Abstract
Effective delivery of luminescent probes for cell imaging requires both cell membrane permeation and directing to discrete target organelles. Combined, these requirements can present a significant challenge for metal complex luminophores, that have excellent properties as imaging probes but typically show poor membrane permeability. Here, we report on highly luminescent Ruthenium polypyridyl complexes based on the parent; [Ru(dpp)2(x-ATAP)](PF6)2 structure, where dpp is 4,7-diphenyl-1,10-phenanthroline and x-ATAP is 5-amino-1,10-phenanthroline with pendant alkyl-acetylthio chains of varying length; where x is 6; 5-Amido-1,10-phenanthroline-(6-acetylthio-hexanyl). 8; 5-Amido-1,10-phenanthroline-(8-acetylthio-octanyl). 11; 5-Amido-1,10-phenanthroline-(11-acetylthio-undecanyl); and 16; 5-Amido-1,10-phenanthroline-(16-acetylthio-hexadecanyl). Soluble in organic media, the alkyl-acetylthiolated complexes form nanoaggregates of low polydispersity in aqueous solution. From dynamic light scattering the nanoaggregate diameter was measured as 189 nm and 135 nm for 5 × 10−6 M aqueous solutions of [Ru(dpp)2(N∧N)](PF6)2 with the hexadecanoyl and hexanyl tails respectivly. The nanoaggregate exhibited dual exponential emission decays with kinetics that matched closely those of the [Ru(dpp)2(16-ATAP)]2+ incorporated into the membrane of a DPPC liposome. Cell permeability and distribution of [Ru(dpp)2(11-ATAP)]2+ or [Ru(dpp)2(16-ATAP)]2+ were evaluated in detail in live HeLa and CHO cell lines and it was found from aqueous media, that the nanoaggregate complexes spontaneously cross the membrane of mammalian cells. This process seems, on the basis of temperature dependent studies to be activated. Fluorescence imaging of live cells reveal that the complexes localize highly specifically within organelles and that organelle localization changes dramatically in switching the pendent alkyl chains from C16 to C11 as well as on cell line identity. Our data suggests that building metal complexes capable of self-assembling into nano-dimensional vesicles in this way may be a useful means of promoting cell membrane permeability and driving selective targeting that is facile and relatively low cost compared to use of biomolecular vectors.
Highlights
Ruthenium(II) polypyridyl complexes are attractive cell imaging probes and potential phototherapeutics because of their amenable optical and redox properties coupled with their synthetic versatility
The x-ATAP ligand was prepared from hydrazine reduction of 5-nitro-1,10 phenanthroline to yield the amino precursor
The zeta potential was measured for the [Ru(dpp)2(16-ATAP)]2+ and [Ru(dpp)2(11-ATAP)]2+ respectively as these were the structures that we focused on for imaging studies
Summary
Ruthenium(II) polypyridyl complexes are attractive cell imaging probes and potential phototherapeutics because of their amenable optical and redox properties coupled with their synthetic versatility. More conventionally used in cell imaging, Ruthenium(II) polypyridyl complexes exhibit exceptionally long-lived emission from their triplet (dπ-π∗) MLCT states that can facilitate environmental sensitivity toward for example pH and O2. Membrane permeabilization can be readily achieved through applying the luminophore to the cell along with organic solvent such as dimethyl sulfoxide (DMSO) or ethanol, or through the use of detergent, but such approaches are not ideal as they disrupt the plasma membrane, and have no capacity for directing the complex within the cell Such methods are not typically suitable for tissue or in-vivo imaging applications. It was predicted that complexes, with acetylthio-alkyl tails might act as metallosurfactants leading to aggregation in aqueous media that might promote permeation of the lipid bilayer of the cell in a similar manner to a liposome, possibly facilitating the uptake of [Ru(dpp)2(x-ATAP)](PF6) into the cytoplasm. While both aggregates are readily membrane permeable, we observed some intriguing differences in localization with chain length
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