasingly important role in tumor treatment. Photodynamic therapy (PDT) has received widespread attention in tumor treatment due to its high specificity and controllable photocytotoxicity. Nevertheless, PDT is susceptible to tumor microenvironment (TME) hypoxia, which greatly reduces the therapeutic effect of tumor treatment. Methods: In this study, a novel multifunctional nano-snowflake probe (USPIO@MnO2@Ce6, UMC) for oxygen-enhanced photodynamic therapy was developed. We have fabricated the honeycomb-like MnO2 to co-load chlorin e6 (Ce6, a photosensitizer) and ultrasmall superparamagnetic iron oxide (USPIO, T1-T2 double contrast agent). Under the high H2O2 level of tumor cells, UMC efficiently degraded and triggered the exposure of photosensitizers to the generated oxygen, accelerating the production of reactive oxygen species (ROS) during PDT. Moreover, the resulting USPIO and Mn2+ allow for MR T1-T2 imaging and transformable PAI for multimodal imaging-guided tumor therapy. Results: TEM and UV-vis spectroscopy results showed that nano-snowflake probe (UMC) was successfully synthesized, and the degradation of UMC was due to the pH/ H2O2 responsive properties. In vitro results indicated good uptake of UMC in 4T-1 cells, with maximal accumulation at 4 h. In vitro and in vivo experimental results showed their imaging capability for both T1-T2 MR and PA imaging, providing the potential for multimodal imaging-guided tumor therapy. Compared to the free Ce6, UMC exhibited enhanced treatment efficiency due to the production of O2 with the assistance of 660 nm laser irradiation. In vivo experiments confirmed that UMC achieved oxygenated PDT under MR/PA imaging guidance in tumor-bearing mice and significantly inhibited tumor growth in tumor-bearing mice, exhibiting good biocompatibility and minimal side effects. Conclusion: The multimodal imaging contrast agent (UMC) not only can be used for MR and PA imaging but also has oxygen-enhanced PDT capabilities. These results suggest that UMC may have a good potential for further clinical application in the future.

Formation of hydrated PEG layers on magnetic iron oxide nanoflowers shows internal magnetisation dynamics and generates high in-vivo efficacy for MRI and magnetic hyperthermia.

Multicore magnetic iron oxide nanoparticles, nanoflowers (NFs), have potential biomedical applications as efficient mediators for AC-magnetic field hyperthermia and as contrast agents for magnetic resonance imaging due to their strong magnetic responses arising from complex internal magnetic ordering. To realise these applications amenable surface chemistry must be engineered that maintain particle dispersion. Here a catechol-derived grafting approach is described to strongly bind polyethylene glycol (PEG) to NFs and provide stable hydrogen-bonded hydrated layers that ensure good long-term colloidal stability in buffers and media even at clinical MRI field strength and high concentration. The approach enables the first comprehensive study into the MRI (relaxivity) and hyperthermic (SAR) efficiencies of fully dispersed NFs. The predominant role of internal magnetisation dynamics in providing high relaxivity and SAR is confirmed, and it is shown that these properties are unaffected by PEG molecular weight or corona formation in biological environments. This result is in contrast to traditional single core nanoparticles which have significantly reduced SAR and relaxivity upon PEGylation and on corona formation, attributed to reduced Brownian contributions and weaker NP solvent interactions. The PEGylated NF suspensions described here exhibit usable blood circulation times and promising retention of relaxivity in-vivo due to the strongly anchored PEG layer. This approach to biomaterials design addresses the challenge of maintaining magnetic efficiency of magnetic nanoparticles in-vivo for applications as theragnostic agents. STATEMENT OF SIGNIFICANCE: Application of multicore magnetic iron-oxide nanoflowers (NFs) as efficient mediators for AC-field hyperthermia and as contrast agents for MR imaging has been limited by lack of colloidal stability in complex media and biosystems. The optimized materials design presented is shown to reproducibly provide PEG grafted NF suspensions of exceptional colloidal stability in buffers and complex media, with significant hyperthermic and MRI utility which is unaffected by PEG length, anchoring group or bio-molecular adsorption. Deposition in the selected pancreatic tumour model mirrors liposomal formulations providing a quantifiable probe of tissue-level liposome deposition and relaxivity is retained in the tumour microenvironment. Hence the biomaterials design addresses the longstanding challenges of maintaining the in vivo magnetic efficiency of nanoparticles as theragnostic agents.

