Therapeutic applications of nanoparticles targeting neutrophil and extracellular traps.

Neutrophils, the most abundant leukocytes in human circulation, are key effectors and regulators of both innate and adaptive immunity which migrate from the bloodstream to sites of inflammation or infection in response to different stimuli. A growing body of evidence has revealed that dysregulated neutrophil activity contributes to the development of several diseases. Targeting their function has been proposed as a potential strategy to treat or mitigate the progression of these disorders. Additionally, neutrophil tropism has been proposed as a strategy to drive therapeutic agents towards targeted disease sites. In this article, we review the proposed nanomedicine approaches to target neutrophils and their components, the regulation of their function and the use of their tropism in drug delivery for therapeutic purposes.

Current knowledge on the tissue distribution of mRNA nanocarriers for therapeutic protein expression.

Exogenously delivered mRNA-based drugs are emerging as a new class of therapeutics with the potential to treat several diseases. Over the last decade, advancements in the design of non-viral delivery tools have enabled mRNA to be evaluated for several therapeutic purposes including protein replacement therapies, gene editing, and vaccines. However, in vivo delivery of mRNA to targeted organs and cells remains a critical challenge. Evaluation of the biodistribution of mRNA vehicles is of utmost importance for the development of effective pharmaceutical candidates. In this review, we discuss the recent advances in the design of nanoparticles loaded with mRNA and extrapolate the key factors influencing their biodistribution following administration. Finally, we highlight the latest developments in the preclinical and clinical translation of mRNA therapeutics for protein supplementation therapy.

Realistic Kidney Tissue Surrogates for Multienergy Computed Tomography-Feasibility and Estimation of Energy-Dependent Attenuation Thresholds for Renal Lesion Enhancement in Low-kV and Virtual Monoenergetic Imaging.

PURPOSE: The aims of this study were to assess if kidney tissue surrogates (KTSs) are superior to distilled water-iodine solutions in the emulation of energy-dependent computed tomography (CT) attenuation characteristics of renal parenchyma and to estimate attenuation thresholds for definite lesion enhancement for low-kV single-energy and low-keV dual-energy virtual monoenergetic imaging. METHODS: A water-filled phantom (diameter, 30 cm) with multiple vials was imaged on a dual-source dual-energy CT (DS-DE) and a single-source split-filter dual-energy CT (SF-DE), both in single-energy mode at 80, 100, 120, 140 kVp and in dual-energy mode at 80/Sn150, 90/Sn150, and 100/Sn150 kVp for DS-DE and AuSn120 kVp for SF-DE. Single-energy images, linear-blended dual-energy images, and virtual monoenergetic imaging at energy levels from 40 to 190 keV were reconstructed. First, attenuation characteristics of KTS in solid and liquid consistencies were compared. Second, solid KTSs were developed to match the CT attenuation of unenhanced renal parenchyma at 120 kVp as retrospectively measured in 100 patients. Third, CT attenuation of KTS-iodine and water-iodine solutions at 8 different iodine concentrations (0-10 mg I/mL) were compared as a function of tube voltage and of keV level using multiple linear regression models. Energy-dependent attenuation thresholds for definite lesion enhancement were calculated. RESULTS: Unenhanced renal parenchyma at 120 kVp measured on average 30 HU on both scanners in the patient cohort. Solid KTS with a water content of 80% emulated the attenuation of unenhanced renal parenchyma (30 HU) more accurately compared with water-iodine solutions (0 HU). Attenuation difference between KTS-iodine and water-iodine solutions converged with increasing iodine concentration and decreasing x-ray energy due to beam-hardening effects. A slight attenuation difference of approximately 2 HU was found between the 2 CT scanners. Attenuation thresholds for definite lesion enhancement were dependent on tube voltage and keV level and ranged from 16.6 to 33.2 HU and 3.2 to 68.3 HU for single-energy and dual-energy CT scan modes for DS-DE and from 16.1 to 34.3 HU and 3.3 to 92.2 HU for SF-DE. CONCLUSIONS: Kidney tissue surrogates more accurately emulate the energy-dependent CT attenuation characteristics of renal parenchyma for multienergy CT compared with conventional water-iodine approaches. Energy-dependent thresholds for definite lesion enhancement could facilitate lesion characterization when imaging at different energies than the traditional 120 kVp.

