In‐Cell Dual Drug Synthesis by Cancer‐Targeting Palladium Catalysts

Abstract

Transition metals have been successfully applied to catalyze non-natural chemical transformations within living cells, with the highly efficient labeling of subcellular components and the activation of prodrugs. In vivo applications, however, have been scarce, with a need for the specific cellular targeting of the active transition metals. Here, we show the design and application of cancer-targeting palladium catalysts, with their specific uptake in brain cancer (glioblastoma) cells, while maintaining their catalytic activity. In these cells, for the first time, two different anticancer agents were synthesized simultaneously intracellularly, by two totally different mechanisms (in situ synthesis and decaging), enhancing the therapeutic effect of the drugs. Tumor specificity of the catalysts together with their ability to perform simultaneous multiple bioorthogonal transformations will empower the application of in vivo transition metals for drug activation strategies.

Palladium‐Mediated Cleavage of Proteins with Thiazolidine‐Modified Backbone in Live Cells

“…This work combines for the first time the delivery and activation, by external stimulus,o fafully synthetic protein and opens new opportunities for employing other palladium species, [65,66] and alternative linkers and chemistries [67] for further understanding of protein function in native environments.…”

Fluorescent and Biocompatible Ruthenium‐Coordinated Oligo(p‐phenylenevinylene) Nanocatalysts for Transfer Hydrogenation in the Mitochondria of Living Cells

“…Synthetic metal catalysts, as an alternative to natural enzymes, have been broadening the scope of intracellular chemical transformations . The design and synthesis of new metal catalysts creates vast possibilities for their application in biosystems, such as developing metal‐based drugs, in situ synthesizing fluorescent molecules and activating prodrugs . However, due to the complexity of cellular environment, the transformation mediated by metal catalysts inside living cells is quite difficult from that in aqueous solution.…”

“…[1][2][3][4] The design and synthesis of new metal catalysts creates vast possibilities for their application in biosys-tems,s uch as developing metal-basedd rugs, in situ synthesizing fluorescent molecules and activating prodrugs. [5][6][7] However,d ue to the complexity of cellular environment,t he transformationm ediatedb ym etal catalysts inside living cells is quite difficult from that in aqueous solution. It requires the metal catalystst op ossessm any propertiesi ncluding good biocompatibility,s tability in physiological conditions, certain water dispersibility as well as hydrophobicity for easy uptakeb yc ells, high activity,e tc.…”

“…Different types of substrate, including aldehyde, ketone, imine, carboxylic acid anda mide, were employed for the transfer hydrogenation catalyzed by OPV-Ru, with HCOONaa sh ydrogen source in D 2 O/[D 6 ]DMSO (v/v = 3:2) at 37 8C ( Figure 5a). These reactions werea ll confirmed by 1 HNMR spectra (Figure S3).…”

“…a) Scope of the OPV-Ru catalyzed transfer hydrogenation. [Substrate] = 2mm,[ OPV-Ru] = 0.4 mm,[HCOONa] = 50 mm,inD 2 Oa nd [D6 ]DMSO (3:2), 37 8C. 1 HNMR was employed to monitor the reaction and determine the yield.…”