Earth-abundant metal-based theranostics, agents that integrate diagnostic and therapeutic functions within the same molecule, may hold a key to developing low-cost personalized medicine. Recently, Jun-Long Zhang group at the College of Chemistry and Molecular Engineering, Peking University, Prof. Jonathan L. Sessler at The University of Texas at Austin, Prof. Jing Zhang at University of Chinese Academy of Sciences, and Prof. Wenkai Zhang at Beijing Normal University have published an article entitled “Nonaromatic Organonickel(II) Phototheranostics” in the Journal of the American Chemical Society (https://pubs.acs.org/doi/10.1021/jacs.2c00710). This is the first time for the biomedical application of organonickel(II) phototheranostics, to reveal the significance of metal-carbon bond and nonaromatic design in metal phototheranostics, and the potential applications of 3d earth-abundant metal complexes in biomedical diagnosis and treatment areas.
Jun-Long Zhang group focused on the research on the rational design of metal phototheranostics with the purpose of clinical transformation by mimicking the natural harvesting antenna that tunes the excited-state dynamics dissipation pathway. In this work, they aimed to replace the pyrrolic nitrogen donor of tetrapyrroles with a σ-donating carbanion, which introduces a metal-carbon bond that is anticipated to affect the excited-state dynamics of d8 metal complexes. Encouraged by previous studies of palladium and platinum complexes (Chem. Sci., 2019, 10, 10170), they synthesized a set of O-linked nonaromatic benzitripyrrin (C^N^N^N) macrocyclic organonickel(II) complexes containing strong σ-donating M―C bonds (Fig. 1).
Fig. 1 Introducing a metal-carbon bond into nickel complexes.
Nickel(II)-carbon bond can significantly increase the lifetime of the excited state in 3d metal complexes due to the enlarged ligand splitting by the strong σ-donating carbanion. The population and dissipation pathway of 3d transition metal complexes thus can be controlled by energy difference or sequence between metal to ligand charge transfer (MLCT) state and metal-centered excited-state (d-d*). Ultrafast transient absorption spectroscopy combined with theoretical calculations revealed that low-lying triplet excited states consisted of both 3MLCT states and 3d-d* states, promoting the intersystem crossing (ISC) process. They can only observe the phosphorescence of Ni(II) tripyrrole complexes at low temperatures due to the quench of Ni―C bond stretching vibration, which induces a high photothermal conversion efficiency in monomer and aggregates (Fig. 2).
Fig. 2 Excited-state dynamics of monomer and J-aggregate in Ni(II) complex.
The inherent excited-state dynamics and energy dissipation pathway of 3d metal complexes made them potential photothermal agents. Proof-of-principle experiments involving thrombus treatment were carried out both in vitro and in vivo. In vitro thrombolysis rate of Ni(II) tetrapyrrole complex nanocapsules was more than two times that of NiTPBP and NiF20TPP nanocapsules under NIR irradiation. After intravenous injection, photoacoustic imaging in vivo and ICP-MS characterization showed the accumulation at the femoral artery thrombus in mice (Fig. 3). It was found that, in combination with 785 nm photo-irradiation for 3 min (0.3 W/cm2), blood clots from a mouse thrombus model were successfully removed as monitored by photoacoustic imaging (PAI). The present work highlights the promise of organonickel(II) complexes as potential theranostics and the benefits that can accrue from manipulating the excited-state features of early transition-metal complexes via, for example, interrupting π-conjugation pathways.
Fig. 3 Proof-of-principle experiments involving thrombus treatment of Ni(II) tripyrrole complex.
Yuhang Yao, a postdoc at Peking University, Guangliu Ran, a Ph.D. student at the Beijing Normal University, and Chun-Liang Hou, a Ph.D. student at University of Chinese Academy of Sciences, are co-first authors of this paper. Prof. Jun-Long Zhang from Peking University, Prof. Jonathan L. Sessler from The University of Texas at Austin, Prof. Jing Zhang from University of Chinese Academy of Sciences and Prof. Wenkai Zhang from Beijing Normal University are the co-corresponding authors. This research was jointly supported by the National Natural Science Foundation of China, Beijing National Laboratory for Molecular Sciences, the Chemistry and Chemical Engineering Guangdong Laboratory in China, and the Robert A. Welch Foundation in USA.
Original link for the paper: https://pubs.acs.org/doi/10.1021/jacs.2c00710.