MR Imaging Reveals Dynamic Aggregation of Multivalent Glycoconjugates in Aqueous Solution.

Glycoconjugates forming from the conjugation of carbohydrates to other biomolecules, such as proteins, lipids, or other carbohydrates, are essential components of mammalian cells and are involved in numerous biological processes. Due to the capability of sugars to form multiple hydrogen bonds, many synthetic glycoconjugates are desirable biocompatible platforms for imaging, diagnostics, drugs, and supramolecular self-assemblies. Herein, we present a multimeric galactose functionalized paramagnetic gadolinium (Gd(III)) chelate that displays spontaneous dynamic aggregation in aqueous conditions.

Synthesis and relaxivity of gadolinium-based DOTAGA conjugated 3-phosphoglycerate.

The synthesis and characterization of a gadolinium-based contrast agent conjugated to 3-phosphoglycerate (Gd-3PG) are reported. The synthetic steps are optimized to incorporate a selective deprotection strategy for a primary -butyl dimethyl silyl (TBS) hydroxyl over a secondary one. The relaxivity of Gd-3PG shows characteristic improvement, likely due to secondary sphere effects and/or an increase in molecular weight (5.

HaloTag-Modified, Ferrocene Labeled Self-Assembled Monolayers for Protein Sensing.

Ferrocene (Fc)-based disulfide molecules of various lengths with amino acid scaffolds and alkane or oligo(phenylene-ethynylene) (OPE) bridges are used in a mixed SAM with a di-(ethylene oxide) terminal mercaptoundecanol diluent (PEG). The relative height of the Fc redox reporter in the SAM is compared to determine if there are protective effects like antifouling and specific detection. The HaloTag-binding motif is used as a proof-of-concept to investigate the electrochemical response to the HaloTag protein due to its known covalent and fast linkage.

HaloTag display enables quantitative single-particle characterisation and functionalisation of engineered extracellular vesicles.

Extracellular vesicles (EVs) play key roles in diverse biological processes, transport biomolecules between cells and have been engineered for therapeutic applications. A useful EV bioengineering strategy is to express engineered proteins on the EV surface to confer targeting, bioactivity and other properties. Measuring how incorporation varies across a population of EVs is important for characterising such materials and understanding their function, yet it remains challenging to quantitatively characterise the absolute number of engineered proteins incorporated at single-EV resolution.

Development of Ln(III) Derivatives as F Parashift Probes.

F parashift probes with paramagnetically shifted reporter nuclei provide attractive platforms to develop molecular imaging probes. These probes enable ratiometric detection of molecular disease markers using a direct detection technique. Here, we describe a series of trivalent lanthanide (Ln(III)) complexes that are structural analogues of the clinically approved MR contrast agent (CA) ProHance to obtain F parashift probes.

Musculoskeletal imaging of senescence.

Senescent cells play a vital role in the pathogenesis of musculoskeletal (MSK) diseases, such as chronic inflammatory joint disorders, rheumatoid arthritis (RA), and osteoarthritis (OA). Cellular senescence in articular joints represents a response of local cells to persistent stress that leads to cell-cycle arrest and enhanced production of inflammatory cytokines, which in turn perpetuates joint damage and leads to significant morbidities in afflicted patients. It has been recently discovered that clearance of senescent cells by novel "senolytic" therapies can attenuate the chronic inflammatory microenvironment of RA and OA, preventing further disease progression and supporting healing processes.

HaloTag display enables quantitative single-particle characterization and functionalization of engineered extracellular vesicles.

Extracellular vesicles (EVs) play key roles in diverse biological processes, transport biomolecules between cells, and have been engineered for therapeutic applications. A useful EV bioengineering strategy is to express engineered proteins on the EV surface to confer targeting, bioactivity, and other properties. Measuring how incorporation varies across a population of EVs is important for characterizing such materials and understanding their function, yet it remains challenging to quantitatively characterize the absolute number of engineered proteins incorporated at single-EV resolution.

Molecular Engineering of Self-Immolative Bioresponsive MR Probes.

