Comparison of Two Chelator Scaffolds as Basis for Cholecystokinin-2 Receptor Targeting Bimodal Imaging Probes.

: Dual-modality probes, combining positron emission tomography (PET) with fluorescence imaging (FI) capabilities in a single molecule, are of high relevance for the accurate staging and guided resection of tumours. We herein present a pair of candidates targeting the cholecystokinin-2 receptor (CCK2R), namely [Ga]Ga-CyTMG and [Ga]Ga-CyFMG. In these probes, the SulfoCy5.

Dlk1 is a novel adrenocortical stem/progenitor cell marker that predicts malignancy in adrenocortical carcinoma.

Disruption of processes involved in tissue development and homeostatic self-renewal is increasingly implicated in cancer initiation, progression, and recurrence. The adrenal cortex is a dynamic tissue that undergoes life-long turnover. Here, using genetic fate mapping and murine adrenocortical carcinoma (ACC) models, we have identified a population of adrenocortical stem cells that express delta-like non-canonical Notch ligand 1 (DLK1).

Receptor-Targeted Peptide Conjugates Based on Diphosphines Enable Preparation of Tc and Re Theranostic Agents for Prostate Cancer.

Benchtop Mo/Tc and W/Re generators enable economical production of molecular theranostic Tc and Re radiopharmaceuticals, provided that simple, kit-based chemistry exists to radiolabel targeting vectors with these radionuclides. We have previously described a diphosphine platform that efficiently incorporates Tc into receptor-targeted peptides. Here, we report its application to label a prostate-specific membrane antigen (PSMA)-targeted peptide with Tc and Re for diagnostic imaging and systemic radiotherapy of prostate cancer.

Selection of radionuclide(s) for targeted alpha therapy based on their nuclear decay properties.

Targeted alpha therapy (TAT) is a promising form of oncology treatment utilising alpha-emitting radionuclides that can specifically accumulate at disease sites. The high energy and high linear energy transfer associated with alpha emissions causes localised damage at target sites whilst minimising that to surrounding healthy tissue. The lack of appropriate radionuclides has inhibited research in TAT.

Spatiotemporal tracking of gold nanorods after intranasal administration for brain targeting.

Intranasal administration is becoming increasingly more attractive as a fast delivery route to the brain for therapeutics circumventing the blood-brain barrier (BBB). Gold nanorods (AuNRs) demonstrate unique optical and biological properties compared to other gold nanostructures due to their high aspect ratio. In this study, we investigated for the first time the brain region-specific distribution of AuNRs and their potential as a drug delivery platform for central nervous system (CNS) therapy following intranasal administration to mice using a battery of analytical and imaging techniques.

MCTR3 reprograms arthritic monocytes to upregulate Arginase-1 and exert pro-resolving and tissue-protective functions in experimental arthritis.

Background: Rheumatoid arthritis (RA) is a progressive degenerative disorder that leads to joint destruction. Available treatments only target the inflammatory component with minimal impact on joint repair. We recently uncovered a previously unappreciated family of pro-resolving mediators, the maresin conjugate in tissue regeneration (MCTR), that display both immunoregulatory and tissue-protective activities.

New Bioconjugated Technetium and Rhenium Folates Synthesized by Transmetallation Reaction with Zinc Derivatives.

The zinc dithiocarbamates functionalized with folic acid and were synthesized with a simple straightforward method, using an appropriated folic acid derivative and a functionalized zinc dithiocarbamate (). Zinc complexes and show very low solubilities in water, making them useful for preparing Tc-99m radiopharmaceuticals with a potentially high molar activity. Thus, the transmetallation reaction in water medium between the zinc complexes or and the cation -[Tc(HO)(CO)], in the presence of the monodentate ligand TPPTS, leads to the formation of the 2 + 1 complexes -[Tc(CO)(SS)(P)] bioconjugated to folic acid ( and ).

Bioconjugated technetium carbonyls by transmetalation reaction with zinc derivatives.

The transmetalation reaction between zinc dithiocarbamates functionalized with organic groups and the cation fac-[Tc(HO)(CO)] has been studied as a new strategy to bind biomolecules to this radionuclide for preparing radiopharmaceuticals with high molar activity. All complexes were obtained in high yields by heating at moderate temperatures and without subsequent purification. The chemical identity was ascertained by HPLC comparison with the homologous rhenium complexes.

