Abstract
The pretargeting strategy has recently emerged in order to overcome the limitations of direct targeting, mainly in the field of radioimmunotherapy (RIT). This strategy is directly dependent on chemical reactions, namely bioorthogonal reactions, which have been developed for their ability to occur under physiological conditions. The Staudinger ligation, the copper catalyzed azide-alkyne cycloaddition (CuAAC) and the strain-promoted [3 + 2] azide–alkyne cycloaddition (SPAAC) were the first bioorthogonal reactions introduced in the literature. However, due to their incomplete biocompatibility and slow kinetics, the inverse-electron demand Diels-Alder (IEDDA) reaction was advanced in 2008 by Blackman et al. as an optimal bioorthogonal reaction. The IEDDA is the fastest bioorthogonal reaction known so far. Its biocompatibility and ideal kinetics are very appealing for pretargeting applications. The use of a trans-cyclooctene (TCO) and a tetrazine (Tz) in the reaction encouraged researchers to study them deeply. It was found that both reagents are sensitive to acidic or basic conditions. Furthermore, TCO is photosensitive and can be isomerized to its cis-conformation via a radical catalyzed reaction. Unfortunately, the cis-conformer is significantly less reactive toward tetrazine than the trans-conformation. Therefore, extensive research has been carried out to optimize both click reagents and to employ the IEDDA bioorthogonal reaction in biomedical applications.
Highlights
Most of the requirements for a bioorthogonal reaction are possessed by the azido group, and it has been extensively employed as click functionality in the literature due to its stability and inertness towards other functional groups present in biological systems [31]
60-fold the kinetics (Table has been tested indoes different systems tems including the labeling of glycol chitosan nanoparticles with copper-64 or pretargeted radioimmunotherapy (PRIT)
Zeglis and coworkers reported several inverse-electron demand Diels-Alder (IEDDA)-mediated pretargeting studies using monoclonal antibodies functionalized with a TCO and a radiolabeled tetrazine [90,91,92,93,94]
Summary
Radiolabeled antibodies have been used over the last decades in radioimmunodiagnosis (RID) and radioimmunotherapy (RIT) to image and treat tumors. They are attractive biovectors due to their ability to target specific antigens expressed at the surface of tumor cells. The biological half-life of antibodies is typically expressed in days and, long-lived radionuclides such as indium-111 (t1⁄2 = 2.8 days), zirconium-89. The long circulation of radiolabeled antibodies in the blood stream is a major challenge since it directly leads to unnecessary radiation exposure to healthy tissues such as the radiosensitive bone marrow [5,7].
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