Preparation and Characterization of Targeted Microbubbles.

Targeting of microbubbles (ultrasound contrast agents for molecular imaging) has been researched for more than two decades. However, methods of microbubble preparation and targeting ligand attachment are cumbersome, complicated, and lengthy. Therefore, there is a need to simplify the targeted microbubble preparation procedure to bring it closer to clinical translation.

Digestive Manifestations in Patients Hospitalized With Coronavirus Disease 2019.

Background & Aims: The prevalence and significance of digestive manifestations in coronavirus disease 2019 (COVID-19) remain uncertain. We aimed to assess the prevalence, spectrum, severity, and significance of digestive manifestations in patients hospitalized with COVID-19.

Methods: Consecutive patients hospitalized with COVID-19 were identified across a geographically diverse alliance of medical centers in North America.

Targeted Ultrasound Contrast Imaging of Tumor Vasculature With Positively Charged Microbubbles.

Purpose: Molecular ultrasound imaging of tumor vasculature is being actively investigated with microbubble contrast agents targeted to neovasculature biomarkers. Yet, a universal method of targeting tumor vasculature independent of specific biomarkers, or in their absence, would be desirable. We report the use of electrostatic interaction to achieve adherence of microbubbles to tumor vasculature and resulting tumor delineation by ultrasound imaging.

Formation of Microbubbles for Targeted Ultrasound Contrast Imaging: Practical Translation Considerations.

For preparation of ligand-decorated microbubbles for targeted ultrasound contrast imaging, it is important to maximize the amount of ligand associated with the bubble shell. We describe optimization of the use of a biocompatible cosurfactant in the microbubble formulation media to maximize the incorporation of targeting ligand-lipid conjugate into the microbubble shell, and thus reduce the fraction of ligand not associated with microbubbles, following amalgamation preparation. The influence of the concentration of a helper cosurfactant propylene glycol (PG) on the efficacy of microbubble preparation by amalgamation and on the degree of association of fluorescent PEG-lipid with the microbubble shell was tested.

Plectin-targeted liposomes enhance the therapeutic efficacy of a PARP inhibitor in the treatment of ovarian cancer.

Advances in genomics and proteomics drive precision medicine by providing actionable genetic alterations and molecularly targeted therapies, respectively. While genomic analysis and medicinal chemistry have advanced patient stratification with treatments tailored to the genetic profile of a patient's tumor, proteomic targeting has the potential to enhance the therapeutic index of drugs like poly(ADP-ribose) polymerase (PARP) inhibitors. PARP inhibitors in breast and ovarian cancer patients with BRCA1/2 mutations have shown promise.

Ultra-Low-Dose Ultrasound Molecular Imaging for the Detection of Angiogenesis in a Mouse Murine Tumor Model: How Little Can We See?

Objectives: The objective of this study was to evaluate the minimum microbubble dose for ultrasound molecular imaging to achieve statistically significant detection of angiogenesis in a mouse model.

Materials And Methods: The preburst minus postburst method was implemented on a Verasonics ultrasound research scanner using a multiframe compounding pulse inversion imaging sequence. Biotinylated lipid (distearoyl phosphatidylcholine-based) microbubbles that were conjugated with antivascular endothelial growth factor 2 (VEGFR2) antibody (MBVEGFR2) or isotype control antibody (MBControl) were injected into mice carrying adenocarcinoma xenografts.

The magnetic field dependence of water T1 in tissues.

The magnetic field dependence of the composite (1)H(2)O nuclear magnetic resonance signal T(1) was measured for excised samples of rat liver, muscle, and kidney over the field range from 0.7 to 7 T (35-300 MHz) with a nuclear magnetic resonance spectrometer using sample-shuttle methods. Based on extensive measurements on simpler component systems, the magnetic field dependence of T(1) of all tissues studied are readily fitted at Larmor frequencies above 1 MHz with a simple relaxation equation consisting of three contributions: a power law, A*ω(-0.

Extreme-values statistics and dynamics of water at protein interfaces.

Immobilized proteins present a unique interface with water. The water translational diffusive motions affect the high-frequency dynamics and the nuclear spin-lattice relaxation as with all surfaces; however, rare binding sites for water in protein systems add very low-frequency components to the dynamics spectrum. Water binding sites in protein systems are not identical, thus distributions of free energies and consequent dynamics are expected.

