scholarly journals Harnessing64Cu/67Cu for a theranostic approach to pretargeted radioimmunotherapy

2020 ◽  
Vol 117 (45) ◽  
pp. 28316-28327
Author(s):  
Outi Keinänen ◽  
Kimberly Fung ◽  
James M. Brennan ◽  
Nicholas Zia ◽  
Matt Harris ◽  
...  
Keyword(s):  
Therapeutic Response ◽  
Alder Reaction ◽  
Beta Particle ◽  
Clinical Tool ◽  
Inverse Electron Demand ◽  
Diels Alder Reaction ◽  
Positron Emission ◽  
Pretargeted Radioimmunotherapy ◽  
Therapy Studies

Over the past decade, theranostic imaging has emerged as a powerful clinical tool in oncology for identifying patients likely to respond to targeted therapies and for monitoring the response of patients to treatment. Herein, we report a theranostic approach to pretargeted radioimmunotherapy (PRIT) based on a pair of radioisotopes of copper: positron-emitting copper-64 (64Cu,t1/2= 12.7 h) and beta particle-emitting copper-67 (67Cu,t1/2= 61.8 h). This strategy is predicated on the in vivo ligation between a trans-cyclooctene (TCO)-bearing antibody and a tetrazine (Tz)-based radioligand via the rapid and bioorthogonal inverse electron-demand Diels–Alder reaction. Longitudinal therapy studies were conducted in a murine model of human colorectal carcinoma using an immunoconjugate of the huA33 antibody modified with TCO (huA33-TCO) and a67Cu-labeled Tz radioligand ([67Cu]Cu-MeCOSar-Tz). The injection of huA33-TCO followed 72 h later by the administration of 18.5, 37.0, or 55.5 MBq of [67Cu]Cu-MeCOSar-Tz produced a dose-dependent therapeutic response, with the median survival time increasing from 68 d for the lowest dose to >200 d for the highest. Furthermore, we observed that mice that received the highest dose of [67Cu]Cu-MeCOSar-Tz in a fractionated manner exhibited improved hematological values without sacrificing therapeutic efficacy. Dual radionuclide experiments in which a single administration of huA33-TCO was followed by separate injections of [64Cu]Cu-MeCOSar-Tz and [67Cu]Cu-MeCOSar-Tz revealed that the positron emission tomography images produced by the former accurately predicted the efficacy of the latter. In these experiments, a correlation was observed between the tumoral uptake of [64Cu]Cu-MeCOSar-Tz and the subsequent therapeutic response to [67Cu]Cu-MeCOSar-Tz.

Temporal Control of Efficient In Vivo Bioconjugation Using a Genetically Encoded Tetrazine-Mediated Inverse-Electron-Demand Diels–Alder Reaction

2020 ◽  
Vol 31 (10) ◽  
pp. 2456-2464
Author(s):  
Byungseop Yang ◽  
Kiyoon Kwon ◽  
Subhashis Jana ◽  
Seoungkyun Kim ◽  
Savanna Avila-Crump ◽  
...  
Keyword(s):  
Alder Reaction ◽  
Diels Alder ◽  
Temporal Control ◽  
Inverse Electron Demand ◽  
Diels Alder Reaction ◽  
Electron Demand

scholarly journals Recent Advances in Bioorthogonal Click Chemistry for Efficient Synthesis of Radiotracers and Radiopharmaceuticals

Molecules ◽  
2019 ◽  
Vol 24 (19) ◽  
pp. 3567 ◽  
Author(s):  
Mushtaq ◽  
Yun ◽  
Jeon
Keyword(s):  
Cycloaddition Reaction ◽  
Reaction Rates ◽  
Alder Reaction ◽  
Diels Alder ◽  
Pharmacokinetic Studies ◽  
Preclinical Research ◽  
Inverse Electron Demand ◽  
Diels Alder Reaction ◽  
Specific Reactions

