Photochemotherapeutic Properties of a Linear Tetrapyrrole Palladium(II) Complex displaying an Exceptionally High Phototoxicity Index.

Photodynamic therapy (PDT) represents a minimally invasive and highly localized treatment strategy to ablate tumors with few side effects. In PDT, photosensitizers embedded within tumors are activated by light and undergo intersystem crossing, followed by energy transfer to molecular oxygen, resulting in the production of toxic singlet oxygen (O). Previously, we reported a robust, linear tetrapyrrole palladium(II) complex, Pd[DMBil1], characterized by its facile and modular synthesis, broad absorption profile, and efficient O quantum yield of Φ = 0.8 in organic media. However, the insolubility of this porphyrinoid derivative in aqueous solution prevents its use under biologically relevant conditions. In this work, we report the synthesis of Pd[DMBil1]-PEG, a water-soluble dimethylbiladiene derivative that is appended with a poly(ethylene) glycol (PEG) functionality. Characterization of this complex shows that this PEGylated biladiene architecture maintains the attractive photophysical properties of the parent complex under biologically relevant conditions. More specifically, the absorption profile of Pd[DMBil1]-PEG closely matches that of Pd[DMBil1] and obeys the Beer-Lambert Law, suggesting that the complex does not aggregate under biologically relevant conditions. Additionally, the emission spectrum of Pd[DMBil1]-PEG retains the fluorescence and phosphorescence features characteristic of Pd[DMBil1]. Importantly, the PEGylated photosensitizer generates O with Φ = 0.57, which is well within the range to warrant interrogation as a potential PDT agent for treatment of cancer cells. The Pd[DMBil1]-PEG is biologically compatible, as it is taken up by MDA-MB-231 triple negative breast cancer (TNBC) cells and has an effective dose (ED) of only 0.354 μM when exposed to λ > 500 nm light for 30 min. Impressively, the lethal dose (LD) of Pd[DMBil1]-PEG without light exposure was measured to be 1.87 mM, leading to a remarkably high phototoxicity index of ∼5300, which is vastly superior to existing photosensitizers that form the basis for clinical PDT treatments. Finally, through flow cytometry experiments, we show that PDT with Pd[DMBil1]-PEG induces primarily apoptotic cell death in MDA-MB-231 cells. Overall these results demonstrate that Pd[DMBil1]-PEG is an easily prepared, biologically compatible, and well-tolerated photochemotherapeutic agent that can efficiently drive the photoinduced apoptotic death of TNBC cells.