Thioguanine restoration through type I photosensitization-superoxide oxidation-glutathione reduction cycles.

UVA-induced deleterious effect of thiopurine prodrugs including azathioprine, 6-mercaptopurine and 6-thioguanine (6-TG) increases the risk of cancer development due to the incorporation of 6-TG in patients' DNA. The catalytic mechanism by which thiobases act as a sustained oxidant producer has yet to be explored, especially through the Type I electron transfer pathway that produces superoxide radicals (O2˙-). Under Fenton-like conditions O2˙- radicals convert to extremely reactive hydroxyl radicals (˙OH), thus carrying even higher risk of biological damage than that induced by the well-studied type II reaction. By monitoring 6-TG/UVA-induced photochemistry in mass spectra and superoxide radicals (O2˙-) via nitro blue tetrazolium (NBT) reduction, this work provides two new findings: (1) in the presence of reduced glutathione (GSH), the production of O2˙-via the type I reaction is enhanced 10-fold. 6-TG thiyl radicals are identified as the primary intermediate formed in the reaction of 6-TG with O2˙-. The restoration of 6-TG and concurrent generation of O2˙- occur via a 3-step-cycle: 6-TG type I photosensitization, O2˙- oxidation and GSH reduction. (2) In the absence of GSH, 6-TG thiyl radicals undergo oxygen addition and sulfur dioxide removal to form carbon radicals (C6) which further convert to thioether by reacting with 6-TG molecules. These findings help explain not only thiol-regulation in a biological system but chemoprevention of cancer.

Distorted Phthalocyanines by Click Chemistry: Photoacoustic, Photothermal, and Surface-Enhanced Resonance Raman Studies.

Distortion of nominally planar phthalocyanine macrocycles affects the excited state dynamics in that most of the excited-state energy decays through internal conversion. A click-type annulation reaction on a perfluorophthalocyanine platform appending a seven-membered ring to the ß-positions on one or more of the isoindoles distorts the macrocycle and modulates solubility. The distorted derivative enables photoacoustic imaging, photothermal effects, and strong surface-enhanced resonance Raman signals.

Nanocomposite liposomes for pH-controlled porphyrin release into human prostate cancer cells.

It is both challenging and desirable to have drug sensitizers released at acidic tumor pH for photodynamic therapy in cancer treatment. A pH-responsive carrier was prepared, in which fumed silica-attached 5,10,15,20-tetrakis(4-trimethylammoniophenyl)porphyrin (TTMAPP) was encapsulated into 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) nanocomposite liposomes. The sizes of agglomerates were determined by dynamic light scattering to be 115 nm for silica and 295 nm for silica-TTMAPP-DOPC liposomes. Morphological changes were also found in TEM images, showing liposome formation at pH 8.5 but collapse upon silanol protonation. TTMAPP release is enhanced from 13% at pH 7.5 to 80% at pH 2.3, as determined spectrophotometrically through dialysis membranes. Fluorescence emission of TTMAPP encapsulated in the dry film of liposomes was reduced to half at pH 8.6 when compared to that at pH 5.4, while the production of singlet oxygen was quintupled at pH 5.0 compared to pH 7.6. Upon treatment of human prostate cancer cells with liposomes containing 6.7 µM, 13 µM, 17 µM and 20 µM TTMAPP, the cell viabilities were determined to be 60%, 18%, 20% and 5% at pH 5.4; 58%, 30%, 25% and 10% at pH 6.3; and 90%, 82%, 68% and 35% at pH 7.4, respectively. Light-induced apoptosis in cancerous cells was only observed in the presence of liposomes at pH 6.3 and pH 5.4 but not at pH 7.4, as indicated by chromatin condensation.