Step-by-Step Design of New Theranostic Nanoformulations: Multifunctional Nanovectors for Radio-Chemo-Hyperthermic Therapy under Physical Targeting.

While investigating the possible synergistic effect of the conventional anticancer therapies, which, taken individually, are often ineffective against critical tumors, such as central nervous system (CNS) ones, the design of a theranostic nanovector able to carry and deliver chemotherapy drugs and magnetic hyperthermic agents to the target radiosensitizers (oxygen) was pursued. Alongside the original formulation of polymeric biodegradable oxygen-loaded nanostructures, their properties were fine-tuned to optimize their ability to conjugate therapeutic doses of drugs (doxorubicin) or antitumoral natural substances (curcumin). Oxygen-loaded nanostructures (diameter = 251 ± 13 nm, ζ potential = -29 ± 5 mV) were finally decorated with superparamagnetic iron oxide nanoparticles (SPIONs, diameter = 18 ± 3 nm, ζ potential = 14 ± 4 mV), producing stable, effective and non-agglomerating magnetic nanovectors (diameter = 279 ± 17 nm, ζ potential = -18 ± 7 mV), which could potentially target the tumoral tissues under magnetic driving and are monitorable either by US or MRI imaging.

Right ventricular endomyocardial biopsy in patients with cardiac magnetic resonance showing left ventricular myocarditis.

AIMS: The aim of this study was to evaluate the sensitivity of right ventricular endomyocardial biopsy (EMB) in myocarditis patients with cardiac magnetic resonance (CMR) and electroanatomical mapping (EAM) showing left ventricular abnormalities. METHODS: We performed right ventricular EMB in 144 consecutive patients (66% men, age 43 ±â€Š15 years) with acute symptoms and CMR-proved diagnosis of left ventricular myocarditis. Right ventricular EMB sensitivity has been evaluated in patients with different localization and extension of abnormal substrate at both CMR and -- when performed -- EAM. Abnormal substrate was defined, respectively, by late gadolinium enhancement (LGE) and low-voltage areas (LVAs). RESULTS: Globally, right ventricular EMB sensitivity was 87.5%. EMB-negative cases had significantly smaller fragment sizes (cumulative area 2.8 ±â€Š1.7 vs. 3.8 ±â€Š1.8 mm2, P = 0.023), and lower LGE surface extension (24.7 ±â€Š14.2 vs. 38.5 ±â€Š20.2%, P = 0.006) and transmurality (32.0 ±â€Š26.1 vs. 49.3 ±â€Š22.6, P = 0.003). Right ventricular EMB sensitivity in patients with LGE involving both right ventricular and interventricular septum (IVS), isolated right ventricular or IVS, and remote left ventricular areas (n = 10, 49 and 67 cases) was 83.3, 84.4 and 90.5%, respectively (P = 0.522). Overall, 34 patients (23.6%) underwent EAM. On the basis of EAM, right ventricular EMB sensitivity was 85.3%: in detail, it was 50.0, 88.2 and 86.7% in patients with both right ventricular and IVS, isolated right ventricular/IVS and distant left ventricular involvement (n = 2, 17 and 15, respectively, P > 0.05). Sample size area was the only factor associated with right ventricular EMB sensitivity (hazard ratio = 1.6/mm2, 95% confidence interval 1.1-2.4, P = 0.013). CONCLUSION: Right ventricular EMB is still an accurate technique to confirm diagnosis in patients with CMR-proved left ventricular myocarditis. In particular, provided there is an adequate sample size, its sensitivity is comparable among patients with heterogeneous LGE or LVA localization.