In recent years, several catalyst-free site-specific reactions have been investigated for the efficient conjugation of biomolecules, nanomaterials, and living cells. Representative functional group pairs for these reactions include the following: (1) azide and cyclooctyne for strain-promoted cycloaddition reaction, (2) tetrazine and trans-alkene for inverse-electron-demand-Diels–Alder reaction, and (3) electrophilic heterocycles and cysteine for rapid condensation/addition reaction. Due to their excellent specificities and high reaction rates, these conjugation methods have been utilized for the labeling of radioisotopes (e.g., radiohalogens, radiometals) to various target molecules. The radiolabeled products prepared by these methods have been applied to preclinical research, such as in vivo molecular imaging, pharmacokinetic studies, and radiation therapy of cancer cells. In this review, we explain the basics of these chemical reactions and introduce their recent applications in the field of radiopharmacy and chemical biology. In addition, we discuss the significance, current challenges, and prospects of using bioorthogonal conjugation reactions.

scholarly journals Immune-informed mucin hydrogels evade fibrotic foreign body response in vivo

2019 ◽  
Author(s):  
Hongji Yan ◽  
Cédric Seignez ◽  
Morgan Hjorth ◽  
Benjamin Winkeljann ◽  
Oliver Lieleg ◽  
...  
Keyword(s):  
Foreign Body ◽  
Alder Reaction ◽  
Foreign Body Response ◽  
Inverse Electron Demand ◽  
Diels Alder Reaction ◽  
Adaptive Immune Cells ◽  
Immune Mediated ◽  
Mucus Gel ◽  
Body Response

AbstractThe immune-mediated foreign body response to biomaterial implants can trigger the formation of insulating fibrotic capsules that can compromise implant function. To address this challenge, we leverage the intrinsic bioactivity of the mucin biopolymer, a heavily glycosylated protein that forms the protective mucus gel covering mucosal epithelia. By using a bioorthogonal inverse electron demand Diels-Alder reaction, we crosslink mucins into implantable hydrogels. We show that mucin hydrogels (Muc-gels) modulate the immune response driving biomaterial-induced fibrosis. Muc-gels did not elicit fibrosis 21 days after implantation in the peritoneal cavity of C57Bl/6 mice, whereas medical-grade alginate hydrogels (Alg-gels) were covered by fibrous tissues. Further, Muc-gels dampened the recruitment of innate and adaptive immune cells to the gel and triggered a pattern of very mild activation marked by a noticeably low expression of the fibrosis-stimulating TGF-β1 cytokine. With this advance in mucin materials, we provide an essential tool to better understand mucin bioactivities and to initiate the development of new mucin-based and mucin-inspired ‘immune-informed’ materials for implantable devices subject to fibrotic encapsulation.

Synthese neuer Pyridin-C-nukleoside der 2 ,3 -Didesoxyribose durch „inverse“ [4+2]-Cycloaddition Synthesis of Novel Pyridine-C-nucleosides of 2,3-Dideoxyribose by „Inverse“ [4+2]-Cycloaddition

1997 ◽  
Vol 52 (7) ◽  
pp. 851-858 ◽  
Author(s):  
Gunther Seitz ◽  
Johanna Siegl
Keyword(s):  
Cycloaddition Reaction ◽  
Alder Reaction ◽  
Diels Alder ◽  
The Novel ◽  
Protecting Group ◽  
Enol Ethers ◽  
Inverse Electron Demand ◽  
Diels Alder Reaction ◽  
Cyclic Ketene Acetals

The anomeric imido esters 5 and 6, appropriate precursors for C-nucleoside synthesis, were prepared and utilized as heterodienophiles in a Diels-Alder reaction with inverse electron demand to yield the novel, protected 1.2.4-triazine C-nucleosides 8 and 9. They could be deprotected by treatment with 70% trifluoroacetic acid to furnish the free C-nucleosides 10 and 11. The triazine „aglycon“ of 8 contains an electron deficient diazadiene system, highly activated to react with various electron rich dienophiles such as enamines, enol ethers and several cyclic ketene acetals in an „inverse“ [4+2]-cycloaddition reaction. The Diels-Alder adducts spontaneously eliminate N2 and after follow-up reactions the O-TBDPS protected pyridine-C-nucleosides 13, 15, 17,19, 21 and 23 are formed. Removal of the protecting group by treatment with CF3CO2H /H2O leads to the corresponding 2’,3’-dideoxy-β-D-ribofuranosyl- pyridines.

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