Theragnostic Target, Prostate-Specific Membrane Antigen—Also Specific for Nonprostatic Malignancies
No abstract prepared.
62 RADIOLOGY AND NUCLEAR MEDICINE↗
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Membrane Specifications for Multi-Configuration Membrane Distillation Model
The data includes the membrane properties and specifications used for multi-configuration membrane distillation desalination. In this study, membranes from CLARCOR, 3M, and Aquastill are tested in counter-current, co-current and air-gap configurations at Colorado School of Mines (CSM), Advanced Water technology Center ( Aqwatech) laboratories. In the data sheets: The "theoretical" worksheet, contains steady-state values of the experimental runs and also provides several calculated values. The "Specifications" worksheet contains the inputs to the experiment. The "Data" spreadsheet contains the entire set of data and the rest of the sheets "20-40", "20-45", ...etc., contain individual portions of the data with variation of feed temperatures.
15 GEOTHERMAL ENERGY↗
Development of Prostate Specific Membrane Antigen (PSMA) Inhibitors Coupled to 99m Tc(CO)3 + with Enhanced Specific Activity for SPECT Imaging
The overall objectives of the project were two fold: 1) the development of new facile reactions for coupling radioactive complexes with biomolecules and 2) the development of a novel molecular imaging targeting vector for Prostate Specific Membrane Antigen (PSMA) for prostate cancer. The didactic approach allowed the synergistic exploration of new technologies for coupling reactions of radioactive complexes that can be applied to a novel targeting moiety. As part of the project, a number of students (undergraduate, graduate and post-doctoral) were trained in radiochemical techniques for preparing and characterizing radiometal complexes. Results from the experiments within the project have generated several presentations and publications.
38 RADIATION CHEMISTRY, RADIOCHEMISTRY, AND NUCLEA↗
Prostate-Specific Membrane Antigen Positron Emission Tomography–Computed Tomography for Prostate Cancer: Distribution of Disease and Implications for Radiation Therapy Planning
Purpose: To explore the prostate-specific membrane antigen (PSMA)–avid distribution of prostate cancer (PC) on positron emission tomography (PET), both at the time of initial diagnosis and at the time of relapse after definitive local treatment. Methods and Materials: A total of 179 PSMA PET scans in patients with nil or ≤3 lesions on conventional imaging were retrospectively categorized into 3 subgroups: group A, high-risk PC with no prior definitive therapy (n=34); group B, prior prostatectomy (n=75); and group C, prior radiation therapy (n=70). The numbers and locations of the PSMA-avid lesions were mapped. The PSMA-positive lesions were identified subjectively by a nuclear medicine physician on the basis of clinical experience and taking into account the recent literature and artefacts. Results: A total of 893 PSMA-avid lesions were identified; at least 1 lesion was detected in 80% of all scans. A high detection rate was present even at very low serum PSA levels (eg, at PSA ≤0.20 ng/mL in group B, the detection rate was 46%). Thirty-eight percent of studies revealed extrapelvic disease (41%, 31%, and 46% in groups A, B, and C, respectively). Almost one-third of all studies showed only oligometastases (24%, 36%, and 31% in groups A, B, and C, respectively). A large proportion of these (40%) were a solitary lesion. Conclusions: Prostate-specific membrane antigen PET demonstrated a large number of otherwise unknown metastatic lesions. Therefore we recommend PSMA PET for more accurate assessment of disease burden in initial staging of high-risk PC, as well as for restaging in patients with prostate-specific antigen relapse after primary therapies. Furthermore, a high proportion of oligometastases on PSMA PET provides a prime opportunity to investigate the role of targeted local therapies for oligometastatic PCs.
62 RADIOLOGY AND NUCLEAR MEDICINE↗
Point-localized, site-specific membrane potential optical recording by single fluorescent nanodiscs
Nanodisc technology was implemented as a platform for voltage nanosensors. A fluorescence (Förster) resonance energy transfer (FRET)-based voltage-sensing scheme employing fluorescent nanodiscs and the hydrophobic ion dipicrylamine was developed and utilized to optically record membrane potentials on the single-nanodisc level. Ensemble and single-nanosensor recordings were demonstrated for HEK293 cells and primary cortical neuron cells. Conjugation of nanodiscs to anti-GABA A antibodies allowed for site-specific membrane potential measurements from postsynaptic sites.