The Addition of Lipid-Based Contrast Medium does not Inactivate the Detergent Sclerosant Sodium Tetradecyl Sulfate in-vitro.

PURPOSE: To investigate if the detergent sclerosant sodium tetradecyl sulfate (STS) is deactivated by the lipid-based contrast agent ethiodised oil. METHOD: 3% STS was mixed with ethiodised oil and room air in a 2:1:4 ratio in two luer lock syringes and a three way connector and agitated to make foam (the Tessari technique) to replicate the clinical use of the products. The assay of STS in the mixture was assessed using the British Pharmacopoeia method. Briefly this is a manual titration method where the solution of STS is mixed with an indicator solution and titrated with hyamine solution of known concentration; the concentration of the STS can then be calculated with the titration results. To further mimic the clinical environment with the presence of blood, the effect of adding increasing amounts of albumin to the STS-ethiodised oil mixture was assessed. RESULTS: The assay of STS in the solution after mixing with ethiodised oil was 3% indicating that the ethiodised oil did not deactivate the STS. The addition of albumin to the STS-contrast mixture resulted in near linear neutralisation of the STS with increasing concentrations in the same quantities as with STS alone. CONCLUSIONS: The mixture of the lipid-based contrast agent ethiodised oil with the detergent sclerosant STS did not affect the availability of the sclerosant. The continued use of STS-ethiodised oil in the management of vascular malformations can be supported.

Co-encapsulating indocyanine green and CT contrast agent within nanoliposomes for trimodal imaging and near infrared phototherapy of cancer.

X-ray CT imaging can be complementary to fluorescence and photoacoustic imaging (FLI and PAI), allowing for high spatial resolution and high-sensitivity multimodal imaging for imaging guided treatment. In this study, the CT contrast agent iohexol was co-encapsulated with indocyanine green (ICG) within nanoliposomes (NLs) to explore their interaction and possible application of this liposomal formulation (LGI) in cancer theranostics. The photophysical properties of LGI were studied to assess the effect of iohexol on ICG that can enhance the efficiency of ICG-based near infrared photodynamic therapy (PDT). The CT, FLI and PA imaging abilities of LGI were also investigated. Furthermore, the near infrared phototherapy of cancer cells in vitro was performed, exhibiting higher phototherapy efficacy of LGI in comparison with other ICG formulations. We conclude that LGI can serve as a highly efficient theranostic nanoplatform for multimodal (fluorescence, CT and PA) imaging and near infrared phototherapy.

No Changes in T1 Relaxometry After a Mean of 11 Administrations of Gadobutrol.

OBJECTIVES: Quantitative T1 relaxometry is the benchmark in imaging potential gadolinium deposition and known to be superior to semiquantitative signal intensity ratio analyses. However, T1 relaxometry studies are rare, commonly limited to a few target structures, and reported results are inconsistent.We systematically investigated quantitative T1 relaxation times (qT1) of a variety of brain nuclei after serial application of gadobutrol. MATERIALS AND METHODS: Retrospectively, qT1 measurements were performed in a patient cohort with a mean number of 11 gadobutrol applications (n = 46) and compared with a control group with no prior gadolinium-based contrast agent administration (n = 48). The following target structures were evaluated: dentate nucleus, globus pallidus, thalamus, hippocampus, putamen, caudate, amygdala, and different white matter areas. Subsequently, multivariate regression analysis with adjustment for age, presence of brain metastases and previous cerebral radiotherapy was performed. RESULTS: No assessed site revealed a significant correlation between qT1 and number of gadobutrol administrations in multivariate regression analysis. However, a significant negative correlation between qT1 and age was found for the globus pallidus as well as anterior and lateral thalamus (P < 0.05 each). CONCLUSIONS: No T1 relaxation time shortening due to gadobutrol injection was found in any of the assessed brain structures after serial administration of 11 doses of gadobutrol.

Ce6/Mn2+-chelated polydopamine@black-TiO2 nanoprobes for enhanced synergistic phototherapy and magnetic resonance imaging in 4T1 breast cancer.

