Journal article
Ruthenium Complexes are pH-Activated Metallo Prodrugs (pHAMPs) with Light-Triggered Selective Toxicity Toward Cancer Cells
Inorganic chemistry, Vol.56(13), pp.7519-7532
07/03/2017
PMID: 28636344
Web of Science ID: WOS:000405056400025
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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(H
O)
]
. 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.
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Details
- Title
- Ruthenium Complexes are pH-Activated Metallo Prodrugs (pHAMPs) with Light-Triggered Selective Toxicity Toward Cancer Cells
- Publication Details
- Inorganic chemistry, Vol.56(13), pp.7519-7532
- Resource Type
- Journal article
- Publisher
- American Chemical Society
- Copyright
- © American Chemical Society
- Identifiers
- WOS:000405056400025; 99381856992906600
- Academic Unit
- Chemistry; Hal Marcus College of Science and Engineering
- Language
- English