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.
We show the intracellular delivery of a homogeneous palladium–peptide catalyst able to bioorthogonally activate a profluorophore inside living prostate cancer cells.
As a novel prodrug activation strategy Pd(0) nanoparticles, entrapped within a modular polymeric support, were used in cell culture, to synthesise the anticancer agent PP-121 from two non-toxic precursors, thereby inducing cell death in the first example of in situ mediated drug synthesis.
Transition metals have been successfully applied to catalyze non-natural chemical transformations within living cells,w ith the highly efficient labeling of subcellular components and the activation of prodrugs.I nv ivo applications, however,have been scarce,with aneed for the specific cellular targeting of the active transition metals.H ere,w es how the design and application of cancer-targeting palladium catalysts, with their specific uptake in brain cancer (glioblastoma) cells, while maintaining their catalytic activity.Inthese cells,f or the first time,t wo different anticancer agents were synthesized simultaneously intracellularly,b yt wo totally different mechanisms (in situ synthesis and decaging), enhancing the therapeutic effect of the drugs.T umor 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.Bioorthogonal reactions have been explored and tuned over the past 20 years to allow them to be successfully applied in an array of cellular manipulations. [1][2][3][4][5][6] However,r eaction conditions within the biological milieu are challenging and only ah andful of such chemical reactions are viable under these demanding conditions.A lthough the use of transition metal catalysis within living systems is non-trivial, due to stability, efficiency and potential poisoning of the catalysts,i th as gained importance with many successes over the past few years. [7][8][9][10][11][12][13] Palladium mediated transformations,e specially, have been employed successfully in an umber of biological settings,including protein modifications and activations. [8,[14][15][16][17][18] These transformations typically use common Pd salts such as Pd(OAc) 2 or allyl 2 Pd 2 Cl 2 in high concentrations,which are not practical for in vivo applications.E ncapsulating Pd catalysts has been shown to improve biocompatibility,thus Rotello and co-workers,f or example,s howed the encapsulation of ah omogeneous Pd catalyst on the surface of gold nanoparticles and their ability to intracellularly activate aprodrug of the anticancer drug 5-fluorouracil. [19] Heterogeneous Pd nanoparticles embedded in polymers have been used successfully in the intra-and extracellular activation of caged fluorophores,a sw ell as Pd-catalyzed prodrug activation via depropargylation reactions and anticancer drug synthesis via Suzuki-Miyaura cross-coupling. [20][21][22][23] Intracellular activation of anticancer prodrugs via Pd-catalyzed chemistries requires the catalysts to be actively targeted. There are an umber of possible targeting scenarios,such as the addition of targeting ligands to the catalyst, thereby enhancing catalyst uptake and tumor specificity, [24] which in combination with ad ual Pdcatalyzed prodrug activation would be astep toward potential in vivo applicability.Herein, we report the synthesis of at argeted, multifunctional Pd catalyst, composed of palladium nanoparticle functionalized flu...
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