77 NANOSCIENCE AND NANOTECHNOLOGY↗
Evaluation of Phage Display Discovered Peptides as Ligands for Prostate-Specific Membrane Antigen (PSMA)
The aim of this study was to identify potential ligands of PSMA suitable for further development as novel PSMA-targeted peptides using phage display technology. The human PSMA protein was immobilized as a target followed by incubation with a 15-mer phage display random peptide library. After one round of prescreening and two rounds of screening, highstringency screening at the third round of panning was performed to identify the highest affinity binders. Phages which had a specific binding activity to PSMA in human prostate cancer cells were isolated and the DNA corresponding to the 15-mers were sequenced to provide three consensus sequences: GDHSPFT, SHFSVGS and EVPRLSLLAVFL as well as other sequences that did not display consensus. Two of the peptide sequences deduced from DNA sequencing of binding phages, SHSFSVGSGDHSPFT and GRFLTGGTGRLLRIS were labeled with 5-carboxyfluorescein and shown to bind and co-internalize with PSMA on human prostate cancer cells by fluorescence microscopy. The high stringency requirements yielded peptides with affinities K D ~1 μM or greater which are suitable starting points for affinity maturation. While these values were less than anticipated, the high stringency did yield peptide sequences that apparently bound to different surfaces on PSMA. These peptide sequences could be the basis for further development of peptides for prostate cancer tumor imaging and therapy.
60 APPLIED LIFE SCIENCES↗
Glycosylatable GFP as a compartment-specific membrane topology reporter
Highlights: Black-Right-Pointing-Pointer An N-linked glycosylation site is introduced near the GFP fluorophore. Black-Right-Pointing-Pointer gGFP is not glycosylated and is fully fluorescent in the cytosol. Black-Right-Pointing-Pointer gGFP is glycosylated and non-fluorescent in the lumen of the ER. Black-Right-Pointing-Pointer gGFP is fused to membrane proteins of known topology. Black-Right-Pointing-Pointer Its applicability as a membrane topology reporter is demonstrated. -- Abstract: Determination of the membrane topology is an essential step in structural and functional studies of integral membrane proteins, yet the choices of membrane topology reporters are limited and the experimental analysis can be laborious, especially in eukaryotic cells. Here, we present a robust membrane topology reporter, glycosylatable green fluorescent protein (gGFP). gGFP is fully fluorescent in the yeast cytosol but becomes glycosylated and does not fluoresce in the lumen of the endoplasmic reticulum (ER). Thus, by assaying fluorescence and the glycosylation status of C-terminal fusions of gGFP to target membrane proteins in whole-cell lysates, the localization of the gGFP moiety (and hence the fusion joint) relative to the ER membrane can be unambiguously determined.
60 APPLIED LIFE SCIENCES↗
Prostate Cancer Targeted X-Ray Fluorescence Imaging via Gold Nanoparticles Functionalized With Prostate-Specific Membrane Antigen (PSMA)
The gold nanoparticle (GNP) as a promising theranostic probe has been increasingly studied. The tumor-targeting efficiency of GNPs is crucial to increase the therapeutic ratio. In this study, we developed PSMA-targeted GNPs to enhance GNP uptake in prostate cancer and developed an x-ray fluorescence imaging system to noninvasively monitor and assess GNP delivery.
62 RADIOLOGY AND NUCLEAR MEDICINE↗
Capturing Biologically Complex Tissue-Specific Membranes at Different Levels of Compositional Complexity
Not Available
59 BASIC BIOLOGICAL SCIENCES↗
Designing Lipids to Target Specific Membrane Phases and Enable Actuation of Membrane Curvature.
Abstract not provided.