In vitro qualitative and quantitative CT assessment of iodinated aerosol nasal deposition using a 3D-printed nasal replica.

Computed tomography can provide high-resolution details on nasal anatomy being potentially useful for the assessment of nasal spray deposition. The purpose of this technical note was to present a method based on CT imaging to assess qualitatively and quantitatively the in vitro spray deposition patterns within the sinonasal cavities of a nasal replica obtained by three-dimensional (3D) printing, using iodinated contrast agent labelled solutions with high spatial and temporal resolution. Using a third generation dual-source CT scanner in single energy mode, scans of a nasal replica were acquired following application of iodinated contrast agent labelled aerosols with an iodine concentration of 92.5 mgl/mL. Two software programmes were then utilised (Osirix MD v.9.0, Pixmeo, Geneva, Switzerland; 3mensio, Pie Medical Imaging, Bilthoven, Netherlands) to generate three-dimensional reconstructions of the scans, thus enabling the rapid detection and visualisation of administered single droplets and their voxel-by-voxel localisation. Using this approach, we achieved recovery rates between 84-98% and 89-109% (depending on the software programme) of the total applied aerosol volume.

Development of an anthropomorphic spine phantom suitable for fusion of MR neurography with interventional flat-panel CT.

PURPOSE: To design a spine phantom suitable for fusion of MR neurography (MRN) with interventional flat panel computed tomography (FPCT) images from tissue-equivalent agarose gels and artificial nerves in MRI, including material with equal attenuation to bone in computed tomography (CT). METHODS: T1-/T2-relaxation times of target tissue were determined in vivo (n = 5) using MR mapping-techniques. Serial dilution of castor oil lipogels was performed ex vivo in order to define correct composition for tissue-equivalent relaxation times. Similarly, serial dilution series of calcium carbonate (CaCO3) and barium sulphate (BaSO4) in synthetic resin were used to adjust radiodensity of selected vertebral bodies (L1-L5) and sacrum in CT. Nerve tissue was simulated with agarose-impregnated polyethylene fibers. Spine phantom was assembled using respective components in anthropomorphic geometry. A fat-saturated, T2-weighted 3D SPACE STIR sequence was acquired for MRN and subsequently fused with an on-site FPCT scan of the phantom. RESULTS: In vivo T1-/T2-values for fat tissue were found to be at 394 ± 16 ms and 161 ± 16 ms, corresponding to a castor oil concentration of 50%. Analogously, bone marrow-equivalent values were measured at 822 ± 21 ms and 67 ± 6 ms, simulated with 40% castor oil. Cortical bone-like radiodensity of 1'115 ± 80 HU was achieved for artificial bone with 30% CaCO3 and 1.5% BaSO4. Simulated nerves were successfully depicted in MRN and fused with FPCT, combining optimal contrasts for nerves and bones on-site. CONCLUSIONS: The customized phantom showed analogous tissue contrasts to in vivo conditions in both MRN and FPCT, facilitating simulations of fusion-image guided spine interventions.

A fibrin-specific monoclonal antibody from a designed phage display library inhibits clot formation and localizes to tumors in vivo.

Fibrin formation from fibrinogen is a rare process in the healthy organism but is a pathological feature of thrombotic events, cancer and a wide range of inflammatory conditions. We have designed and constructed an antibody phage display library (containing 13 billion clones) for the selective recognition of the N-terminal peptide of fibrin alpha chain. The key structural feature for selective fibrin binding was a K94E mutation in the VH domain. From this library, an antibody was isolated (termed AP2), which recognizes the five N-terminal amino acids of fibrin with high affinity (Kd=44nM), but does not bind to fibrinogen. The AP2 antibody could be expressed in various formats (scFv, small immune protein and IgG) and inhibited fibrin clot formation in a concentration-dependent manner. Moreover, the AP2 antibody stained the fibrin-rich provisional stroma in solid tumors but did not exhibit any detectable staining toward normal tissues. Using a radioiodinated antibody preparation and quantitative biodistribution studies in tumor-bearing mice, AP2 was shown to selectively localize to fibrin-rich F9 murine teratocarcinomas, but not to SKRC-52 human kidney cancer xenografts. Collectively, the experiments indicate that the AP2 antibody recognizes fibrin in vitro and in vivo. The antibody may facilitate the development of fibrin-specific therapeutic agents.