Self-Immolative Photosensitizers for Self-Reported Cancer Phototheranostics

Abstract

Photosensitizers to precise target and change fluorescence upon light illumination could accurately self-report where and when the photosensitizers work, enabling us to visualize the therapeutic process and precisely regulate treatment outcomes, which is the unremitting pursuit of precision and personalized medicine. Here, we report self-immolative photosensitizers by adopting a strategy of light-manipulated oxidative cleavage of CC bonds that can generate a burst of reactive oxygen species, to cleave to release self-reported red-emitting products and trigger nonapoptotic cell oncosis. Strong electron-withdrawing groups are found to effectively suppress the CC bond cleavage and phototoxicity via studying the structure–activity relationship, allowing us to elaborate NG1–NG5 that could temporarily inactivate the photosensitizer and quench the fluorescence by different glutathione (GSH)-responsive groups. Thereinto, NG2 with 2-cyano-4-nitrobenzene-1-sulfonyl group displays excellent GSH responsiveness than the other four. Surprisingly, NG2 shows better reactivity with GSH in weakly acidic condition, which inspires the application in weakly acidic tumor microenvironment where GSH elevates. To this end, we further synthesize NG-cRGD by anchoring integrin αvβ3 binding cyclic pentapeptide (cRGD) for tumor targeting. In A549 xenografted tumor mice, NG-cRGD successfully deprotects to restore near-infrared fluorescence because of elevated GSH in tumor site, which is subsequently cleaved upon light irradiation releasing red-emitting products to report photosensitizer working, while effectively ablating tumors via triggered oncosis. The advanced self-immolative organic photosensitizer may accelerate the development of self-reported phototheranostics in future precision oncology.

Photochemical and biological dual-effects enhance the inhibition of photosensitizers for tumour growth

“…2d, S19 and S21†), the production of ROS in living cells was investigated using 2, 7-dichlorodihydrofluorescein diacetate (DCFH-DA) as a ROS indicator and DHE as an O 2 ˙ − indicator. 14,39 As can be seen in Fig. 6, in all cases the cells exhibited strong fluorescence signals corresponding to ROS and O 2 ˙ − production in the presence of ZZ-NN and ZZ-EDA with photo-irradiation (800 nm, 9.15 mW cm −2 , 3.0 min).…”

Nanoprobe-based molecular imaging for tumor stratification

“…188 Wang et al reported a photosensitizer called NG-cRGD, which consisted of a cyclic pentapeptide (cRGD) that specifically targeted integrin avb3 in tumors, and a 2-cyano-4nitrobenzene-1-sulfonyl group that was responsive to glutathione. 189 NG-cRGD incorporated a strong electronabsorbing group that effectively inhibited the breaking of CQC bonds and the associated phototoxicity. This led to the temporary inactivation and fluorescence burst of the photosensitizer.…”

Efficient hydroxyl radical generation of an activatable phthalocyanine photosensitizer: oligomer higher than monomer and nanoaggregate

“…1–3 Most photosensitizers (PSs), in clinical and preclinical settings, generate singlet oxygen ( 1 O 2 ) via the type II mechanism, which involves energy transfer between the excited triplet state ( 3 PS*) and O 2 . 4,5 Because of the abnormal proliferation of cancer cells, the limited O 2 supply severely hinders the efficacy of these PSs for PDT. 6–8 Distinguished from type II PSs, the type I PSs produce reactive oxygen species (ROS), 9–11 such as superoxide (O 2 ˙ − ), 12–18 hydroxyl radical (˙OH), 19 and hydrogen peroxide (H 2 O 2 ), 20,21 through an electron or hydrogen proton transfer process, with ˙OH being the most reactive.…”