Bioorthogonal Swarming: In Situ Generation of Dendrimers.

With the aid of bioorthogonal chemistry, we demonstrate the fabrication of synthetic dendrimers in situ around living cells. Using tetrazine dienophile and aminooxyl/hydrazide aldehyde chemistries, the density of functional groups on the dendrimers exponentially amplified intensities of fluorescent markers in antibody-targeted live cell imaging. This novel "swarming" approach highlights the power of bioorthogonal chemistry and provides a route to non-natural chemical structures on cells, paving the way for the generation of various artificial cellular nanostructures and scaffolds.

Multifunctional, histidine-tagged polymers: antibody conjugation and signal amplification.

A polymer scaffold, with multiple reactive centres, was synthesised by RAFT polymerisation and conjugated to the antibody herceptin. A hexahistidine RAFT agent enabled the rapid and simple purification of polymer-protein conjugates, while the tetrazine conjugation strategy allows myriad cargos to be attached and amplified.

Radical polymerization inside living cells.

Polymerization reactions conducted inside cells must be compatible with the complex intracellular environment, which contains numerous molecules and functional groups that could potentially prevent or quench polymerization reactions. Here we report a strategy for directly synthesizing unnatural polymers in cells through free radical photopolymerization using a number of biocompatible acrylic and methacrylic monomers. This offers a platform to manipulate, track and control cellular behaviour by the in cellulo generation of macromolecules that have the ability to alter cellular motility, label cells by the generation of fluorescent polymers for long-term tracking studies, as well as generate a variety of nanostructures within cells.

Surface Charge-Dependent Cellular Uptake of Polystyrene Nanoparticles.

The evaluation of the role of physicochemical properties in the toxicity of nanoparticles is important for the understanding of toxicity mechanisms and for controlling the behavior of nanoparticles. The surface charge of nanoparticles is suggested as one of the key parameters which decide their biological impact. In this study, we synthesized fluorophore-conjugated polystyrene nanoparticles (-PLNPs), with seven different types of surface functional groups that were all based on an identical core, to evaluate the role of surface charge in the cellular uptake of nanoparticles.

Electrodrugs: an electrochemical prodrug activation strategy.

The term electroceutical has been used to describe implanted devices that deliver electrical stimuli to modify biological function. Herein, we describe a new concept in electroceuticals, demonstrating for the first time the electrochemical activation of metal-based prodrugs. This is illustrated by the controlled activation of Pt(iv) prodrugs into their active Pt(ii) forms within a cellular context allowing selectivity and control of where, when and how much active drug is generated.

Intracellular delivery of a catalytic organometallic complex.

A homogeneous carbene-based palladium catalyst was conjugated to a cell-penetrating peptide, allowing intracellular delivery of catalytically active Pd complexes that demonstrated bioorthogonal activation of a profluorophore within prostate cancer cells.

In-Cell Dual Drug Synthesis by Cancer-Targeting Palladium Catalysts.

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.

Palladium-mediated in situ synthesis of an anticancer agent.

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.

Copper Catalysis in Living Systems and In Situ Drug Synthesis.

The copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction has proven to be a pivotal advance in chemical ligation strategies with applications ranging from polymer fabrication to bioconjugation. However, application in vivo has been limited by the inherent toxicity of the copper catalyst. Herein, we report the application of heterogeneous copper catalysts in azide-alkyne cycloaddition processes in biological systems ranging from cells to zebrafish, with reactions spanning from fluorophore activation to the first reported in situ generation of a triazole-containing anticancer agent from two benign components, opening up many new avenues of exploration for CuAAC chemistry.

Tuning the luminescent properties of Pt(II) acetylide complexes through varying the electronic properties of N-heterocyclic carbene ligands.

This Article reports the synthesis, structural characterization, electrochemistry, and photophysical investigations of five groups of luminescent Pt(II) alkynyl complexes bearing N-heterocyclic carbene (NHC) ligands with varying electronic properties. Complexes of the type [Pt(pmdb)(C≡CR)2] 1a-c, [Pt(pm2tz)(C≡CR)2] 2a-d, [Pt(pm3tz)(C≡CR)2] 3a-c, [Pt(ppim)(C≡CR)2] 4(a, b, e), and [Pt(ppbim)(C≡CR)2] 5(a, b, e), where pmdb =1,1'-dipentyl-3,3'-methylene-dibenzimidazoline-2,2'-diylidene, pm2tz = 1,1'-dipentyl-3,3'-methylene-di-1,2,4-triazoline-5,5'-diylidene, pm3tz = 1,1'-dipentyl-3,3'-methylene-di-1,3,4-triazoline-5,5'-diylidene, ppim = 3-pentyl-1-picolylimidazoline-2-ylidene, and ppbim = 3-pentyl-1-picolylbenzimidazoline-2-ylidene, and R = 4-C6H4F, C6H5, 4-C6H4OMe, SiMe3, and 4-C6H4N(C6H5)2, were prepared, and the consequences of the electronic properties of the NHC ligands on the phosphorescent emission efficiencies were studied. Moreover, the emission quantum efficiencies of the previously reported complexes [Pt(pmim)(C≡CR)2] where pmim = 1,1'-dipentyl-3,3'-methylene-diimidazoline-2,2'-diylidene and R = 4-C6H4F 6a, C6H5 6b, and 4-C6H4OMe 6c were also recorded in neat solid and in 10 wt % PMMA film.