Development Of Contrast Agents Research Articles

Ultrasound Contrast Imaging: Fundamentals and Emerging Technology

The development of microbubble contrast agents has broadened the scope of medical ultrasound imaging. Along with dedicated imaging techniques, these agents provide enhanced echoes from the blood pool and have enabled diagnostic ultrasound to assess and quantify microvascular blood flow. Contrast-enhanced ultrasound is currently used worldwide with clinical indications in cardiology and radiology, and it continues to evolve and develop through innovative technological advancements. In this review article, we present an overview of the basic microbubble physics and bubble-specific imaging techniques that enable this modality, and follow this with a discussion on new and emerging applications.

Engineering Responsive Ultrasound Contrast Agents Through Crosslinked Networks on Lipid-Shelled Microbubbles.

Ultrasound imaging with contrast agents, especially with lipid-shelled microbubbles, has become a vital tool in clinical diagnostics. Efforts to adapt these agents for molecular imaging have typically focused on targeted binding. More recently, crosslinking the lipid shell to alter its mechanical properties, followed by decrosslinking upon exposure to a stimulus, has been shown as a promising approach for imaging soluble molecular targets. Nevertheless, a systematic study of the influence of crosslinker concentration and structure on the mechanical properties of microbubbles has not been undertaken. An improved understanding of the role of these parameters is necessary to more effectively design contrast agents that detect proteases, an informative class of soluble disease markers. Here, the influence of crosslinker parameters on the acoustic properties of microbubbles, developing a model of crosslinker network formation on microbubble shells that explains the experimental observations, are studied. By incorporating cleavable elements that respond to UV light or proteolysis, kinetically resolved acoustic detection of these stimuli and the relevance of crosslinker design are demonstrated. The framework established in this study can be readily adapted to other protease-cleavable units and provides a basis for the future development of responsive ultrasound contrast agents for molecular imaging of proteolytic activity.

Carbon dots doped with barium as a novel contrast agent for efficient CT X-ray attenuation

The development of novel radiological contrast agents based on carbon dots (CDs) is attracting substantial interest because of their unique properties, such as biocompatibility, fabrication simplicity, colloidal stability and low cost. In this communication, the suitability of barium-doped carbon dots (Ba-CDs) for computed tomography (CT) X-ray attenuation has been assessed for the first time. Morphological analysis showed that Ba-CDs are quasi-spherical in shape with a mean particle size of ∼7.8 ± 2.3 nm. Chemical analysis revealed that the Ba(II) ion concentration in the Ba-CDs was ∼1.15 at%. The prepared Ba-CDs exhibit excellent fluorescent properties and good X-ray attenuation efficiency (13.2 ± 0.51 HU/mM), suggesting their potential applicability as an effective CT radiological contrast agent.

Lactoferrin-Conjugated Polylactic Acid Nanobubbles Encapsulated Perfluoropentane as a Contrast Agent for Ultrasound/Magnetic Resonance Dual-Modality Imaging

The development of contrast agents that can be activated by multiple modes is of great significance for tumor diagnosis. In this study, the lactoferrin (Lf)-conjugated polylactic acid (PLLA) nanobubbles (Lf-PLLA NBs) were used to encapsulate liquid perfluoropentane (PFP) with the double emulsion method, creating PFP loaded (PFP/Lf-PLLA) NBs for the ultrasound/magnetic resonance dual-modality imaging of subcutaneous tumor. The particle diameter and stability of nanobubbles were investigated by photon correlation spectroscopy. The biocompatibility of nanobubbles was preliminarily evaluated by cell proliferation and migration assay, hemolysis rate, and blood biochemistry analysis. A B-mode clinical ultrasound real-time imaging system was used to perform ultrasonic imaging in vivo. Magnetic resonance imaging in vivo was applied with a clinical 3.0 T magnetic resonance imaging (MRI) scanner system. The mean particle diameter of PFP/Lf-PLLA NBs was 320.2 ± 4.1 nm with a low polydispersity index (PDI, 0.145 ± 0.025), and the NBs were negatively charged (−11.4 ± 0.4 mV). The transmission electron microscopy (TEM) results showed that PFP/Lf-PLLA NBs exhibited highly monodispersed and possessed an obvious spherical structure of nanocapsules. Nanobubbles had good stability at 4°C. Different concentrations of the PFP/Lf-PLLA NBs solution had no effect on the cell in cytotoxicity and cell migration, and the results of hemolysis rate and blood biochemistry assay also indicated the good biocompatibility of NBs. On the ultrasound/magnetic resonance imaging of tumor-bearing mice, PFP/Lf-PLLA NBs showed significantly enhanced contrast ability of tumor tissue. Therefore, PFP/Lf-PLLA NBs had great potential to be a contrast agent for tumor dual-modality imaging in vivo.

