Exploring the cellular accumulation of metal complexes

Abstract

Transition metal complexes offer great potential as diagnostic and therapeutic agents, and a growing number of biological applications have been explored. To be effective, these complexes must reach their intended target inside the cell. Here we review the cellular accumulation of metal complexes, including their uptake, localization, and efflux. Metal complexes are taken up inside cells through various mechanisms, including passive diffusion and entry through organic and metal transporters. Emphasis is placed on the methods used to examine cellular accumulation, to identify the mechanism(s) of uptake, and to monitor possible efflux. Conjugation strategies that have been employed to improve the cellular uptake characteristics of metal complexes are also described.

Figure 1. Flow cytometry analysis of cellular uptake

(A) The sample stream containing the cells are injected into a flowing stream of sheath fluid, which focuses the sample stream to roughly one cell in diameter. The luminescence and light scatter are recorded for each cell as it passes through the laser beam. (B) Histograms are shown representing cells treated with different metal complexes. Untreated cells display some background luminescence. Complexes with greater uptake exhibit increased luminescence intensity.

Figure 2. Routes into the cell

Passive diffusion, facilitated diffusion, active protein transporters, and several endocytic pathways are illustrated. Inhibitors and activators of each pathway are shown.

Figure 3. Metal complexes whose cellular accumulation have been explored

Top row: cisplatin, a Eu(III) complex that enters cells by macropinocytosis, an Ir(III) polypyridine complex, the drug candidate KP1019, and a Ru(II) arene complex. Bottom row: a Au(I) phosphine complex that accumulates in mitochondria, the radiopharmaceutical [^99mTc]Sestamibi, a Ru(II) dipyridophenazine complex, a Eu(III) complex that stains nucleoli, and a Rh(III) metalloinsertor that binds DNA mismatches.

Figure 4. Cellular uptake of dipyridophenazine (dppz) complexes of Ru(II)

The lipophilic complex [Ru(DIP)₂dppz]²⁺ is observed inside HeLa cells at lower incubation concentrations and shorter times (top, 5 µM for 2 h) than [Ru(bpy)₂dppz]²⁺ (bottom, 20 µM for 72 h). Structures of complexes are shown at left. Scale bars are 10 µm.