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Probing the Redox and Photophysical Properties of Ru(II)-Pt(II) Supramolecular Complexes as Efficient Photodynamic Therapy Agents
Higgins, Samantha Lake Hopkins
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Mixed-metal Ru(II)-Pt(II) supramolecular complexes having the [(Ph₂phen)₂Ru(BL)PtCl₂]₂+ (Ph₂phen = 4,7-diphenyl-1,10-phenanthroline, and BL (bridging ligand) = dpp = 2,3-bis(2-pyridyl)pyrazine, or dpq = 2,3-bis(2-pyridyl)quinoxaline) structural motif were synthesized and their redox, photophysical, and photochemical properties studied. Subsequently the application of the Ru(II)-Pt(II) bimetallic complexes in light activated DNA modification and cytotoxicity were evaluated. The supramolecular design entails covalently coupling an efficient Ru(II) chromophore for photodynamic therapy (PDT) activity through a polyazine bridging ligand (dpp or dpq) to a cis-PtCl₂ bioactive site for covalent binding to biological substrates. The bioactive site is comparable to the first generation Pt-based chemotherapy agent cisplatin, cis-[PtCl₂(NH₃)₂]. The Ph₂phen ligand is known in [Ru(Ph₂phen)₃]²+ to provide enhanced excited state lifetime and increase quantum efficiency for singlet oxygen generation in comparison to the phen analog (Φ₁₀₂ = 0.97, Ph₂phen and Φ₁₀₂ = 0.54, phen). The redox and photophysical properties were analyzed at each synthetic step providing systematic evaluation of the complex properties. The [(Ph₂phen₂2Ru(BL)PtCl₂](PF₆)₂ complexes display reversible RuII/III oxidations at +1.61 (dpp) and +1.63 (dpq) V vs. Ag/AgCl with an irreversible PtII/IV oxidation occurring prior at +1.51 V vs. Ag/AgCl. Four reversible ligand reductions occur at -0.45 (dpp0/-), -1.15 (dpp-/2-), -1.33 (Ph₂phen0/-), and -1.52 (Ph₂phen0/-) V vs. Ag/AgCl. For the [(Ph₂phen)₂Ru(dpq)PtCl₂](PF₆)₂ complex, the first two reductions shift to more positive potentials at -0.19 and -0.95 V vs. Ag/AgCl, while the TL reductions remain generally unperturbed. The electronic absorption spectroscopy for the [(Ph₂phen)₂Ru(dpq)PtCl₂](PF₆)₂, BL = dpp or dpq, complexes is dominated in the UV region by Ph₂phen (274 nm) and BL-based (310-320 nm) π⟶ π* transitions and in the visible region by metal-to-ligand charge transfer (MLCT) transitions at 424 nm (Ru(dπ)→ Ph₂phen(π*) 1CT) and 517 nm (Ru(dπ)→ dpp(π*) 1CT) or 600 nm (Ru(dπ)→ dpq(π*) 1CT). Steady-state and time-resolved emission spectroscopy shows that upon attaching Pt to the Ru monometallic precursor the λmaxem shifts from 664 nm for [(Ph₂phen)2Ru(dpp)](PF₆)₂ to 740 nm for [(Ph₂phen)₂Ru(dpp)PtCl₂](PF₆)₂ and the excited state lifetime is reduced from 820 ns to 44 ns in accordance with the energy gap law. The τ = 44 ns for the Ru(dπ)→ dpp(π*) 3CT excited state was somewhat unexpected upon TL variation given the lack of formal involvement of Ph₂phen in the emissive state. This likely results from the Ph₂phen contribution to the formally Ru(dπ) donor orbital. Although not typically done, given the complexity of the study the Φ₁₀₂ was quantified for the [(Ph₂phen)₂Ru(BL)PtC₂]Cl₂ (BL = dpp, Φ₁₀₂ = 0.07 or dpq, Φ₁₀₂ = 0.03) complexes supporting 1O2 generation via energy transfer from the 3MLCT excited state. The thermal and photochemical interactions of the [(Ph₂phen₂2Ru(BL)PtCl₂]Cl₂ (BL = dpp or dpq) supramolecular complexes were studied in the presence of DNA and U87MG cancer cells. Thermal binding at the cis-PtCl₂ BAS in the Ru(II)-Pt(II) architecture