PEGylated amphiphilic polymeric manganese(II) complexes as magnetic resonance angiographic agents.

Currently, the most commonly used clinical magnetic resonance imaging (MRI) contrast agents, Gd(III) chelates, have been found to be associated with nephrogenic systemic fibrosis (NSF) in renally compromised patients. Toxicity concerns related to Gd(III)-based agents prompted intensive research toward the development of safe, efficient, and long-cycle non-Gd contrast agents. Herein, three amphiphilic polymeric manganese (Mn) ligands (mPEG1k-P(L-a-HMDI)-mPEG1k, mPEG2k-P(L-a-HMDI)-mPEG2k and mPEG4k-P(L-a-HMDI)-mPEG4k) were synthesized, and then end-capped respectively with different molecular weights of polyethylene glycol monomethyl ether (mPEG 1 kD, 2 kD and 4 kD) to obtain amphiphilic polymer Mn ligands. After being chelated with Mn(II), these amphiphilic polymer Mn complexes show significantly higher T1 relaxivity than the small molecule Mn complex (MnL) at 0.5 T, 1.5 T and 3.0 T magnetic fields, respectively. Then, mPEG2k-P(MnL-a-HMDI)-mPEG2k with relatively high T1 relaxivities (23.2, 14.4 and 9.7 mM-1s-1 at 0.5 T, 1.5 T and 3.0 T, respectively), low CMC (4.7 mg L-1), reasonable size (48 nm) and excellent stability among these three polymer Mn complexes was selected for in vivo MR imaging of vascular vessels. The results suggest that mPEG2k-P(MnL-a-HMDI)-mPEG2k has an excellent and relatively long time-window vascular enhancement effect even at a low dose of 0.05 mmol Mn kg-1 BW, and could play a role in the diagnosis of vascular diseases (0.1 mmol Mn kg-1 BW). Therefore, mPEG2k-P(MnL-a-HMDI)-mPEG2k may be considered as a potential blood pool contrast agent.

Development of an MRI contrast agent for both detection and inhibition of the amyloid-β fibrillation process

A curcumin derivative conjugated with Gd-DO3A (Gd-DO3A-Comp.B) was synthesised as an MRI contrast agent for detecting the amyloid-β (Aβ) fibrillation process. Gd-DO3A-Comp.B inhibited Aβ aggregation significantly and detected the fibril growth at 20 μM of Aβ with 10 μM of probe concentration by T1-weighted MR imaging.

NMR Relaxivities of Paramagnetic Lanthanide-Containing Polyoxometalates.

The current trend for ultra-high-field magnetic resonance imaging (MRI) technologies opens up new routes in clinical diagnostic imaging as well as in material imaging applications. MRI selectivity is further improved by using contrast agents (CAs), which enhance the image contrast and improve specificity by the paramagnetic relaxation enhancement (PRE) mechanism. Generally, the efficacy of a CA at a given magnetic field is measured by its longitudinal and transverse relaxivities r1 and r2, i.e., the longitudinal and transverse relaxation rates T1−1 and T2−1 normalized to CA concentration. However, even though basic NMR sensitivity and resolution become better in stronger fields, r1 of classic CA generally decreases, which often causes a reduction of the image contrast. In this regard, there is a growing interest in the development of new contrast agents that would be suitable to work at higher magnetic fields. One of the strategies to increase imaging contrast at high magnetic field is to inspect other paramagnetic ions than the commonly used Gd(III)-based CAs. For lanthanides, the magnetic moment can be higher than that of the isotropic Gd(III) ion. In addition, the symmetry of electronic ground state influences the PRE properties of a compound apart from diverse correlation times. In this work, PRE of water 1H has been investigated over a wide range of magnetic fields for aqueous solutions of the lanthanide containing polyoxometalates [DyIII(H2O)4GeW11O39]5– (Dy-W11), [ErIII(H2O)3GeW11O39]5– (Er-W11) and [{ErIII(H2O)(CH3COO)(P2W17O61)}2]16− (Er2-W34) over a wide range of frequencies from 20 MHz to 1.4 GHz. Their relaxivities r1 and r2 increase with increasing applied fields. These results indicate that the three chosen POM systems are potential candidates for contrast agents, especially at high magnetic fields.