Real-time detection of bio-event in whole animals provides essential information for understanding biological and therapeutic processes. Magnetic resonance (MR) imaging represents a non-invasive approach to generating three-dimensional anatomic images with high spatial-temporal resolution and unlimited depth penetration. We have developed several self-immolative enzyme-activatable agents that provide excellent in vivo contrast and function as gene expression reporters.

Engineered Nonviral Protein Cages Modified for MR Imaging.

Diagnostic medical imaging utilizes magnetic resonance (MR) to provide anatomical, functional, and molecular information in a single scan. Nanoparticles are often labeled with Gd(III) complexes to amplify the MR signal of contrast agents (CAs) with large payloads and high proton relaxation efficiencies (relaxivity, ). This study examined the MR performance of two structurally unique cages, AaLS-13 and OP, labeled with Gd(III).

Modulation of Hedgehog Signaling for the Treatment of Basal Cell Carcinoma and the Development of Preclinical Models.

Basal Cell Carcinoma (BCC) is the most commonly diagnosed cancer worldwide. While the survivability of BCC is high, many patients are excluded from clinically available treatments due to health risks or personal choice. Further, patients with advanced or metastatic disease have severely limited treatment options.

Functional Disruption of Gli1-DNA Recognition via a Cobalt(III) Complex.

The aberrant activation of the Gli family of zinc finger transcription factors (ZFTFs) is associated with several types of human cancer, including medulloblastoma and basal cell carcinoma. We have reported the use of cobalt(III) Schiff-base complexes (Co(III)-sb) as potent inhibitors of ZFTFs in vivo. These complexes inhibit transcription by displacing the zinc finger domain's structural Zn(II) ion, destabilizing the alpha helix necessary for DNA recognition.

Delivery of Targeted Co(III)-DNA Inhibitors of Gli Proteins to Disrupt Hedgehog Signaling.

The Hedgehog (Hh) signaling pathway is integral for embryonic development and normal cell maintenance. However, aberrant expression of the Hh pathway is recognized as the oncogenic driving force for basal cell carcinoma (BCC). Current chemotherapeutic treatments that inhibit Hh signaling allow treatment of only locally advanced and metastatic BCCs via inhibition of the transmembrane protein, smoothened.

Real-time MR tracking of AAV gene therapy with βgal-responsive MR probe in a murine model of GM1-gangliosidosis.

Transformative results of adeno-associated virus (AAV) gene therapy in patients with spinal muscular atrophy and Leber's congenital amaurosis led to approval of the first two AAV products in the United States to treat these diseases. These extraordinary results led to a dramatic increase in the number and type of AAV gene-therapy programs. However, the field lacks non-invasive means to assess levels and duration of therapeutic protein function in patients.

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.

Towards Imaging Pt Chemoresistance Using Gd(III)-Pt(II) Theranostic MR Contrast Agents.

Cisplatin and related Pt(II) chemotherapeutics are indispensable tools for the treatment of various solid tumors. Despite their widespread clinical use in approximately 50 % of chemotherapy regimens, they are hindered by issues with off-target toxicity and chemoresistance, both innate and acquired. To date, there is no effective way to predict the outcome of Pt(II) chemotherapy because the genes associated with resistance are not completely known or understood.

Cobalt(III) Schiff base complexes stabilize non-fibrillar amyloid-β aggregates with reduced toxicity.

The aggregation of amyloid-β (Aβ) is believed to be foundational to the pathogenesis of Alzheimer's disease (AD). In vitro aggregation kinetics have been shown to correlate with rates of disease progression in both AD patients and animal models, thus proving to be a useful metric for testing Aβ-targeted therapeutics. Here we present evidence of cobalt(III) Schiff base complex ([Co(acetylacetonate)(NH)]Cl; Co(III)-sb) modulation of Aβ aggregation kinetics by a variety of complementary techniques.

Maximizing Magnetic Resonance Contrast in Gd(III) Nanoconjugates: Investigation of Proton Relaxation in Zirconium Metal-Organic Frameworks.

