Harnessing Hypoxia‐Dependent Cyanine Photocages for In Vivo Precision Drug Release

Abstract

Photocaging holds promise for the precise manipulation of biological events in space and time. However, current near‐infrared (NIR) photocages are oxygen‐dependent for their photolysis and lack of timely feedback regulation, which has proven to be the major bottleneck for targeted therapy. Herein, we present a hypoxia‐dependent photo‐activation mechanism of dialkylamine‐substituted cyanine (Cy‐NH) accompanied by emissive fragments generation, which was validated with retrosynthesis and spectral analysis. For the first time, we have realized the orthogonal manipulation of this hypoxia‐dependent photocaging and dual‐modal optical signals in living cells and tumor‐bearing mice, making a breakthrough in the direct spatiotemporal control and in vivo feedback regulation. This unique photoactivation mechanism overcomes the limitation of hypoxia, which allows site‐specific remote control for targeted therapy, and expands the photo‐trigger toolbox for on‐demand drug release, especially in a physiological context with dual‐mode optical imaging under hypoxia.

Taking phototherapeutics from concept to clinical launch

“…Oxygen dependency limits the utility of this scaffold in hypoxic settings, such as the tumour microenvironment. However, an analogue of the cyanine scaffold has recently been described that operates independently of oxygen by employing a photoinduced electron transfer drug release mechanism 71 . Finally, the incorporation of a cyanine-based caged chemotherapeutic onto an antibody 67 and in micelles 71 demonstrates the feasibility of using this chromophore in carrier-based constructs.…”

Rational design of stable heptamethine cyanines and development of a biomarker-activatable probe for detecting acute lung/kidney injuries via NIR-II fluorescence imaging

“…The poor stability is often associated with long conjugated polyenes such as heptamethine cyanines, 7,9,[30][31][32] and it would be ideal if their stability could be improved, which surely would be conducive to their broad usage in the biomedical field. Therefore, the chemostability of HP-N1, HP-N2 and HP-N3 towards various oxidizing (e.g., H 2 O 2 ) and reducing (e.g., GSH) agents was evaluated in aqueous solutions.…”

Development of Photoremovable Linkers as a Novel Strategy to Improve the Pharmacokinetics of Drug Conjugates and Their Potential Application in Antibody–Drug Conjugates for Cancer Therapy

“…Nonetheless, the photolysis reliance of cyanine fluorophore scaffold on the concentration of singlet oxygen in the tumor tissue is the major factor that hinders the application of this type of linker under hypoxia conditions, which is more often the case in many tumor tissues. Recently, photocage P(Cy-N-CPT) (55), a hypoxia suitable dialkylamine-substituted cyanine (Cy-NH) linker, was developed by Zhang et al [58]. This diblock copolymer can be activated under acidic conditions in a hypoxic tumor environment and undergoes the subsequent photolysis for cleavage.…”