Development of a Nanoscale Chemical Exchange Saturation Transfer Magnetic Resonance Imaging Contrast Agent That Measures pH.

AcidoCEST MRI can measure the extracellular pH (pHe) of the tumor microenvironment in mouse models of human cancers and in patients who have cancer. However, chemical exchange saturation transfer (CEST) is an insensitive magnetic resonance imaging (MRI) contrast mechanism, requiring a high concentration of small-molecule agent to be delivered to the tumor. Herein, we developed a nanoscale CEST agent that can measure pH using acidoCEST MRI, which may decrease the requirement for high delivery concentrations of agent. We also developed a monomer agent for comparison to the polymer. After optimizing CEST experimental conditions, we determined that the polymer agent could be used during acidoCEST MRI studies at 125-fold and 488-fold lower concentration than the monomer agent and iopamidol, respectively. We also determined that both agents can measure pH with negligible dependence on temperature. However, pH measurements with both agents were dependent on concentration, which may be due to concentration-dependent changes in hydrogen bonding and/or steric hindrance. We performed in vivo acidoCEST MRI studies using the three agents to study a xenograft MDA-MB-231 model of mammary carcinoma. The tumor pHe measurements were 6.33 ± 0.12, 6.70 ± 0.15, and 6.85 ± 0.15 units with iopamidol, the monomer agent, and polymer agent, respectively. The higher pHe measurements with the monomer and polymer agents were attributed to the concentration dependence of these agents. This study demonstrated that nanoscale agents have merit for CEST MRI studies, but consideration should be given to the dependence of CEST contrast on the concentration of these agents.

Development of an Effective Tumor-Targeted Contrast Agent for Magnetic Resonance Imaging Based on Mn/H-Ferritin Nanocomplexes.

Magnetic resonance imaging (MRI) is one of the most sophisticated diagnostic tools that is routinely used in clinical practice. Contrast agents (CAs) are commonly exploited to afford much clearer images of detectable organs and to reduce the risk of misdiagnosis caused by limited MRI sensitivity. Currently, only a few gadolinium-based CAs are approved for clinical use. Concerns about their toxicity remain, and their administration is approved only under strict controls. Here, we report the synthesis and validation of a manganese-based CA, namely, Mn@HFn-RT. Manganese is an endogenous paramagnetic metal able to produce a positive contrast like gadolinium, but it is thought to result in less toxicity for the human body. Mn ions were efficiently loaded inside the shell of a recombinant H-ferritin (HFn), which is selectively recognized by the majority of human cancer cells through their transferrin receptor 1. Mn@HFn-RT was characterized, showing excellent colloidal stability, superior relaxivity, and a good safety profile. In vitro experiments confirmed the ability of Mn@HFn-RT to efficiently and selectively target breast cancer cells. In vivo, Mn@HFn-RT allowed the direct detection of tumors by positive contrast enhancement in a breast cancer murine model, using very low metal dosages and exhibiting rapid clearance after diagnosis. Hence, Mn@HFn-RT is proposed as a promising CA candidate to be developed for MRI.

Magnetic Resonance Imaging of PSMA-Positive Prostate Cancer by a Targeted and Activatable Gd(III) MR Contrast Agent.

