Rémi Châtre

The advent of bioorthogonal chemistry has led to the development of powerful chemical tools that enable increasingly ambitious applications. In particular, these tools have made it possible to achieve what is considered to be the holy grail of many researchers involved in chemical biology: to perform unnatural chemical reactions within living organisms. In this minireview, we present an update of bioorthogonal reactions that have been carried out in animals for various applications. We outline the advances made in the understanding of fundamental biological processes, and the development of innovative imaging and therapeutic strategies using bioorthogonal chemistry.

The design of innovative therapeutic strategies enabling the selective destruction of tumor cells while sparing healthy tissues remains highly challenging in cancer therapy. Here, we show that the combination of two targeted therapies, including bevacizumab (Bev), and a β-glucuronidase-responsive albumin-binding prodrug of monomethyl auristatin E (MMAE), is efficient for the treatment of colorectal cancer implanted in mice. This combined therapy produces a therapeutic activity superior to that of the association of FOLFOX and Bev currently used to treat patients with this pathology. The increased anticancer efficacy is due to either a synergistic or an additive effect between Bev and MMAE selectively released from the glucuronide prodrug in the tumor microenvironment. Since numerous drug delivery systems such as antibody–drug conjugates employ MMAE as a cytotoxic payload, this finding may be of great interest for improving their therapeutic index by combining them with Bev, particularly for the therapy of colorectal cancer.

-acetylglucosaminidase was a hallmark of several solid tumours. Having identified this glycosidase as a potential target for cancer therapy, we designed an enzyme-responsive albumin-binding prodrug of the potent monomethyl auristatin E programmed for the selective release of the drug in the tumour microenvironment. This tumour activated therapy produced a remarkable therapeutic efficacy on orthotopic triple-negative mammary xenografts in mice, leading to the disappearance of tumours in 66% of treated animals. Thus, this study shows the potential of induced-volatolomics for the exploration of biological processes as well as the discovery of novel therapeutic strategies.

Enhancing the selectivity of anticancer drugs currently used in the clinic is of great interest in order to propose more efficient chemotherapies with fewer side effects for patients. In this context, we developed a β-cyclodextrin trimer that binds to circulating albumin to form the corresponding bioconjugate in the bloodstream. This latter can then entrap doxorubicin following its i.v. administration via the formation of a host-guest inclusion complex and deliver the drug in tumors. In this study, we demonstrate that the β-cyclodextrin trimer improves the therapeutic efficacy of doxorubicin for the treatment of a subcutaneous murine Lewis lung carcinoma (LLC) implanted in C57BL/6 mice. This outcome is associated with an increased deposition of doxorubicin in malignant tissues when used in combination with the β-cyclodextrin trimer compared to the administration of the drug alone.