Black titanium dioxide (TiO2) nanoparticles have attracted great attention due to their application in photothermal therapy (PTT). However, single-mode phototherapy has the risk of recurrence, and the high-dose laser usually imposed to improve the PTT performance can bring a potential threat to security. Here, polydopamine (PDA)-coated black TiO2 (b-P25@PDA) nanoparticles with a core-shell structure were synthesized for enhanced PTT; then, synergistic phototherapy nanoprobes (b-P25@PDA-Ce6 (Mn)) were constructed by coupling chlorin e6 (Ce6) and chelating Mn2+ for simultaneous photodynamic therapy (PDT)/PTT and magnetic resonance (MR) imaging, in which a low-dose laser was used and imaging-guided phototherapy with high efficiency and high safety was achieved. The prepared nanoprobes showed high photothermal conversion efficiency (32.12%), high reactive oxygen generation and excellent MR imaging. In the 4T1 tumor-bearing nude mouse model, the tumors completely disappeared under the combination of PDT/PTT with a low-dose laser but were only partially inhibited by single PDT and single PTT. The current work developed a multifunctional black TiO2-based nanoprobe for enhanced synergistic PDT/PTT and MR imaging, which will be important for the safe and efficient visualized theranostics of cancers.

Monodispersed plasmonic Prussian blue nanoparticles for zero-background SERS/MRI-guided phototherapy.

Surface-enhanced Raman scattering (SERS) and magnetic resonance imaging (MRI)-guided phototherapy are new breakthroughs in cancer therapeutics due to their complementary advantages, such as enhanced imaging spatial resolution and depth. Herein, we synthesized monodispersed Prussian blue-encapsulated gold nanoparticles (Au@PB NPs), in which the plasmonic gold core plus coordination polymer of cyanide (C[triple bond, length as m-dash]N) and iron ions coincidently become a superexcellent contrast agent for both MRI and zero-background SERS imaging. PB, as a signal source for MR and SERS, can be easily assembled onto single Au NPs, of which iron ions possess high relaxation efficiency for in vivo MRI, e.g., the longitudinal and transversal relaxation efficiency values are 0.86 mM-1 s-1 (r1) and 5.42 mM-1 s-1 (r2), respectively. Furthermore, with the help of the plasmonic enhancement of the gold core, the C[triple bond, length as m-dash]N groups exhibit a specific, strong, and stable (3S) SERS emission in the Raman-silent region (1800-2800 cm-1), allowing accurate in vivo imaging at the single or even subcellular level. More importantly, PB has remarkable absorption properties in the near infrared region, and can be used as a photosensitizer for photothermal (PT) and photodynamic (PD) therapy simultaneously. Hence, the ideal integration of a plasmonic Au core and PB shell into a single monodispersed MR-guided NP, with zero-background SERS signals, is an important candidate for both tumor navigation and in situ PT/PD treatment guided by SERS/MR dual-mode imaging.

Comparing HCC arterial tumour vascularisation on baseline imaging and after lipiodol cTACE: how do estimations of enhancing tumour volumes differ on contrast-enhanced MR and CT?