Prostate-specific membrane antigen (PSMA) is a transmembrane protein that is highly expressed in aggressive prostate cancer (PCa) and has been extensively studied as a PCa diagnostic imaging biomarker. Multiple imaging modalities have exploited PSMA as a biomarker including magnetic resonance (MR), Optical, and PET imaging. Of all the imaging MR imaging provides the most detailed information, concurrently providing anatomical, functional, and potentially molecular information. However, the lower sensitivity of MR requires development of molecular MR contrast agents that provides high signal-to-noise ratios. Herein, we report the first targeted and activatable Gd(III)-based MR contrast agents prostate cancer probe 1 and 2 (PCP-1 and -2). We successfully used PCP-2 to differentiate between PSMA+ and PSMA- prostate cancer cells with both in vitro fluorescence imaging and in vivo MR imaging. The in vivo MR imaging results were further supported by ex vivo fluorescence imaging studies, showcasing the unique bimodal feature of PCP-2. Furthermore, PCP-2 highlights a unique molecular MR probe design strategy that improved the sensitivity of traditional biomarker-targeted MR imaging, addressing a critical unmet need in molecular MR imaging field. This work represents the first example of a targeted and activatable MR contrast agent that can be systemically administered in vivo to highlight PSMA+ prostate tumors, paving the way for the clinical translation of MR PSMA imaging.

MP44-06 ULTRASOUND CONTRAST-ENHANCED VOIDING CYSTOURETHROGRAM FOR DIAGNOSIS OF VESICOURETERAL REFLUX: SINGLE-INSTITUTION EXPERIENCE

You have accessJournal of UrologyPediatric Urology II (MP44)1 Sep 2021MP44-06 ULTRASOUND CONTRAST-ENHANCED VOIDING CYSTOURETHROGRAM FOR DIAGNOSIS OF VESICOURETERAL REFLUX: SINGLE-INSTITUTION EXPERIENCE Thomas Williams, Lane Palmer, John Amodio, and Jeffrey Palmer Thomas WilliamsThomas Williams More articles by this author , Lane PalmerLane Palmer More articles by this author , John AmodioJohn Amodio More articles by this author , and Jeffrey PalmerJeffrey Palmer More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002065.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The current standard diagnostic method for vesicoureteral reflux (VUR) is fluoroscopic voiding cystography (VCUG). However, exposure to this inherent ionizing radiation may increase the risk of developing a malignancy in this vulnerable population. The development of stable and reproducible intravesical ultrasound contrast agents and techniques offer an opportunity to diagnose VUR without radiation exposure. This study highlights a large volume, single-institution’s experience of ultrasound contrast-enhanced VCUG and reported outcomes. METHODS: Retrospective chart review for 143 pediatric patients who underwent ultrasound contrast-enhanced VCUG at a single children’s hospital between 2018 and 2020. Technique involved several voiding and filling cycles with 1cc of Lumason® microbubbles, mixed with normal saline, and instilled via catheter gravity drip. Primary outcomes measured grade of VUR (International Reflux Grading System) as interpreted by a trained pediatric radiologist. Additionally, related anatomical findings, indications for exam, and clinical outcomes were reported. RESULTS: Mean age ranged from newborn to 14 years of age (18.7 ± 33.6 months, mean ± SD). The predominant indication for examination was prenatal hydronephrosis, 85 patients (59.4%) followed by history of urinary tract infection, 46 patients (32.2%). Overall, VUR was detected in 41 patients (28.7%) with total of 58 renal units. VUR was more commonly noted on the left side - 31 renal units (53.4%) but without difference in reflux grade (3.1 vs 3.0). Reflux grade breakdown was Grade I (0), Grade II (19), Grade III (23), Grade IV (9), and Grade V (7). There were no complications. CONCLUSIONS: Ultrasound contrast-enhanced VCUG is a safe and efficient alternative to the diagnosis of VUR without exposure to ionizing radiation. Future studies should continue to explore exam reproducibility and comparison between that of fluoroscopic VCUG. Source of Funding: None © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e794-e795 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Thomas Williams More articles by this author Lane Palmer More articles by this author John Amodio More articles by this author Jeffrey Palmer More articles by this author Expand All Advertisement Loading ...

Folic Acid-Conjugated CuFeSe2 Nanoparticles for Targeted T2-Weighted Magnetic Resonance Imaging and Computed Tomography of Tumors In Vivo.

