An Activatable Photosensitizer Targeted to γ‐Glutamyltranspeptidase

Abstract

We adopted a spirocyclization-based strategy to design γ-glutamyl hydroxymethyl selenorhodamine green (gGlu-HMSeR) as a photo-inactive compound that would be specifically cleaved by the tumor-associated enzyme γ-glutamyltranspeptidase (GGT) to generate the potent photosensitizer HMSeR. gGlu-HMSeR has a spirocyclic structure and is colorless and does not show marked phototoxicity toward low-GGT-expressing cells or normal tissues upon irradiation with visible light. In contrast, HMSeR predominantly takes an open structure, is colored, and generates reactive oxygen species upon irradiation. The γ-glutamyl group thus serves as a tumor-targeting moiety for photodynamic therapy (PDT), switching on tumor-cell-specific phototoxicity. To validate this system, we employed chick chorioallantoic membrane (CAM), a widely used model for preliminary evaluation of drug toxicity. Photoirradiation after gGlu-HMSeR treatment resulted in selective ablation of implanted tumor spheroids without damage to healthy tissue.

Hybrid Rhodamine Fluorophores in the Visible/NIR Region for Biological Imaging

“…Thirteen years later, Se‐rhodamine dye 87 (λ em =557 nm) was again exploited. The Urano group adopted a spirocyclization‐based strategy to design a photosensitizer (gGlu‐HMSeR) that was specifically activated by the tumor‐associated enzyme γ‐glutamyltranspeptidase (GGT); upon activation, a potent photosensitizer (HMSeR) was released in order to selectively ablate implanted tumor spheroids without damage to the healthy tissues (Figure ) . Recently, Hanaoka's group also employed 87 to design a Se‐rhodamine‐based hypoxia‐sensitive fluorescence probe.…”

“…TheU rano group adopted as pirocyclization-based strategy to design ap hotosensitizer (gGlu-HMSeR) that was specifically activated by the tumor-associated enzyme g-glutamyltranspeptidase (GGT);u pon activation, ap otent photosensitizer (HMSeR) was released in order to selectively ablate implanted tumor spheroids without damage to the healthy tissues ( Figure 8). [50] Recently,Hanaokasgroup also employed 87 to design aSerhodamine-based hypoxia-sensitive fluorescence probe.T his was achieved by introducing an azo moiety into the conjugated system of rhodamine fluorophores. [51] When Naganos group studied Si-rhodamine fluorophores,t hey also investigated Ge-substituted rhodamine dyes 88 (l em = 649 nm) and Te -substituted rhodamine dyes 89-90.F luorophore 89 has al ow quantum yield (< 0.001) but can be oxidized to fluorescent Te O-rhodamines 90 (l em = 686 nm) with ah igher quantum yield of 0.18.…”

Recent Advances in the Development of Optical Imaging Probes for γ‐Glutamyltranspeptidase

“…Recently, Urano et al. extended the strategy to develop the first GGT‐activatable photosensitizer ( 6 ) through using hydroxymethyl selenorhodamine green (HMSeR) instead of HMRG . It was found that the photodynamic activity of 6 could be rapidly activated by GGT‐overexpressing cancer cells, triggering tumor‐specific phototoxicity (Figure B).…”

An Activatable Photosensitizer Targeting Human NAD(P)H: Quinone Oxidoreductase 1

“…Lastly, theranostic prodrugs providing both real‐time hNQO1 activity monitoring and anticancer drug release in a single molecule have also been reported . However, despite the diverse set of probes currently exploiting hNQO1, to date, there are no reports of an hNQO1‐targeted optical therapeutic that can be used for PDT . With this in mind, we sought out to develop the first activatable PS (aPS) targeting hNQO1.…”

“…[31,32] However,d espite the diverse seto fp robesc urrently exploitingh NQO1, to date, there are no reportso fa nh NQO1targeted optical therapeutic that can be used for PDT. [33][34][35][36][37][38] With this in mind, we sought out to develop the first activatable PS (aPS)t argeting hNQO1.…”