OBJECTIVES: In this study, pre-treatment target lesion vascularisation in either contrast-enhanced (CE) CT or MRI and post-treatment lipiodol deposition in native CT scans were compared in HCC patients who underwent their first cTACE treatment. We analysed the impact of stratification according to cTACE selectivity on these correlations. METHODS: Seventy-eight HCC patients who underwent their first cTACE procedure were retrospectively included. Pre-treatment tumour vascularisation in arterial contrast phase and post-treatment lipiodol deposition in native CT scans were evaluated using the qEASL (quantitative tumour enhancement) method. Correlations were analysed using scatter plots, the Pearson correlation coefficient (PCC) and linear regression analysis. Subgroup analysis was performed according to lobar, segmental and subsegmental execution of cTACE. RESULTS: Arterial tumour volumes in both baseline CE CT (R2 = 0.83) and CE MR (R2 = 0.82) highly correlated with lipiodol deposition after cTACE. The regression coefficient between lipiodol deposition and enhancing tumour volume was 1.39 for CT and 0.33 for MR respectively, resulting in a ratio of 4.24. After stratification according to selectivity of cTACE, the regression coefficient was 0.94 (R2 = 1) for lobar execution, 1.38 (R2 = 0.96) for segmental execution and 1.88 (R2 = 0.89) for subsegmental execution in the CE CT group. CONCLUSIONS: Volumetric lipiodol deposition can be used as a reference to compare different imaging modalities in detecting vital tumour volumes. That approach proved CE MRI to be more sensitive than CE CT. Selectivity of cTACE significantly impacts the respective regression coefficients which allows for an innovative approach to the assessment of technical success after cTACE with a multitude of possible applications. KEY POINTS: • Lipiodol deposition after cTACE highly correlates with pre-treatment tumour vascularisation and can be used as a reference to compare different imaging modalities in detecting vital tumour volumes. • Lipiodol deposition also correlates with the selectivity of cTACE and can therefore be used to quantify the technical success of the intervention.

Photoacoustic ratiometric assessment of mitoxantrone release from theranostic ICG-conjugated mesoporous silica nanoparticles.

A theranostic nanosystem based on indocyanine green (ICG) covalently conjugated to mesoporous silica nanoparticles (MSNs) loaded with the anticancer drug mitoxantrone (MTX) is proposed as an innovative photoacoustic probe. Taking advantage of the characteristic PA signal displayed by both ICG and MTX, a PA-ratiometric approach was applied to assess the drug release profile from the MSNs. After complete in vitro characterization of the nanoprobe, a proof-of-concept study has been carried out in tumour-bearing mice to evaluate in vivo its effectiveness for cancer imaging and chemotherapeutic agent delivery.

A multifunctional theranostic contrast agent for ultrasound/near infrared fluorescence imaging-based tumor diagnosis and ultrasound-triggered combined photothermal and gene therapy.

PURPOSE: Encapsulated microbubbles (MBs) have been reported as new theranostic carriers for simultaneous imaging and ultrasound (US)-triggered therapy. Here, we designed a dual-modality US/NIRF contrast agent and extended its applications from image contrast enhancement to combined diagnosis and therapy with US-directed and site-specific targeting. METHODS: Gold nanorods (AuNRs) resonant at 880 nm together with the NIR797 dye were first encapsulated in lipid-shelled MBs to construct fluorescent gold microbubbles (NIR797/AuMBs) via thin film hydration and mechanical shaking in the presence of sulfur hexafluoride (SF6) gas. Then, polyethylenimine (PEI)-DNA complexes were electrostatically conjugated onto the surface of the NIR797/AuMBs, forming theranostic encapsulated MBs (PEI-DNA/NIR797/AuMBs). The potential of the PEI-DNA/NIR797/AuMBs for use as a dual-modality contrast enhancement agent was evaluated in vitro and in vivo. The antitumor effect of US/NIR laser irradiation mediating double-fusion suicide gene and photothermal therapy was also investigated using Bel-7402 cells and xenografts. RESULTS: The developed theranostic AuMB complexes could not only provide excellent US and NIRF imaging to detect tumors but also serve as an efficient US-triggered carrier for gene delivery and photothermal ablation of tumors in xenografted nude mice. And US + laser exposure group showed a much higher rate of cell inhibition, apoptosis and necrosis as well as a higher Bel-7402 xenograft inhibition rate than the single gene therapy or single exposure (US or laser) group. CONCLUSIONS: PEI-DNA/NIR797/AuMBs would be of great value for providing more comprehensive diagnostic information and to guide more accurate and effective synergistic cancer therapy. STATEMENT OF SIGNIFICANCE: This is an original paper focusing on developing a dual-modality US/NIRF contrast agent and extended its applications from image contrast enhancement to combined diagnosis and therapy with US-directed and site-specific targeting. The developed theranostic AuMB complexes could not only provide excellent US and NIRF imaging to detect tumors but also serve as an efficient US-triggered carrier for gene delivery and photothermal ablation of tumors in xenografted nude mice. PEI-DNA/NIR797/AuMBs would be of great value for providing more comprehensive diagnostic information and to guide more accurate and effective synergistic cancer therapy.