BackgroundDevelopment of new long-circulating contrast agents for computed tomography (CT) and magnetic resonance imaging (MRI) of different biological systems still remains a great challenge. Here, we report the synthesis of folic acid (FA)-targeted CuFeSe2 nano-contrast agent for CT and MRI imaging in vitro and in vivo.Methods and ResultsIn our study, CuFeSe2 was fabricated through a facile and green aqueous reaction and then further aminated through silanization. The amine-functionalized CuFeSe2-NH2 nanoparticles enable the covalent conjugation of folate-conjugated polyethylene glycol (FA-PEG-COOH) as a targeting ligand onto their surface, which could improve the dispersion and endue the targetability of nanoparticles, respectively. The formed multifunctional CuFeSe2-PEG-FA nanoparticles were characterized via different techniques, which exhibited outstanding dispersion, good biocompatibility and excellent FA-targeted capability. Meanwhile, the nanoparticles were quite safe in the given concentration range as confirmed by in vitro and in vivo toxicity assay. Importantly, CuFeSe2-PEG-FA nanoparticles were successfully applied in CT/MRI dual-modality imaging in vitro and in vivo, which showed a better imaging performance and targeted capability.ConclusionTherefore, the constructed CuFeSe2-PEG-FA nanoparticles have a great potential as an efficient contrast agent for dual-modality imaging of different biological systems.

In situ characterization of microparticulate optoacoustic contrast agents in an intracardiac perfusion mouse model

Extrinsically administered light-absorbing agents may greatly enhance the sensitivity and imaging performance of optoacoustic tomography (OAT). Beyond the use of targeted contrast agents in functional and molecular imaging applications, tracking of highly absorbing microparticles has recently been shown to facilitate super-resolution volumetric angiography and mapping of blood flow. However, in vivo characterization of new types of microparticulate absorbing agents is often hindered due to their potential toxicity, incompatible dimensions, or sub-optimal extinction spectrum shadowed by strong background absorption of hemoglobin. Herein, we used an intracardiac perfusion mouse model to individually track the perfusion of absorbing particles through the cerebral vasculature by acquiring a sequence of high-frame-rate 3D OAT images. The particles were injected in the left ventricle of the heart after substitution of blood by an artificial cerebrospinal fluid post mortem, which has further contributed to minimizing the background OAT signals induced by hemoglobin absorption. The presented approach can greatly aid the development of new microparticulate contrast agents with optimized performance for various OAT imaging applications.

A Smart Glutathione and H2O2 Dual-Responsive Signal Inversion Magnetic Resonance Imaging Contrast Agent for Tumor Diagnosis

本文主要开发了一种谷胱甘肽（GSH）和H2O2双响应信号反转磁共振成像造影剂SPION@DMSN@PEG，该造影剂主要由可降解介孔二氧化硅纳米粒子（DMSN）和超顺磁性氧化铁纳米粒子（SPION）组成。小鼠体内MRI成像研究显示，该造影剂可在肿瘤部位实现对肿瘤的T2加权成像，随着DMSN在酸性且富含谷胱甘肽和过氧化氢的肿瘤微环境条件下降解，造影剂可从T2信号向T1信号转变，最终转变为T1信号3002 Accurate bioimaging of internal body tissues plays a key role in achieving precise medical diagnosis. Magnetic resonance imaging (MRI) as one of the clinically used bioimaging modalities is largely hampered by the occurrence of false-positive imaging (artifacts). The use of contrast agents has tremendously contributed to the improvement of the accuracy of MRI, however, developing a dual-responsive contrast agent that capable of effectively switching from T 2 to T 1 contrast enhancement in vivo still remains a challenge. Here, we demonstrated the synthesis of a glutathione (GSH) and H 2 O 2 dual-responsive “signal inversion” contrast agent, which mainly comprised of superparamagnetic iron oxide nanoparticles (SPION) and degradable mesoporous silica nanoparticles (DMSN). The contrast agent achieved T 2 -weighted imaging in tumor site, and enabled an efficacious switch to T 1 -weighted imaging upon the GSH- and H 2 O 2 -mediated degradation of DMSN. The characteristics of the signal transformation largely reduced the artifacts to enhance the accuracy of MRI. Interestingly, the in vivo evaluations revealed prominence of the T 2 -weighted imaging up to 2 h post-intravenous injection, which was succeeded by T 1 -weighted imaging that gradually increased with time and became dominant after 24 h. It was therefore expected that the findings shown in this work would guide the development of other contrast agents alike for more robust and accurate bioimaging by using MRI. A glutathione (GSH) and H 2 O 2 dual-responsive “signal inversion” contrast agent (SPION@DMSN@PEG) is synthesized in this work, which achieves T 2 -weighted magnetic resonance imaging (MRI) in tumor site, and enables an efficacious switch to T 1 -weighted MRI upon the GSH- or H 2 O 2 -mediated degradation of DMSN.