Sasaki, Darryl Y.↗
Treatment of Prostate Cancer with CD46-targeted 225 Ac Alpha Particle Radioimmunotherapy
Radiopharmaceutical therapy is changing the standard of care in prostate cancer and other malignancies. We previously reported high CD46 expression in prostate cancer and developed an antibody–drug conjugate and immunoPET agent based on the YS5 antibody, which targets a tumor-selective CD46 epitope. Here, we present the preparation, preclinical efficacy, and toxicity evaluation of [ 225 Ac]DOTA-YS5, a radioimmunotherapy agent based on the YS5 antibody. [ 225 Ac]DOTA-YS5 was developed, and its therapeutic efficiency was tested on cell-derived (22Rv1, DU145), and patient-derived (LTL-545, LTL484) prostate cancer xenograft models. Biodistribution studies were carried out on 22Rv1 tumor xenograft models to confirm the targeting efficacy. Toxicity analysis of the [ 225 Ac]DOTA-YS5 was carried out on nu/nu mice to study short-term (acute) and long-term (chronic) toxicity. Biodistribution study shows that [ 225 Ac]DOTA-YS5 agent delivers high levels of radiation to the tumor tissue (11.64% ± 1.37%ID/g, 28.58% ± 10.88%ID/g, 29.35% ± 7.76%ID/g, and 31.78% ± 5.89%ID/g at 24, 96, 168, and 408 hours, respectively), compared with the healthy organs. [ 225 Ac]DOTA-YS5 suppressed tumor size and prolonged survival in cell line–derived and patient-derived xenograft models. Toxicity analysis revealed that the 0.5 μCi activity levels showed toxicity to the kidneys, likely due to redistribution of daughter isotope 213 Bi. [ 225 Ac]DOTA-YS5 suppressed the growth of cell-derived and patient-derived xenografts, including prostate-specific membrane antigen–positive and prostate-specific membrane antigen–deficient models. Overall, this preclinical study confirms that [ 225 Ac]DOTA-YS5 is a highly effective treatment and suggests feasibility for clinical translation of CD46-targeted radioligand therapy in prostate cancer.
62 RADIOLOGY AND NUCLEAR MEDICINE↗
Micronutrient metal speciation is controlled by competitive organic chelation in grassland soils
Many elements are scarcely soluble in aqueous conditions found in high pH environments, such as calcareous grassland soils, unless complexed to strong binding organic ligands. To overcome this limitation, some plants and microbes produce chelators that solubilize micronutrient metals such as Fe, Ni, Cu, and Zn from mineral phases. These complexes are taken up by organisms via specific membrane receptors, thereby differentially impacting the bioavailability of these metals to the plant and microbial community. Although the importance of these chelation strategies for individual organisms has been well established, little is known about which pathways coexist within rhizosphere microbiomes or how they interact and compete for metal binding. Identifying these metallo-organic species within natural ecosystems has remained a formidable analytical challenge due to the vast diversity of compounds and poorly defined metabolic processes in complex soil matrix. Herein, we employed recently developed liquid chromatography (LC) mass spectrometry (MS) methods to characterize the speciation of water-soluble dissolved trace elements (Fe, Ni, Cu, and Zn) from Kansas Prairie soil. Both plant and fungal chelators were identified, revealing compound-specific patterns of chelation to biologically essential metals. Numerous metabolites typically implicated in plant iron acquisition and homeostasis, including mugineic acids, deoxymugineic acid, nicotianamine, and hydroxynicotianamine, dominated the speciation of divalent metals such as Ni, Cu, and Zn (2-57 pmol / g soil). In contrast, the fungal siderophore ferricrocine bound comparatively more trivalent Fe (9pmol / g soil). These results define biochemical pathways that underpin the regulation of metals in the grassland rhizosphere. They also raise new questions about the competition of these compounds for metal binding and their bioavailability to different members of the rhizosphere population. Even small structural differences result in significant differences in their environmental metal speciation, and likely impact metal uptake within the rhizosphere of calcareous soils.
Boiteau, Rene M.↗
Formation of supported lipid bilayers containing phase-segregated domains and their interaction with gold nanoparticles
The cell membrane represents an important biological interface that nanoparticles may encounter after being released into the environment. Interaction of nanoparticles with cellular membranes may alter membrane structure and function, lead to their uptake into cells, and elicit adverse biological responses. Supported lipid bilayers have proven to be valuable ex vivo models for biological membranes, allowing investigation of their mechanisms of interaction with nanoparticles with a degree of control impossible in living cells. To date, the majority of research on nanoparticle interaction with supported lipid bilayers has employed membranes composed of single or binary mixtures of phospholipids. Cellular membranes contain a wide variety of lipids and exhibit lateral organization. Ordered membrane domains enriched in specific membrane components are referred to as lipid rafts and have not been explored with respect to their interaction with nanoparticles. Here we develop model lipid raft-containing membranes amenable to investigation by a variety of surface-sensitive analytical techniques and demonstrate that lipid rafts influence the extent of nanoparticle attachment to model membranes. We determined conditions that allow reliable formation of bilayers containing rafts enriched in sphingomyelin and cholesterol and confirmed their morphology by structured illumination and atomic force microscopies. We demonstrate that lipid rafts increase attachment of cationic gold nanoparticles to model membranes under near physiological ionic strength conditions (0.1 M NaCl) at pH 7.4. We anticipate that these results will serve as the foundation for and motivate further study of nanoparticle interaction with compositionally varied lipid rafts.
