Bioorthogonal Uncaging of Cytotoxic Paclitaxel through Pd Nanosheet–Hydrogel Frameworks

Abstract

The promising potential of bioorthogonal catalysis in biomedicine is inspiring incremental efforts to design strategies that regulate drug activity in living systems. To achieve this, it is not only essential to develop customized inactive prodrugs and biocompatible metal catalysts but also the right physical environment for them to interact and enable drug production under spatial and/or temporal control. Toward this goal, here, we report the first inactive precursor of the potent broad-spectrum anticancer drug paclitaxel (a.k.a. Taxol) that is stable in cell culture and labile to Pd catalysts. This new prodrug is effectively uncaged in cancer cell culture by Pd nanosheets captured within agarose and alginate hydrogels, providing a biodegradable catalytic framework to achieve controlled release of one of the most important chemotherapy drugs in medical practice. The compatibility of bioorthogonal catalysis and physical hydrogels opens up new opportunities to administer and modulate the mobility of transition metal catalysts in living environs.

Metal substrate catalysis in the confined space for platinum drug delivery

“…Hydrogels have been widely used as solid supports to immobilize different types of catalysts, 28 including for therapy purposes. 29 Furthermore, they are appealing materials for delivery, because of their excellent biocompatibility and high water content. 30 These soft materials can be applied in surgical implants, locally injected or administered systematically via intravenous infusion, 31 and used to fabricate therapeutic patches for intra- and transdermal release of pharmaceuticals.…”

Transition Metal‐Promoted Reactions in Aqueous Media and Biological Settings

“…The Pd-promoted uncaging reaction consists of ad epropargylation of the p-(propargyloxy)benzyl hydroxamate derivativeo ft he drug (Figure 47). [122] In 2018, Bernardes and co-workers reported the development of ab ifunctional linker bearing ap ropargyl carbamate and as ubstituted thioether which allows for both stereospecific protein modification and ap alladium triggered uncagingo f as pecific drug. NMR experiments confirmed the critical role of the thioether,a si ts sulfur atom coordinates the palladium centerd irecting the cleavage of the proximal propargyl carbamate.…”

“…The Pd‐promoted uncaging reaction consists of a depropargylation of the p ‐(propargyloxy)benzyl hydroxamate derivative of the drug (Figure 47). [122] …”

Exosomes in Immune Regulation

“…However, they had no such effects on cells from the U87 glioma cell line and vice versa [ 204 ]. Pd has also been exploited to uncage the active metabolites of irinotecan [ 205 ] as well as the cytotoxic paclitaxel [ 206 ].…”