Nitroxyl Radical as a Theranostic Contrast Agent in Magnetic Resonance Redox Imaging.

Significance: In vivo assessment of paramagnetic and diamagnetic conversions of nitroxyl radicals based on cyclic redox mechanism can be an index of tissue redox status. The redox mechanism of nitroxyl radicals, which enables their use as a normal tissue-selective radioprotector, is seen as being attractive on planning radiation therapy.Recent Advances: In vivo redox imaging using nitroxyl radicals as redox-sensitive contrast agents has been developed to assess tissue redox status. Chemical and biological behaviors depending on chemical structures of nitroxyl radical compounds have been understood in detail. Polymer types of nitroxyl radical contrast agents and/or nitroxyl radical-labeled drugs were designed for approaching theranostics.Critical Issues: Nitroxyl radicals as magnetic resonance imaging (MRI) contrast agents have several advantages compared with those used in electron paramagnetic resonance (EPR) imaging, while support by EPR spectroscopy is important to understand information from MRI. Redox-sensitive paramagnetic contrast agents having a medicinal benefit, that is, nitroxyl-labeled drug, have been developed and proposed.Future Directions: A development of suitable nitroxyl contrast agent for translational theranostic applications with high reaction specificity and low normal tissue toxicity is under progress. Nitroxyl radicals as redox-sensitive magnetic resonance contrast agents can be a useful tool to detect an abnormal tissue redox status such as disordered oxidative stress. Antioxid. Redox Signal. 36, 95–121.

Cerium-based Dual-Modality Imaging Contrast Agent for Efficient Retention in Tumor Acidic Microenvironment

Design and fabrication of highly effective, targeted, intelligent and multifunctional innovative theranostic agents with innovative alternative materials become pressing concerns. Nanoparticles are suitable for the incorporation of multifunction by modulating such a specific structure in a nanoscale and have been developed as multifunctional intelligent contrast agent theranostic nanoplatform on account of being performed multifunctional integration easily, for instance, controlled release function, targeting function, multi-stimuli sensitive function, biocompatibility, bio-degradation and other functions for promoting performance, effectiveness and efficiency. In this work, the CdTe@SiO 2 @CeO 2 core-shell nanoparticles were synthesized and assessed as a pH responsive dual-modality imaging contrast agent. The CdTe@SiO 2 core was participated as fluorescent label and the CeO 2 shell was partaken as CT tag. As a latent auxiliary scheme, this study explored the dual-modality combination between fluorescence imaging and CT imaging to localize tumor on the xenograft tumor models. All assessments acknowledged that this CdTe@SiO 2 @CeO 2 core-shell nanoparticle was an effective dual-modality contrast medium for tumor mapping on murine tumor models. The development of nanoparticulate contrast agents for multimodality diagnostic imaging and therapy has been intensively pursued in recent years. In this work, a pH responsive fluorescent-CT dual-modality imaging contrast agent was synthesized and assessed on murine tumor models. It's an effective fluorescent-CT dual-modality contrast medium for tumor mapping on murine tumor models, and a great potentiality would be demonstrated in surgical guidance in future clinic application.

Translational Photoacoustic Imaging for Disease Diagnosis, Monitoring, and Surgical Guidance: introduction to the feature issue.

This feature issue of Biomedical Optics Express covered all aspects of translational photoacoustic research. Application areas include screening and diagnosis of diseases, imaging of disease progression and therapeutic response, and image-guided treatment, such as surgery, drug delivery, and photothermal/photodynamic therapy. The feature issue also covers relevant developments in photoacoustic instrumentation, contrast agents, image processing and reconstruction algorithms.