Rhenium Sulfide Nanoparticles as a Biosafe Spectral CT Contrast Agent for Gastrointestinal Tract Imaging and Tumor Theranostics in Vivo.

Spectral computed tomography (CT) imaging as a novel imaging technique shows promising prospects in the accurate diagnosis of various diseases. However, clinically iodinated contrast agents suffer from poor signal-to-noise ratio, and emerging heavy-metal-based CT contrast agents arouse great biosafety concern. Herein, we show the fabrication of rhenium sulfide (ReS2) nanoparticles, a clinic radiotherapy sensitizer, as a biosafe spectral CT contrast agent for the gastrointestinal tract imaging and tumor theranostics in vivo by teaching old drugs new tricks. The ReS2 nanoparticles were fabricated in a one-pot facile method at room temperature, and exhibited sub-10 nm size, favorable monodispersity, admirable aqueous solubility, and strong X-ray attenuation capability. More importantly, the proposed nanoparticles possess an outstanding spectral CT imaging ability and undoubted biosafety as a clinic therapeutic agent. Besides, the ReS2 nanoparticles possess appealing photothermal performance due to their intense near-infrared absorption. The proposed nano-agent not only guarantees obvious contrast enhancement in gastrointestinal tract spectral CT imaging in vivo, but also allows effective CT imaging-guided tumor photothermal therapy. The proposed "teaching old drugs new tricks" strategy shortens the time and cuts the cost required for clinical application of nano-agents based on existing clinical toxicology testing and trial results, and lays down a low-cost, time-saving, and energy-saving method for the development of multifunctional nano-agents toward clinical applications.

Extent and spatial distribution of left atrial arrhythmogenic sites, late gadolinium enhancement at magnetic resonance imaging, and low-voltage areas in patients with persistent atrial fibrillation: comparison of imaging vs. electrical parameters of fibrosis and arrhythmogenesis.

AIMS: Atrial fibrosis contributes to arrhythmogenesis in atrial fibrillation and can be detected by MRI or electrophysiological mapping. The current study compares the spatial correlation between delayed enhancement (DE) areas to low-voltage areas (LVAs) and to arrhythmogenic areas with spatio-temporal dispersion (ST-Disp) or continuous activity (CA) in atrial fibrillation (AF). METHODS AND RESULTS: Sixteen patients with persistent AF (nine long-standing) underwent DE-magnetic resonance imaging (1.25 mm × 1.25 mm × 2.5 mm) prior to pulmonary vein isolation. Left atrial (LA) voltage mapping was acquired in AF and the regional activation patterns of 7680 AF wavelets were analysed. Sites with ST-Disp or CA were characterized (voltage, duration) and their spatial relationship to DE areas and LVAs <0.5 mV was assessed. Delayed enhancement areas and LVAs covered 55% and 24% (P < 0.01) of total LA surface, respectively. Delayed enhancement area was present at 61% of LVAs, whereas low voltage was present at 28% of DE areas. Most DE areas (72%) overlapped with atrial high-voltage areas (>0.5 mV). Spatio-temporal dispersion and CA more frequently co-localized with LVAs than with DE areas (78% vs. 63%, P = 0.02). Regional bipolar voltage of ST-Disp vs. CA was 0.64 ± 0.47 mV vs. 0.58 ± 0.51 mV. All 28 ST-Disp and 56 CA areas contained electrograms with prolonged duration (115 ± 14 ms) displaying low voltage (0.34 ± 0.11 mV). CONCLUSION: A small portion of DE areas and LVAs harbour the arrhythmogenic areas displaying ST-Disp or CA. Most arrhythmogenic activities co-localized with LVAs, while there was less co-localization with DE areas. There is an important mismatch between DE areas and LVAs which needs to be considered when used as target for catheter ablation.