Contrast-induced nephropathy (CIN) or contrast-induced acute kidney injury (CI-AKI) is an iatrogenic acute kidney injury observed after intravascular administration of contrast media for ...intravascular diagnostic procedures or therapeutic angiographic intervention. High risk patients including those with chronic kidney disease (CKD), diabetes mellitus with impaired renal function, congestive heart failure, intraarterial intervention, higher volume of contrast, volume depletion, old age, multiple myeloma, hypertension, and hyperuricemia had increased prevalence of CIN. Although CIN is reversible by itself, some patients suffer this condition without renal recovery leading to CKD or even end-stage renal disease which required long term renal replacement therapy. In addition, both CIN and CKD have been associated with increasing of mortality. Three pathophysiological mechanisms have been proposed including direct tubular toxicity, intrarenal vasoconstriction, and excessive production of reactive oxygen species (ROS), all of which lead to impaired renal function. Reports from basic and clinical studies showing potential preventive strategies for CIN pathophysiology including low- or iso-osmolar contrast media are summarized and discussed. In addition, reports on pharmacological interventions to reduce ROS and attenuate CIN are summarized, highlighting potential for use in clinical practice. Understanding this contributory mechanism could pave ways to improve therapeutic strategies in combating CIN.
Despite recent technological advancements in microcomputed tomography (micro-CT) and contrast agent development, preclinical contrast agents are still predominantly iodine-based. Higher contrast can ...be achieved when using elements with higher atomic numbers, such as lanthanides; lanthanides also have X-ray attenuation properties that are ideal for spectral CT. However, the formulation of lanthanide-based contrast agents at the high concentrations required for vascular imaging presents a significant challenge. In this work, we developed an erbium-based contrast agent that meets micro-CT imaging requirements, which include colloidal stability upon redispersion at high concentrations, evasion of rapid renal clearance, and circulation times of tens of minutes in small animals. Through systematic studies with poly(ethylene glycol) (PEG)-poly(propylene glycol), PEG-polycaprolactone, and PEG-poly(l-lactide) (PLA) block copolymers, the amphiphilic block copolymer PEG114-PLA53 was identified to be ideal for encapsulating oleate-coated lanthanide-based nanoparticles for in vivo intravenous administration. We were able to synthesize a contrast agent containing 100 mg/mL of erbium that could be redispersed into colloidally stable particles in saline after lyophilization. Contrast enhancement of over 250 HU was achieved in the blood pool for up to an hour, thereby meeting the requirements of live animal micro-CT.
The purpose of this review is to describe trends in microbubble application in molecular imaging.
Microbubbles are used for contrast ultrasound imaging as blood-pool agents in cardiology and ...radiology. Their promise as targeted agents for molecular imaging is now being recognized. Microbubbles can be functionalized with ligand molecules that bind to molecular markers of disease. Potential clinical applications of molecular imaging with microbubble-based ultrasound contrast agents are in the monitoring of the biomarker status of vascular endothelium, visualizing tumor vasculature, and imaging inflammation and ischemia-reperfusion injury zones and thrombi.
Four new N‐ethylcarbazole‐linked aza‐boron‐dipyrromethene (aza‐BODIPY) dyes (8 a,b and 9 a,b) were synthesized and characterized. The presence of the N‐ethylcarbazole moiety shifts their absorption ...and fluorescence spectra to the near‐infrared region, λ≈650–730 nm, of the electromagnetic spectrum. These dyes possess strong molar absorptivity in the range of 3–4×104 m−1 cm−1 with low fluorescence quantum yields. The triplet excited state and singlet oxygen generation of these dyes were enhanced upon iodination at the core position. The core‐iodinated dyes 9 a,b showed excellent triplet quantum yields of about 90 and 75 %, with singlet oxygen generation efficiency of about 70 and 60 % relative to that of the parent dyes. Derivatives 8 a,b showed dual absorption profiles, in contrast to dyes 9 a,b, which had the characteristic absorption band of aza‐BODIPY dyes. DFT calculations revealed that the electron density was spread over the iodine and dipyrromethene plane of 9 a,b, whereas in 8 a,b the electron density was distributed on the carbazole group and dipyrromethene plane of aza‐BODIPY. The uniqueness of these aza‐BODIPY systems is that they exhibit efficient triplet‐state quantum yields, high singlet oxygen generation yields, and good photostability. Furthermore, the photoacoustic (PA) characteristics of these aza‐BODIPY dyes was explored, and efficient PA signals for 8 a were observed relative to blood serum with in vitro deep‐tissue imaging, thereby confirming its use as a promising PA contrast agent.
Observation at depth: Carbazole‐linked aza‐boron‐dipyrromethene (aza‐BODIPY) dyes show favorable photophysical properties, as well as efficient triplet and singlet oxygen generation quantum yields. Furthermore, the efficient photoacoustic (PA) signals produced by these dyes makes them excellent candidates for photodynamic therapy and as contrast agents for photoacoustic imaging (see figure).
