Micellar nanoreactors: towards biorthogonal activation of prodrugs

Krishna Vippala ^1,2,3 Shreyas Wagle ^1,2 Roey Amir ^1,2,4,5,6

¹Department of Organic Chemistry, School of Chemistry, Faculty of Exact Sciences, Tel Aviv University, Israel
²Tel-Aviv University Center for Nanoscience and Nanotechnology, Tel Aviv University, Israel
³Analytical Technological Unit, Teva Pharmaceuticals, Israel
⁴ADAMA Center for Novel Delivery Systems in Crop Protection, Tel Aviv University, Israel
⁵BLAVATNIK Center for Drug Discovery, Tel Aviv University, Israel
⁶The Center for Physics and Chemistry of Living Systems, Tel Aviv University, Israel

Micellar nanoreactors have been used to perform complex reactions between insoluble reactants and catalysts in aqueous media.¹ Recent evidence suggests that palladium (Pd) can be used to perform depropargylation reactions in vivo.² This opens up new ways for using micellar nanoreactors for biomedical applications, in addition to their usage in green chemistry. In order to design a nano scaffolds that can house an abiotic metal catalyst, three key features need to be taken into consideration: (i) The scaffold should make the catalyst soluble in water while keeping its activity; (ii) The scaffold should be biocompatible and finally (iii) The scaffold should be able to reach the desired location in the body. Therefore, the rational design, construction, and optimization of metal containing micellar nanoreactors could be the key for their translation to clinical applications.

Toward this goal, we designed and synthesized a set of polymer-dendron hybrid amphiphiles (PDH) that have ligands embedded in their core, which can form micelles of nano size in aqueous solution. We used these PDH to encapsulate insoluble Pd salts inside the micellar core and tested their ability to perform depropargylation reactions of model compounds. We investigated how the structural change in the dendritic architecture and lipophilicity of the substrate influence the reactions rate. This study offers some important insights on how the structural changes in the dendritic architecture influence the reaction rate. Understanding the relation between PDH design and the reaction rate will allow the design of new micellar systems for biorthogonal prodrug activation in the future.

References

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(2) Yusop, R. M.; Unciti-Broceta, A.; Johansson, E. M. V; Sánchez-Martín, R. M.; Bradley, M. Palladium-Mediated Intracellular Chemistry. Nat. Chem. 2011, 3 (3), 239–243. https://doi.org/10.1038/nchem.981.