Organ Biodistribution of Radiolabelled γδ T Cells Following Liposomal Alendronate Administration in Different Mouse Tumour Models.

Vγ9Vδ2 T cell immunotherapy has been shown to be effective in delaying tumour growth in both pre-clinical and clinical studies. It has been pointed out the importance of the ability of cells to accumulate within tumours and the association with therapeutic efficacy in clinical studies of adoptive T cell transfer. We have previously reported that alendronate liposomes (L-ALD) increase the efficacy of this therapy after localised or systemic injection of γδ T cells in mice, inoculated with ovarian, melanoma, pancreatic or experimental lung metastasis tumour models, respectively.

Cancer associated fibroblast FAK regulates malignant cell metabolism.

Emerging evidence suggests that cancer cell metabolism can be regulated by cancer-associated fibroblasts (CAFs), but the mechanisms are poorly defined. Here we show that CAFs regulate malignant cell metabolism through pathways under the control of FAK. In breast and pancreatic cancer patients we find that low FAK expression, specifically in the stromal compartment, predicts reduced overall survival.

F-Trifluoromethanesulfinate Enables Direct C-H F-Trifluoromethylation of Native Aromatic Residues in Peptides.

F labeling strategies for unmodified peptides with [F]fluoride require F-labeled prosthetics for bioconjugation more often with cysteine thiols or lysine amines. Here we explore selective radical chemistry to target aromatic residues applying C-H F-trifluoromethylation. We report a one-step route to [F]CFSONH from [F]fluoride and its application to direct [F]CF incorporation at tryptophan or tyrosine residues using unmodified peptides as complex as recombinant human insulin.

Neutron Activated Sm Sealed in Carbon Nanocapsules for Imaging and Tumor Radiotherapy.

Radiation therapy along with chemotherapy and surgery remain the main cancer treatments. Radiotherapy can be applied to patients externally (external beam radiotherapy) or internally (brachytherapy and radioisotope therapy). Previously, nanoencapsulation of radioactive crystals within carbon nanotubes, followed by end-closing, resulted in the formation of nanocapsules that allowed ultrasensitive imaging in healthy mice.

Systemic delivery and SPECT/CT in vivo imaging of I-labelled oncolytic adenoviral mutants in models of pancreatic cancer.

Early phase clinical trials have demonstrated good therapeutic index for oncolytic adenoviruses in patients with solid tumours when administered intratumorally, resulting in local tumour elimination. Entrapment and binding of adenovirus to erythrocytes, blood factors, and neutralising antibodies have prevented efficient systemic delivery and targeting of distant lesions in the clinic. We previously generated the novel replication-selective Ad-3∆-A20T to improve tumour targeting by increasing the viral dose at distant sites.

Erratum: Site-specific stabilization of minigastrin analogs against enzymatic degradation for enhanced cholecystokinin-2 receptor targeting: Erratum.

[This corrects the article DOI: 10.7150/thno.24378.

AGR2, a unique tumor-associated antigen, is a promising candidate for antibody targeting.

Anterior gradient 2 (AGR2), a protein disulfide isomerase, shows two subcellular localizations: intracellular (iAGR2) and extracellular (eAGR2). In healthy cells that express AGR2, the predominant form is iAGR2, which resides in the endoplasmic reticulum. In contrast, cancer cells secrete and express eAGR2 on the cell surface.

Membrane Radiolabelling of Exosomes for Comparative Biodistribution Analysis in Immunocompetent and Immunodeficient Mice - A Novel and Universal Approach.

Extracellular vesicles, in particular exosomes, have recently gained interest as novel drug delivery vectors due to their biological origin and inherent intercellular biomolecule delivery capability. An in-depth knowledge of their biodistribution is therefore essential. This work aimed to develop a novel, reliable and universal method to radiolabel exosomes to study their biodistribution.

New Developments in Imaging Cell-Based Therapy.

Cancer immunotherapy is now established as a central therapeutic pillar in hematologic oncology. Cell-based therapies, with or without genetic modification ex vivo, have reached the clinic as the standard of care in limited indications and remain the subject of intense preclinical and translational development. Expanding on this, related therapeutic approaches are in development for solid-tumor and nonmalignant indications, broadening the scope of this technology.