Patients with triple-negative breast cancer (TNBC) have dismal prognoses due to the lack of therapeutic targets and susceptibility to lymph node (LN) metastasis. Therefore, it is essential to develop ...more effective approaches to identify early TNBC tissues and LNs. In this work, a magnetic resonance imaging (MRI) contrast agent (Mn-iCOF) was constructed based on the Mn(II)-chelated ionic covalent organic framework (iCOF). Because of the porous structure and hydrophilicity, the Mn-iCOF has a high longitudinal relaxivity (r 1) of 8.02 mM–1 s–1 at 3.0 T. For the tumor-bearing mice, a lower dose (0.02 mmol Mn/kg) of Mn-iCOF demonstrated a higher signal-to-noise ratio (SNR) value (1.8) and longer retention time (2 h) compared to a 10-fold dose of commercial Gd-DOTA (0.2 mmol Gd/kg). Moreover, the Mn-iCOF can provide continuous and significant MR contrast for the popliteal LNs within 24 h, allowing for accurate evaluation and dissection of LNs. These excellent MRI properties of the Mn-iCOF may open new avenues for designing more biocompatible MRI contrast agents with higher resolutions, particularly in the diagnosis of TNBC.
A library of 10 Mn-containing complexes capable of switching reversibly between the Mn(II) and Mn(III) oxidation states was prepared and evaluated for potential usage as MRI reporters of tissue ...redox activity. We synthesized N-(2-hydroxybenzyl)-N,N′,N′-ethylenediaminetriacetic acid (HBET) and N-(2-hydroxybenzyl-N,N′,N′-trans-1,2-cyclohexylenediaminetriacetic acid (CyHBET) ligands functionalized (−H, −OMe, −NO2) at the 5-position of the aromatic ring. The Mn(II) complexes of all ligands and the Mn(III) complexes of the 5-H and 5-NO2 functionalized ligands were synthesized and isolated, but the Mn(III) complexes with the 5-OMe functionalized ligands were unstable. 1H relaxivity of the 10 isolable complexes was measured at pH 7.4 and 37 °C, 1.4 T. Thermodynamic stability, pH-dependent complex speciation, hydration state, water exchange kinetics of the Mn(II) complexes, and pseudo-first order reduction kinetics of the Mn(III) complexes were studied using a combination of pH-potentiometry, UV–vis spectroscopy, and 1H and 17O NMR measurements. The effects of ligand structural and electronic modifications on the Mn(II/III) redox couple were studied by cyclic voltammetry. The Mn(II) complexes are potent relaxation agents as compared to the corresponding Mn(III) species with MnII(CyHBET)(H2O)2– exhibiting a 7.5-fold higher relaxivity (3.3 mM–1 s–1) than the oxidized form (0.4 mM–1 s–1). At pH 7.4, Mn(II) exists as a mixture of fully deprotonated (ML) and monoprotonated (HML) complexes and Mn(II) complex stability decreases as the ligands become more electron-releasing (pMn for 10 μM MnII(CyHBET–R′)(H2O)2– decreases from 7.6 to 6.2 as R′ goes from −NO2 to −OMe, respectively). HML speciation increases as the electron-releasing nature of the phenolato-O donor increases. The presence of a water coligand is maintained upon conversion from HML to ML, but the water exchange rate of ML is faster by up to 2 orders of magnitude (k ex 310 for HMnII(CyHBET)(H2O)− and MnII(CyHBET)(H2O)2– are 1.2 × 108 and 1.0 × 1010 s–1, respectively). The Mn(II/III) redox potential can be tuned over a range of 0.30 V (E 1/2 = 0.27–0.57 V) through electronic modifications to the 5-substituent of the aromatic ligand component. However, care must be taken in tuning the ligand electronics to avoid Mn(III)–ligand autoredox. Taken together, these results serve to establish criteria for optimizing Mn(III) versus Mn(II) relaxivity differentials, complex stability, and Mn(II/III) redox potential.
In parallel with the rapidly growing and widespread use of nanomedicine in the clinic, we are also witnessing the development of so-called theranostic agents that combine diagnostic and therapeutic ...properties. Among them, ultra-small gold nanoclusters (Au NCs) show promising potential due to their optical properties and activatable therapeutic activities under irradiation. Furthermore, due to their hydrodynamic diameter of smaller than 6 nm and unique biophysical properties, they also present intriguing behaviors in biological and physio-pathological environments. In this review, we aim to present the latest research studies published on such nanoparticles in animals. We also propose guidelines to identify the main physico-chemical parameters that govern the behaviour of Au NCs after administration in small animals, notably concerning their renal elimination and their ability to accumulate in tumors. Then, we present recent advances in their use as theranostic agents putting them in parallel with other contrast agents.
Selective killing of cancer cells while minimizing damage to healthy tissues is the goal of clinical radiation therapy. This therapeutic ratio can be improved by image-guided radiation delivery and ...selective radiosensitization of cancer cells. Here, we have designed and tested a novel trimodal theranostic nanoparticle made of bismuth and gadolinium for on-site radiosensitization and image contrast enhancement to improve the efficacy and accuracy of radiation therapy. We demonstrate in vivo magnetic resonance (MR), computed tomography (CT) contrast enhancement, and tumor suppression with prolonged survival in a non-small cell lung carcinoma model during clinical radiation therapy. Histological studies show minimal off-target toxicities due to the nanoparticles or radiation. By mimicking existing clinical workflows, we show that the bismuth–gadolinium nanoparticles are highly compatible with current CT-guided radiation therapy and emerging MR-guided approaches. This study reports the first in vivo proof-of-principle for image-guided radiation therapy with a new class of theranostic nanoparticles.
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