was compared to cisplatin displaying similar reduced migration through the gel attributed to covalent binding to DNA. DNA photocleavage studies provided evidence of efficient strand cleavage when excited at 455 nm likely enhanced by producing 1O2 locally at the DNA target. DNA photobinding by the [(Ph₂phen)₂Ru(dpp)PtCl₂]Cl₂ complex was observed utilizing low energy light where typical Pt(II) agents do not absorb. This is the first example of MLCT excitation of a Ru(II)-Pt(II) complex to induce a photobinding event. MLCT excitation enhances electron density on the dpp making the Pt(II) a weaker Lewis acid and promoting halide loss. In addition, this system is photoactivated with low energy red light in the therapeutic window. These studies validate the supramolecular design and show that coupling a Ru(II) chromophore for PDT activity and a cis- PtCl₂ binding moiety for covalent DNA targeting affords a complex applicable in photochemotherapies. Analysis of cytotoxicity in the dark for [(Ph₂phen)₂Ru(dpp)PtCl₂]Cl₂ and cisplatin afforded LC50 values of 100 μM, which are confirmed by previous reports for cisplatin and the currently used chemotherapy, TMZ in U87MG cells. Photolysis of the [(Ph₂phen)₂Ru(dpp)PtCl₂]Cl₂ resulted in substantial reduction in the observed LC50 values to approximately 5 μM. The enhanced cytotoxicity via excitation into the formally Ru(dπ)→ BL(π*) CT excited state of [(Ph₂phen)2Ru(dpp)PtCl2]Cl2 indicates that the bimetallic complex undergoes an efficient light activated mechanism of action. The Ru(II)-Pt(II) complex displays substantially lower LC50 values through PDT action than currently used clinical treatments with LC50 values of 100 μM. The [(Ph₂phen)₂Ru(BL)PtCl₂]₂+ (BL = dpp or dpq) mixed-metal supramolecules utilizing the Ph₂phen TL have displayed surprising results. The direct coupling of the cis-PtCl₂ moiety to the (Ph₂phen)₂Ru(BL) chromophore display dramatically enhanced photophysical properties, relative to the bpy and phen systems with a longer excited state lifetime and improved light activated interactions with DNA, which was not previously observed for directly coupled Ru(II)- Pt(II) systems. The Ph₂phen TL positively influence the bioactivity compared to the typical deactivation observed in the bpy and phen systems. Probing the [(Ph₂phen)₂Ru(BL)PtCl₂]₂+ (BL = dpp or dpq) biological interactions confirms the importance of coupling an efficient light absorbing and 1O2 generating PDT-type unit with a cis-PtCl2 DNA binding unit for applications in covalent DNA photomodification, DNA photocleavage, and photocytotoxicity. It is proposed that excitation using visible light into the formally Ru(dπ)→ BL(π*) CT excited state leads to enhanced electron density on the BL and weakened Lewis acidity at the Pt(II) center, which facilitates halide loss for efficient biological substrate modification. Upon coordination of the Ru(II)-Pt(II) complexes at the biological substrate, 1O2 is localized providing effective targeting of the highly reactive oxygen species. The visible light induced activity of the [(Ph₂phen)₂Ru(BL)PtCl₂]₂+ (BL = dpp or dpq) supramolecules suggests a new mode of action in relation to cisplatin, which was further supported by the enhanced photocytotoxicity observed in the presence of U87MG cells. The results indicate that the Ru(II)-Pt(II) supramolecular structural motif hold great promise as a future photochemotherapy agent.
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