Click and Bioorthogonal Chemistry: The Future of Active Targeting of Nanoparticles for Nanomedicines?

Over the years, click and bioorthogonal reactions have been the subject of considerable research efforts. These high-performance chemical reactions have been developed to meet requirements not often provided by the chemical reactions commonly used today in the biological environment, such as selectivity, rapid reaction rate, and biocompatibility. Click and bioorthogonal reactions have been attracting increasing attention in the biomedical field for the engineering of nanomedicines. In this review, we study a compilation of articles from 2014 to the present, using the terms "click chemistry and nanoparticles (NPs)" to highlight the application of this type of chemistry for applications involving NPs intended for biomedical applications. This study identifies the main strategies offered by click and bioorthogonal chemistry, with respect to passive and active targeting, for NP functionalization with specific and multiple properties for imaging and cancer therapy. In the final part, a novel and promising approach for "two step" targeting of NPs, called pretargeting (PT), is also discussed; the principle of this strategy as well as all the studies listed from 2014 to the present are presented in more detail.

Optimization of IEDDA bioorthogonal system: Efficient process to improve trans-cyclooctene/tetrazine interaction.

The antibody pretargeting approach for radioimmunotherapy (RIT) using inverse electron demand Diels-Alder cycloaddition (IEDDA) constitutes an emerging theranostic approach for solid cancers. However, IEDDA pretargeting has not reached clinical trial. The major limitation of the IEDDA strategy depends largely on trans-cyclooctene (TCO) stability. Indeed, TCO may isomerize into the more stable but unreactive cis-cyclooctene (CCO), leading to a drastic decrease of IEDDA efficiency. We have thus developed both efficient and reproducible synthetic pathways and analytical follow up for (PEGylated) TCO derivatives, providing high TCO isomeric purity for antibody modification. We have set up an original process to limit the isomerization of TCO to CCO before the mAbs' functionalization to allow high TCO/tetrazine cycloaddition.