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Click-Chemistry: optimized drug delivery from nanomicelles into tumor cells

​Researchers at SCBM (DMTS), in collaboration with the university of Poitiers, have used a click-and-release chemistry approach to mass-release an anti-cancer drug into cells from cleavable nanomicelles, thanks to a bioorthogonal activation process. A step towards the development of new nanomedicines

Published on 10 November 2023

Click-chemistry and bio-orthogonal chemistry, which consists in preparing molecular objects by creating (click) and/or breaking (release) bonds between "building blocks" thanks to a few highly efficient and selective chemical reactions, and which was awarded the 2022 Nobel Prize in Chemistry, is being used successfully at SCBM for several years. As proof of this, Frédéric Taran was awarded the Seqens prize by the French Academy of Sciences on October 2023 for the last 10 years of his research work in bioorthogonal chemistry. In this study, Frédéric Taran's laboratory used a targeted bioorthogonal approach to rapidly release drugs from micelles internalized​ in tumor cells in vitro.


In the field of nanomedicine, the development of micellar vectors for tumor diagnosis and therapy is booming, but still faces technological and methodological obstacles, including uncontrolled drug release and the lack of specificity of targeted strategies. "On-demand" drug delivery, made possible by the design of nanovectors that react dynamically in the targeted microenvironment to external stimuli (enzymatic, pH or physical), has been successfully developed. Based on the introduction of cleavable links at the right place in the nanomicelle structure, this approach has overcome a number of obstacles. However, difficulties in controlling endogenous triggers such as pH or enzymes in healthy and pathological tissues, as well as the lack of focus and depth of penetration of external stimuli into tissues, remain major challenges in this field.


The promising alternative strategy presented here involved the use of several bioorthogonal reactions to control the disassembly of cleavable sydnonimine-based nanomicelles and the release of their encapsulated drug content induced by the addition of cyclooctynes (clik-and-release according to the Strain-Promoted SydnonImine-Cycloalkyne cycloaddition reaction, SPSIC). In other words, the nanoparticle and the "bioorthogonal trigger" are inert when they are not localized together in the target organ, and it is their accumulation on the site to be treated that will trigger the destruction of the nanomicelle and the release of its contents. The researchers were able to trigger the massive release of Entinostat, a powerful anti-cancer agent, after internalization of 4 cleavable micelles in cultured cancer cells. In particular, they show that release of the drug following the click-and-release reaction in the micelles is followed by stronger and faster antiproliferative activity than that observed after simple passive diffusion of the drug out of the micelle core.

This dual-targeting strategy, with triggering controlled by a bioorthogonal reaction at the site to be treated, could lead to more selective and effective therapies without the side effects often encountered with conventional treatments.

Contact : Frédéric Taran ( )

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