89Zr-DFO-Isatuximab for CD38-Targeted ImmunoPET Imaging of Multiple Myeloma and Lymphomas.

Multiple myeloma (MM) is the second most prevalent hematological malignancy. It remains incurable despite the availability of novel therapeutic approaches, marking an urgent need for new agents for noninvasive targeted imaging of MM lesions. CD38 has proven to be an excellent biomarker due to its high expression in aberrant lymphoid and myeloid cells relative to normal cell populations. Using isatuximab (Sanofi), the latest FDA-approved CD38-targeting antibody, we have developed Zirconium-89(89Zr)-labeled isatuximab as a novel immunoPET tracer for the in vivo delineation of MM and evaluated the extension of its applicability to lymphomas. In vitro studies validated the high binding affinity and specificity of 89Zr-DFO-isatuximab for CD38. PET imaging demonstrated the high performance of 89Zr-DFO-isatuximab as a targeted imaging agent to delineate tumor burden in disseminated models of MM and Burkitt's lymphoma. Ex vivo biodistribution studies confirmed that high accumulations of the tracer in bone marrow and bone skeleton correspond to specific disease lesions as they are reduced to background in blocking and healthy controls. This work demonstrates the promise of 89Zr-DFO-isatuximab as an immunoPET tracer for CD38-targeted imaging of MM and certain lymphomas. More importantly, its potential as an alternative to 89Zr-DFO-daratumumab holds great clinical relevance.

Luminescent Carbon Nanodots Doped with Gadolinium (III): Purification Criteria, Chemical and Biological Characterization of a New Dual Fluorescence/MR Imaging Agent.

Carbon Dots (CDs) are luminescent quasi-spherical nanoparticles, possessing water solubility, high biocompatibility, and tunable chemical and physical properties for a wide range of applications, including nanomedicine and theranostics. The evaluation of new purification criteria, useful to achieve more reliable CDs, free from the interference of artifacts, is currently an object of debate in the field. Here, new CDs doped with gadolinium (Gd (III)), named Gd@CNDs, are presented as multifunctional probes for Magnetic Resonance Imaging (MRI). This new system is a case of study, to evaluate and/or combine different purification strategies, as a crucial approach to generate CDs with a better performance. Indeed, these new amorphous Gd@CNDs display good homogeneity, and they are free from emissive side products. Gd@CNDs (7-10 nm) contain 7% of Gd (III) w/w, display suitable and stable longitudinal relaxivity (r1 ) and with emissive behavior, therefore potentially useful for both MR and fluorescence imaging. They show good biocompatibility in both cellular and in vivo studies, cell permeability, and the ability to generate contrast in cellular pellets. Finally, MRI recording T1 -weighted images on mice after intravenous injection of Gd@CNDs, show signal enhancement in the liver, spleen, and kidney 30 min postinjection.

Recent Advances in Radiometals for Combined Imaging and Therapy in Cancer.

Nuclear medicine is defined as the use of radionuclides for diagnostic and therapeutic applications. The imaging modalities positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are based on γ-emissions of specific energies. The therapeutic technologies are based on ß- -particle-, α-particle-, and Auger electron emitters. In oncology, PET and SPECT are used to detect cancer lesions, to determine dosimetry, and to monitor therapy effectiveness. In contrast, radiotherapy is designed to irreparably damage tumor cells in order to eradicate or control the disease's progression. Radiometals are being explored for the development of diagnostic and therapeutic radiopharmaceuticals. Strategies that combine both modalities (diagnostic and therapeutic), referred to as theranostics, are promising candidates for clinical applications. This review provides an overview of the basic concepts behind therapeutic and diagnostic radiopharmaceuticals and their significance in contemporary oncology. Select radiometals that significantly impact current and upcoming cancer treatment strategies are grouped as clinically suitable theranostics pairs. The most important physical and chemical properties are discussed. Standard production methods and current radionuclide availability are provided to indicate whether a cost-efficient use in a clinical routine is feasible. Recent preclinical and clinical developments and outline perspectives for the radiometals are highlighted in each section.

Pre-targeting with ultra-small nanoparticles: boron carbon dots as drug candidates for boron neutron capture therapy.

Boron neutron capture therapy (BNCT) is a promising cancer treatment exploiting the neutron capture capacity and subsequent fission reaction of boron-10. The emergence of nanotechnology has encouraged the development of nanocarriers capable of accumulating boron atoms preferentially in tumour cells. However, a long circulation time, required for high tumour accumulation, is usually accompanied by accumulation of the nanosystem in organs such as the liver and the spleen, which may cause off-target side effects. This could be overcome by using small-sized boron carriers via a pre-targeting strategy. Here, we report the preparation, characterisation and in vivo evaluation of tetrazine-functionalised boron-rich carbon dots, which show very fast clearance and low tumour uptake after intravenous administration in a mouse HER2 (human epidermal growth factor receptor 2)-positive tumour model. Enhanced tumour accumulation was achieved when using a pretargeting approach, which was accomplished by a highly selective biorthogonal reaction at the tumour site with trans-cyclooctene-functionalised Trastuzumab.

Potential peptidic proteasome inhibitors by incorporation of an electrophilic trap based on amino acid derived α-substituted sulfonyl fluorides.

Peptido sulfonyl fluoride derivatives were designed and synthesized containing a substituent on the alpha position (αPSFs) with respect to the sulfonyl fluoride electrophilic trap. The chemical reactivity of these α-substituted amino sulfonyl fluorides was studied and compared with the previously described ß-substituted amino sulfonyl fluorides in order to get a deeper insight into the importance of the immediate structural environment of the sulfonyl fluoride moiety. Unfortunately, the poor solubility of the resulting αPSFs precluded a proper evaluation of their biological activity.

Proteasome inhibition by new dual warhead containing peptido vinyl sulfonyl fluorides.

The success of inhibition of the proteasome by formation of covalent bonds is a major victory over the long held-view that this would lead to binding the wrong targets and undoubtedly lead to toxicity. Great challenges are now found in uncovering ensembles of new moieties capable of forming long lasting ties. We have introduced peptido sulfonyl fluorides for this purpose. Tuning the reactivity of this electrophilic trap may be crucial for modulating the biological action. Here we describe incorporation of a vinyl moiety into a peptido sulfonyl fluoride backbone, which should lead to a combined attack of the proteasome active site threonine on the double bond and the sulfonyl fluoride. Although this led to strong proteasome inhibitors, in vitro studies did not unambiguously demonstrate the formation of the proposed seven-membered ring structure. Possibly, formation of a seven-membered covalent adduct with the proteosomal active site threonine can only be achieved within the context of the enzyme. Nevertheless, this dual warhead concept may provide exclusive possibilities for duration and selectivity of proteasome inhibition.