Mitochondrial‐DNA‐Targeted Ir^III‐Containing Metallohelices with Tunable Photodynamic Therapy Efficacy in Cancer Cells

Abstract

The development of DNA‐targeted photodynamic therapy (PDT) agents for cancer treatment has drawn substantial attention. Herein, the design and synthesis of dinuclear IrIII‐containing luminescent metallohelices with tunable PDT efficacy that target mitochondrial DNA in cancer cells are reported. The metallohelices are fabricated using dynamic imine‐coupling chemistry between aldehyde end‐capped fac‐Ir(ppy)3 handles and linear alkanediamine spacers, followed by reduction of the imine linkages. The length and odd–even character of the diamine alkyl linker determined the stereochemistry (helicates vs. mesocates). Compared to the helicates, the mesocates exhibit improved apoptosis‐induction upon white‐light irradiation. Molecular docking studies indicate that the mesocate with a proper length of diamine spacers shows stronger affinity for the minor groove of DNA. This study highlights the potential of DNA‐targeting IrIII‐containing metallohelices as PDT agents.

Metallohelices emulate the properties of short cationic α-helical peptides

“…For example Duan linked two preorganised fac iridium( iii ) complexes, via reductive amination, to give the mesocate 6 . 22 There is thus an important balance to be struck between allowing the dynamic ligand exchange processes that furnish thermodynamic control in the self-assembly process, and the stability of the final system to hydrolysis or other substitution.…”

“…Several in vitro studies with ‘naked’ DNA have demonstrated that various metallohelices can bind duplex DNA, since the first report by Lehn and co-workers. 51 Apparent binding constants have been measured for several compounds via ethidium bromide displacement, including P - 2 [Fe( ii ) analogue], 52 racemic - 3 -Co( iii ), 53 meso - 6 , 22 Δ- 9a , 36 ‡ ‡ In metallohelices such as 9 the metal coordination units have the opposite helical configuration to the bridging ligand strands, so the helical descriptors P and M are unsuitable, so absolute configuration descriptors for the metal centres Δ and Λ are used. Δ- 10 , 36 Δ- 12 , 47 Δ- 13 , 38 Δ- 15 ; 47 the measured K app lie in the range 10 6 to 10 8 , although we note the strong dependency on ionic strength.…”

“…Notably, meso - 6 has an overall neutral charge, and still displaces cationic ethidium bromide from calf-thymus DNA, with K app = 1 × 10 7 . 22 …”

“… 46,53 Duan and co-workers have recently demonstrated that the neutral Ir( iii ) mesocate 6 can be used for photodynamic therapy, with activity in MCF-7 cells observed upon white light irradiation ( Table 2 ). 22 It is worth noting that the metallohelices exhibiting anticancer activity are all cationic, whist the charge neutral complex 6 has an IC 50 > 30 μM without irradiation, and the neutral Ln(III) helicate 5 exhibited no effects on the cell viability of HeLa (cervical cancer) cells treated for 24 h at 500 μM (rendering these useful luminescence probes for diagnostics). 82 …”

Ultrasmall Barium Titanate Nanoparticles for Highly Efficient Hypoxic Tumor Therapy via Ultrasound Triggered Piezocatalysis and Water Splitting

“…17 The activated photosensitizer will convey the energy of light to O 2 , generating ROS to kill tumor cells. 18 Despite PDT having been tested in the clinic for tumor treatment, an O 2 shortage in the tumor microenvironment and limited tissue-penetrating depth of light are two defects as reported. 19,20 Different from light-triggered PDT, SDT utilizes high tissue-penetrating ultrasound waves to irradiate sonosensitizers to trigger O 2 to subsequently generate ROS for tumor destruction.…”