Ruthenium Complexes are pH-Activated Metallo Prodrugs (pHAMPs) with Light-Triggered Selective Toxicity Toward Cancer Cells

Abstract

Metallo prodrugs that take advantage of the inherent acidity surrounding cancer cells have yet to be developed. We report a new class of pH-activated metallo prodrugs (pHAMPs) that are activated by light- and pH-triggered ligand dissociation. These ruthenium complexes take advantage of a key characteristic of cancer cells and hypoxic solid tumors (acidity) that can be exploited to lessen the side effects of chemotherapy. Five ruthenium complexes of the type [(N,N)Ru(PL)] were synthesized, fully characterized, and tested for cytotoxicity in cell culture (1: N,N = 2,2'-bipyridine (bipy) and PL, the photolabile ligand, = 6,6'-dihydroxybipyridine (6,6'-dhbp); 2: N,N = 1,10-phenanthroline (phen) and PL = 6,6'-dhbp; 3: N,N = 2,3-dihydro-[1,4]dioxino[2,3-f][1,10]phenanthroline (dop) and PL = 6,6'-dhbp; 4: N,N = bipy and PL = 4,4'-dimethyl-6,6'-dihydroxybipyridine (dmdhbp); 5: N,N = 1,10-phenanthroline (phen) and PL = 4,4'-dihydroxybipyridine (4,4'-dhbp). The thermodynamic acidity of these complexes was measured in terms of two pK values for conversion from the acidic form (X) to the basic form (X) by removal of two protons. Single-crystal X-ray diffraction data is discussed for 2, 2, 3, 4, and 5. All complexes except 5 showed measurable photodissociation with blue light (λ = 450 nm). For complexes 1-4 and their deprotonated analogues (1-4), the protonated form (at pH 5) consistently gave faster rates of photodissociation and larger quantum yields for the photoproduct, [(N,N)Ru(HO)]. This shows that low pH can lead to greater rates of photodissociation. Cytotoxicity studies with 1-5 showed that complex 3 is the most cytotoxic complex of this series with IC values as low as 4 μM (with blue light) versus two breast cancer cell lines. Complex 3 is also selectively cytotoxic, with sevenfold higher toxicity toward cancerous versus normal breast cells. Phototoxicity indices with 3 were as high as 120, which shows that dark toxicity is avoided. The key difference between complex 3 and the other complexes tested appears to be higher uptake of the complex as measured by inductively coupled plasma mass spectrometry, and a more hydrophobic complex as compared to 1, which may enhance uptake. These complexes demonstrate proof of concept for dual activation by both low pH and blue light, thus establishing that a pHAMP approach can be used for selective targeting of cancer cells.

Electrospun oral formulations for combined photo-chemotherapy of colon cancer

“…Greater selectivity for cancerous over non-cancerous cells has been noted previously for electrosprayed poly(vinylpyrrolidone) particles [7], but those formulations were very rapid dissolving, and thus could not practicably be used for cancer treatment. The selectivity values observed in this work are of the same order of magnitude as other reports in the literature, for instance with graphene oxide based delivery systems [37] or Ru-based anticancer prodrugs [38]. Overall therefore, the coaxial fibers appear to have potential for combined photo-chemotherapy.…”

Enhanced cellular uptake and photochemotherapeutic potential of a lipophilic strained Ru(ii) polypyridyl complex

“…Generally, it is expected that the photochemically generated metal aqua complexes are responsible for the biological effect of the complex, similarly to cisplatin. 47 However, our group and others have demonstrated that the ejected ligand could be potent. [20][21][22] Both dissociating ligands, bipy and BC, were therefore included in cell survival studies to investigate their potential cytotoxic effect.…”

Synthesis, characterization, DNA binding, topoisomerase inhibition, and apoptosis induction studies of a novel cobalt(III) complex with a thiosemicarbazone ligand

“…Transition metal complexes are particularly suited to controlled drug release, having bonds that are highly responsive to their environment [121]. Such cases are applied when prodrug complexes can be designed that are inert under normal physiological conditions, but become labile with a change in environment such as redox status, pH, or the localized application of light [126][127][128]. By not activating a drug before it reaches its target, side reactions and premature metabolism that can lead to undesirable side effects to normal cells can be reduced tremendously [110][111][112][113][114][115][116]127,129].…”