cellular membranes↗
Understanding the Structure and Dynamics of Complex Biomembrane Interactions by Neutron Scattering Techniques
The membrane is one of the key structural materials of biology at the cellular level. Composed predominantly of a bilayer of lipids with embedded and bound proteins, it defines the boundaries of the cell and many organelles essential to life and therefore is involved in almost all biological processes. Membrane-specific interactions, such as drug binding to a membrane receptor or the interactions of an antimicrobial compound with the lipid matrix of a pathogen membrane, are of interest across the scientific disciplines. Herein we present a review, aimed at nonexperts, of the major neutron scattering techniques used in membrane studies: small-angle neutron scattering, neutron membrane diffraction, neutron reflectometry, quasielastic neutron scattering, and neutron spin echo. Neutron scattering techniques are well suited to studying biological membranes. The nondestructive nature of cold neutrons means that samples can be measured for long periods without fear of beam damage from ultraviolet, electron, or X-ray radiation, and neutron beams are highly penetrating, thus offering flexibility in samples and sample environments. Most important is the strong difference in neutron scattering lengths between the two most abundant forms of hydrogen, protium and deuterium. Changing the relative amounts of protium/deuterium in a sample allows the production of a series of neutron scattering data sets, enabling the observation of differing components within complex membrane architectures. This approach can be as simple as using the naturally occurring neutron contrast between different biomolecules to study components in a complex by changing the solution H 2 O/D 2 O ratio or as complex as selectively labeling individual components with hydrogen isotopes. This review presents an overview of each experimental technique with the neutron instrument configuration, related sample preparation and sample environment, and data analysis, highlighted by a special emphasis on using prominent neutron contrast to understand structure and dynamics. This review gives researchers a practical introduction to the often enigmatic suite of neutron beamlines, thereby lowering the barrier to taking advantage of these large-facility techniques to achieve new understandings of membranes and their interactions with other molecules.
59 BASIC BIOLOGICAL SCIENCES↗
Biological Membrane Organization and Cellular Signaling
To execute their many vital functions, cell membranes are highly organized. Here, we review how membrane structure shapes signal transduction across membranes. Recent experimental and computational advances have shed significant light on mechanisms linking the function of membrane signaling proteins to the composition and physical properties of the membrane lateral structures in which they are embedded. We provide an overview of the structural characteristics of membranes containing heterogeneous mixtures of lipids and other molecules and summarize work on “raft” domains in model and cell membranes, as determined by microscopy, spectroscopy, neutron scattering, and computer simulations. We discuss the principles of partitioning of proteins into membranes and how the structure, dynamics, and function of membrane-embedded and peripheral proteins can be modulated by specific membrane components and physical properties of membranes and raft domains. Lastly, we report on challenges and future directions toward a molecular-level understanding of how membrane organization gives rise to various context-dependent cellular signaling.
60 APPLIED LIFE SCIENCES↗
Hydration Mimicry by Membrane Ion Channels
Ions transiting biomembranes might pass readily from water through ion-specific membrane proteins if these protein channels provide environments similar to the aqueous solution hydration environment. In fact, bulk aqueous solution is an important reference condition for the ion permeation process. Assessment of this hydration mimicry concept depends on understanding the hydration structure and free energies of metal ions in water in order to provide a comparison for the membrane channel environment. To refine these considerations, we review local hydration structures of ions in bulk water and the molecular quasi-chemical theory that provides hydration free energies. In doing so, we note some current views of ion binding to membrane channels and suggest new physical chemical calculations and experiments that might further clarify the hydration mimicry concept.
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