Title page for ETD etd-03022012-183410

Type of Document Dissertation
Author Higgins, Samantha Lake Hopkins
URN etd-03022012-183410
Title Probing the Redox and Photophysical Properties of Ru(II)-Pt(II) Supramolecular Complexes as Efficient Photodynamic Therapy Agents
Degree PhD
Department Chemistry
Advisory Committee
Advisor Name Title
Brewer, Karen J. Committee Chair
Deck, Paul A. Committee Member
Robertson, John L. Committee Member
Winkel, Brenda S. J. Committee Member
Yee, Gordon T. Committee Member
  • supramolecular
  • ruthenium(II)
  • photodynamic therapy
  • platinum(II)
  • and DNA
Date of Defense 2012-02-16
Availability unrestricted
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 (Φ1O2 = 0.97, Ph2phen and Φ1O2 = 0.54, phen). The redox and photophysical properties were analyzed at each synthetic step providing systematic evaluation of the complex properties. The [(Ph2phen)2Ru(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(BL)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 Φ1O2 was quantified for the [(Ph2phen)2Ru(BL)PtCl2]Cl2 (BL = dpp, Φ1O2 = 0.07 or dpq, Φ1O2 = 0.03) complexes supporting 1O2 generation via energy transfer from the 3MLCT excited state.

The thermal and photochemical interactions of the [(Ph2phen)2Ru(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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