Rational Design, Synthesis and Preliminary Evaluation of Novel Fusarinine C-Based Chelators for Radiolabeling with Zirconium-89.

Fusarinine C (FSC) has recently been shown to be a promising and novel chelator for Zr. Here, FSC has been further derivatized to optimize the complexation properties of FSC-based chelators for Zr-labeling by introducing additional carboxylic groups. These were expected to improve the stability of Zr-complexes by saturating the 8-coordination sphere of [Zr] Zr, and also to introduce functionalities suitable for conjugation to targeting vectors such as monoclonal antibodies.

DOTA-MGS5, a New Cholecystokinin-2 Receptor-Targeting Peptide Analog with an Optimized Targeting Profile for Theranostic Use.

Molecular imaging and targeted radiotherapy with radiolabeled cholecystokinin-2 receptor (CCK2R) targeting peptide probes holds high promise to improve the clinical management of patients with metastatic medullary thyroid carcinoma and other CCK2R-expressing malignancies. Low stability and suboptimal targeting of currently available radiolabeled peptide analogs has prompted us to seek new stabilization strategies. In this study, we present a new minigastrin analog with site-specific C-terminal modifications showing a highly optimized targeting profile.

Site-specific stabilization of minigastrin analogs against enzymatic degradation for enhanced cholecystokinin-2 receptor targeting.

Minigastrin (MG) analogs show high affinity to the cholecystokinin-2 receptor (CCK2R) and have therefore been intensively studied to find a suitable analog for imaging and treatment of CCK2R-expressing tumors. The clinical translation of the radioligands developed thus far has been hampered by high kidney uptake or low enzymatic stability. In this study, we aimed to develop new MG analogs with improved targeting properties stabilized against degradation through site-specific amino acid modifications.

Functionalised Carbon Nanotubes Enhance Brain Delivery of Amyloid-Targeting Pittsburgh Compound B (PiB)-Derived Ligands.

Alzheimer's disease (AD) is a neurodegenerative disorder characterised by brain accumulation of toxic protein aggregates, including extracellular amyloid beta (Aβ) plaques, inflammation, neuronal death and progressive cognitive dysfunction. Current diagnostic modalities, based on cognitive tests, fail to detect early AD onset, thus emphasising the need to develop improved methods for pre-symptomatic disease detection. Building on the properties of the Pittsburgh Compound B (PiB), an Aβ-binding molecule suitable to use as positron emission tomography (PET) imaging agent, and aiming at using a more clinically available modality (like magnetic ressonance imaging, MRI), PiB derivatives have been conjugated to the macrocyclic chelator 1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (DO3A) monoamide.

Clinically compliant spatial and temporal imaging of chimeric antigen receptor T-cells.

The unprecedented efficacy of chimeric antigen receptor (CAR) T-cell immunotherapy of CD19 B-cell malignancy has established a new therapeutic pillar of hematology-oncology. Nonetheless, formidable challenges remain for the attainment of comparable success in patients with solid tumors. To accelerate progress and rapidly characterize emerging toxicities, systems that permit the repeated and non-invasive assessment of CAR T-cell bio-distribution would be invaluable.

Anesthesia and Monitoring of Animals During MRI Studies.

The use of imaging represents a major impact on the refinement and the reduction of in vivo studies in animal models, in particular for allowing longitudinal monitoring of the onset and the progression of disease within the same animal, and studying the biological effects of drug candidate and their therapeutic effectiveness. But the use of imaging procedures can affect animal physiology, and the need to anesthetize the animals for imaging entails potential health risks. During anesthesia, there is an inevitable autonomic nervous system depression which induces cardiovascular depression, respiratory depression, and hypothermia.

Novel Hyaluronic Acid Conjugates for Dual Nuclear Imaging and Therapy in CD44-Expressing Tumors in Mice .

Hyaluronic acid, a natural CD44 receptor ligand, has attracted attention in the past years as a macromolecular delivery of anticancer agents to cancer. At the same time, the clinical applications of Gemcitabine (Gem) have been hindered by its short biological half-life, high dose and development of drug resistance. This work reports the synthesis of a hyaluronic acid (HA) conjugate for nuclear imaging, and Gem delivery to CD44-expressing solid tumors in mice.