Ultrasound contrast agents: microbubbles made simple for the pediatric radiologist.

The ability to provide prompt, real-time, easily accessible and radiation-free diagnostic assessments makes ultrasound (US) one of the most versatile imaging modalities. The introduction and development of stable microbubble-based ultrasound contrast agents (UCAs) in the early 1990s improved visualization of complex vascular structures, overcoming some of the limitations of B-mode and Doppler imaging. UCAs have been used extensively in the adult population to visualize vasculature and to evaluate perfusion and blood flow dynamics in organs and lesions. Since the first observations that air bubbles within a liquid can generate a strong echogenic effect, to the early makeshift approaches with agitated saline, and later to the development of industrially produced and federally approved UCAs, these agents have evolved to become both clinically and commercially viable. Perhaps the most exciting potential of UCAs is being uncovered by current research that explores the use of these agents for molecular imaging and therapeutic applications. As contrast-enhanced ultrasound (CEUS) becomes more widely available, it is important for pediatric radiologists to understand the physics of the interaction between the US signal and the microbubbles in order to properly utilize them for the highest level of diagnostic imaging and interventions. In this article we introduce the composition of UCAs and the physics of their behavior in US, and we offer a brief history of their development over the last decades.

Photophysical Properties of Indocyanine Green in the Shortwave Infrared Region.

With the growing development of new contrast agents for optical imaging using near-infrared and shortwave infrared (SWIR) wavelengths, it is essential to have consistent bench-marks for emitters in these regions. Indocyanine green (ICG), a ubiquitous and FDA-approved organic dye and optical imaging agent, is commonly employed as a standard for photophysical properties and biological performance for imaging experiments at these wavelengths. Yet, its reported photophysical properties across organic and aqueous solvents vary greatly in the literature, which hinders its ability to be used as a consistent benchmark. Herein, we measure photophysical properties in organic and aqueous solvents using InGaAs detection (~950-1,700 nm), providing particular relevance for SWIR imaging.

Necrosis binding of Ac-Lys0(IRDye800CW)-Tyr3-octreotate: a consequence from cyanine-labeling of small molecules

BackgroundThere is a growing body of nuclear contrast agents that are repurposed for fluorescence-guided surgery. New contrast agents are obtained by substituting the radioactive tag with, or adding a fluorescent cyanine to the molecular structure of antibodies or peptides. This enables intra-operative fluorescent detection of cancerous tissue, leading to more complete tumor resection. However, these fluorescent cyanines can have a remarkable influence on pharmacokinetics and tumor uptake, especially when labeled to smaller targeting vectors such as peptides. Here we demonstrate the effect of cyanine-mediated dead cell-binding of Ac-Lys0(IRDye800CW)-Tyr3-octreotate (800CW-TATE) and how this can be used as an advantage for fluorescence-guided surgery.ResultsBinding of 800CW-TATE could be blocked with DOTA0-Tyr3-octreotate (DOTA-TATE) on cultured SSTR2-positive U2OS cells and was absent in SSTR2 negative U2OS cells. However, strong binding was observed to dead cells, which could not be blocked with DOTA-TATE and was also present in dead SSTR2 negative cells. No SSTR2-mediated binding was observed in frozen tumor sections, possibly due to disruption of the cells in the process of sectioning the tissue before exposure to the contrast agent. DOTA-TATE blocking resulted in an incomplete reduction of 61.5 ± 5.8% fluorescence uptake by NCI-H69-tumors in mice. Near-infrared imaging and dead cell staining on paraffin sections from resected tumors revealed that fluorescence uptake persisted in necrotic regions upon blocking with DOTA-TATE.ConclusionThis study shows that labeling peptides with cyanines can result in dead cell binding. This does not hamper the ultimate purpose of fluorescence-guided surgery, as necrotic tissue appears in most solid tumors. Hence, the necrosis binding can increase the overall tumor uptake. Moreover, necrotic tissue should be removed as much as possible: it cannot be salvaged, causes inflammation, and is tumorigenic. However, when performing binding experiments to cells with disrupted membrane integrity, which is routinely done with nuclear probes, this dead cell-binding can resemble non-specific binding. This study will benefit the development of fluorescent contrast agents.