4'-Nitrobiphenyl thioglucoside as the Smallest, fluorescent photosensitizer with cancer targeting ligand.

We have previously developed a glucose-linked biphenyl photosensitizer that can pass through glucose transporters, aiming for cancer-selective photodynamic therapy (PDT). Its small size (MW: 435) will allow oral administration and a fast clearance avoiding photosensitivity. However, its fluorescence efficiency was quite low, causing difficulty in monitoring cellular uptake. We thus synthesized a series of monosaccharide-linked biphenyl derivatives with a sulfur atom replacing an oxygen atom, in search of a photosensitizer with a brighter fluorescence. Among them, 4'-nitrobiphenyl thioglucoside showed a fluorescence emission extending to near infra-red region with a strength three times greater than that of the previous compound. This compound was found to have a higher 1O2-producing efficiency (ΦΔ: 0.75) than the previous compound (ΦΔ: 0.65). The thioglucoside indicated a significant photodamaging effect (IC50: 250 µM) against cancer cells. Although the galactose and mannose analogs exerted similar photodamaging effects, they were moderately toxic in the dark at a concentration of 300 µM. The thioglucoside and thiomannoside were at least partially uptaken through glucose transporters as demonstrated by inhibition with cytochalasin B, whereas no inhibition was observed for the galactoside. The behavior of d-glucose toward the cellular uptakes of these photosensitizers was bipolar: inhibitory at a low concentration and recovery or acceleratory at a higher concentration. These results indicate that 4'-nitrobiphenyl thioglucoside is the smallest (MW: 393) cancer-targeting photosensitizer with a trackable fluorescence property.

A Twist-Assisted Biphenyl Photosensitizer Passable Through Glucose Channel.

While the development of low-molecular-weight drugs is saturating, agents for photodynamic therapies (PDTs) may become alternative seeds in pharmaceutical industry. Among them, orally administrative, cancer-selective, and side effect-free photosensitizers (PSs) that can be activated by tissue-penetrative near-infrared (NIR) lights are strongly demanded. We discovered such a PS from scratch by focusing on a twist-assisted spin-orbit charge transfer intersystem crossing (ISC) mechanism in a biphenyl derivative, which was demonstrated by thorough photophysical studies. The unique ISC mechanism enables the PS to be small and slim so as to pass through glucose transporters and exert a PDT effect selectively on a cancer cell line. The smallness will allow for oral administration and fast clearance, which have been agenda of approved PSs with larger molecular weights. We also demonstrated that our PS was able to be activated with an NIR pulse laser through two-photon excitation.