Water-proton-spin-lattice-relaxation dispersion of paramagnetic protein solutions.

The paramagnetic contributions to water-proton-spin-lattice relaxation rate constants in protein systems spin-labeled with nitroxide radicals were re-examined. As noted by others, the strength of the dipolar coupling between water protons and the protein-bound nitroxide radical often appears to be larger than physically reasonable when the relaxation is assumed to be controlled by 3-dimensional diffusive processes in the vicinity of the spin label. We examine the effects of the surface in biasing the diffusive exploration of the radical region and derive a relaxation model that incorporates 2-dimensional dynamics at the interfacial layer.

Water and backbone dynamics in a hydrated protein.

Rotational immobilization of proteins permits characterization of the internal peptide and water molecule dynamics by magnetic relaxation dispersion spectroscopy. Using different experimental approaches, we have extended measurements of the magnetic field dependence of the proton-spin-lattice-relaxation rate by one decade from 0.01 to 300 MHz for (1)H and showed that the underlying dynamics driving the protein (1)H spin-lattice relaxation is preserved over 4.

Dimensionality of diffusive exploration at the protein interface in solution.

The dynamics of water are critically important to the energies of interaction between proteins and substrates and determine the efficiency of transport at the interface. The magnetic field dependence of the nuclear spin-lattice relaxation rate constant 1/T(1) of water protons provides a direct characterization of water diffusional dynamics at the protein interface. We find that the surface-average translational correlation time is 30-40 ps and the magnetic field dependence of the water proton 1/T(1) is characteristic of two-dimensional diffusion of water in the protein interfacial region.

Changes in protein structure and dynamics as a function of hydration from (1)H second moments.

We report the proton second moment obtained directly from the Free Induction Decay (FID) of the NMR signal of variously hydrated bovine serum albumin (BSA) and hen egg white lysozyme (HEWL) and from the width of the NMR Z-spectrum of the cross-linked protein gels of different concentrations. The second moment of the proteins decreases in a continuous stepwise way as a function of increasing water content, which suggests that the structural and dynamical changes occur in small incremental steps. Although the second moment is dominated by the short range distances of nearest neighbors, the changes in the second moment show that the protein structure becomes more open with increasing hydration level.

Relaxation of protons by radicals in rotationally immobilized proteins.

Proton spin-lattice relaxation by paramagnetic centers may be dramatically enhanced if the paramagnetic center is rotationally immobilized in the magnetic field. The details of the relaxation mechanism are different from those appropriate to solutions of paramagnetic relaxation agents. We report here large enhancements in the proton spin-lattice relaxation rate constants associated with organic radicals when the radical system is rigidly connected with a rotationally immobilized macromolecular matrix such as a dry protein or a cross-linked protein gel.

Paramagnetic relaxation of protons in rotationally immobilized proteins.

The proton magnetic relaxation dispersion profiles are reported over the proton Larmor frequency range from 0.01 to 30 MHz for cross-linked gels and for the dry lyophilized bovine serum albumin covalently labeled at lysine with diethylenetriaminepentaacetic acid chelates of either Gd(III) or Mn(II) ions. The proton spin-lattice relaxation dispersion for the cross-linked paramagnetic protein gel is accurately represented as a sum of two major relaxation contributions.

The aqueous reference for ESR oximetry.

The interaction of molecular oxygen with derivatives of nitroxide EPR spin labels has been investigated using nuclear spin-relaxation spectroscopy in aqueous and nonaqueous solvents. The proton spin-lattice relaxation rate induced by oxygen provides a measure of the local concentration of oxygen, which we find is dependent on solvent. In water, the hydrophobic effect increases the local concentration of oxygen in the nonpolar portions of solute molecules.

Chromium(III) complexes as intermolecular probes.

Metal ion complexes provide flexible paramagnetic centers that may be used to define intermolecular contacts in a variety of solution phase environments because both the charge and electronic relaxation properties of the complex may be varied. For most complex ions, there are several proton equilibria that may change the effective charge on the complex as a function of pH which in turn affects the efficacy of application for defining the electrostatic surfaces of co-solute molecules. We report here spectrophotometric and nuclear spin relaxation studies on aqueous solutions of chromium(III) complexes of EDTA, DTPA, and bis-amides of both.