Gadolinium(III) nanoconjugate contrast agents (CAs) provide significant advantages over small-molecule complexes for magnetic resonance imaging (MRI), namely increased Gd(III) payload and enhanced proton relaxation efficiency (relaxivity, ). Previous research has demonstrated that both the structure and surface chemistry of the nanomaterial substantially influence contrast. We hypothesized that inserting Gd(III) complexes in the pores of a metal-organic framework (MOF) might offer a unique strategy to further explore the parameters of nanomaterial structure and composition, which influence relaxivity.

Targeted Radiosensitizers for MR-Guided Radiation Therapy of Prostate Cancer.

Adjuvant radiotherapy is frequently prescribed to treat cancer. To minimize radiation-related damage to healthy tissue, it requires high precision in tumor localization and radiation dose delivery. This can be achieved by MR guidance and targeted amplification of radiation dose selectively to tumors by using radiosensitizers.

A Ln(III)-3-hydroxypyridine pH responsive probe optimized by DFT.

Differences in tissue pH can be diagnostic of cancer and other conditions that shift cell metabolism. Paramagnetic probes are promising tools for pH mapping in vivo using magnetic resonance spectroscopy (MRS) as they provide uniquely shifted MR signals that change with pH. Here, we demonstrate a 3-hydroxy-6-methylpyridyl coordinating group as a new pH-responsive reporter group for Ln(III) MRS probes.

Gd(iii)-Pt(iv) theranostic contrast agents for tandem MR imaging and chemotherapy.

Pt(iv) prodrugs have emerged as versatile therapeutics for addressing issues regarding off-target toxicity and the chemoresistance of classic Pt(ii) drugs such as cisplatin and carboplatin. There is significant potential for Pt(iv) complexes to be used as theranostic agents, yet there are currently no reported examples of Gd(iii)-Pt(iv) agents for simultaneous MR imaging and chemotherapy. Here we report the synthesis, characterization, and efficacy of two Gd(iii)-Pt(iv) agents, and .

A Multimodal Ca(II) Responsive Near IR-MR Contrast Agent Exhibiting High Cellular Uptake.

Ca(II) ions are critical for the proper function of neurons by contributing to synaptic signaling and regulating neuronal plasticity. Dysregulation of Ca(II) is associated with a number of pathologies that cause neurodegeneration; therefore the ability to monitor Ca(II) intracellularly is an important target for molecular imaging. Contrast-enhanced MR imaging is a promising modality for imaging changes in Ca(II) concentrations.

Self-Immolative Activation of β-Galactosidase-Responsive Probes for In Vivo MR Imaging in Mouse Models.

Our lab has developed a new series of self-immolative MR agents for the rapid detection of enzyme activity in mouse models expressing β-galactosidase (β-gal). We investigated two molecular architectures to create agents that detect β-gal activity by modulating the coordination of water to Gd . The first is an intermolecular approach, wherein we designed several structural isomers to maximize coordination of endogenous carbonate ions.

Molecular Magnetic Resonance Imaging with Gd(III)-Based Contrast Agents: Challenges and Key Advances.

In an era of personalized medicine, the clinical community has become increasingly focused on understanding diseases at the cellular and molecular levels. Magnetic resonance imaging (MRI) is a powerful imaging modality for acquiring anatomical and functional information. However, it has limited applications in the field of molecular imaging due to its low sensitivity.

Inhibition of Amyloid-β Aggregation by Cobalt(III) Schiff Base Complexes: A Computational and Experimental Approach.

Coordination complexes have emerged as prominent modulators of amyloid aggregation via their interaction with the N-terminal histidine residues of amyloid-β (Aβ). Herein, we report the synthesis and characterization of a novel cobalt(III) Schiff base complex with methylamine axial ligands, and we present both computational and experimental data demonstrating the reduction of β-sheet formation by this complex. The computations include molecular dynamics simulations of both monomeric and pentameric Aβ, which demonstrate decreased formation of β-sheet structures, destabilization of preformed β-sheets, and suppression of aggregation.