Achieving a localised effect of chemotherapy confined to the tumour site remains a major challenge in cancer treatment. Despite significant advances in targeted and precision medicine, many drugs still fail to discriminate between malignant and healthy cells, leading to narrow therapeutic windows and systemic toxicity. Therefore, novel therapeutic approaches that selectively direct drugs to the tumour site are needed. In addition, eliminating cancer stem cells (CSCs) remains a critical hurdle. Although they constitute a minority of the tumour, CSCs play a key role in patient relapse – they are resistant to standard chemotherapy and are capable of regenerating the tumour. Due to their close resemblance to healthy stem cells, selective treatments targeting CSCs remain scarce. For instance, while growing evidence supports a key role of autophagy in maintaining CSCs in solid tumours, the protective role of this process in normal cells raises safety concerns for autophagy inhibition.
In this context, photopharmacology emerges as a promising solution.1 It is based on using light to modulate the biological activity of drugs with high precision, employing two possible designs: photoswitches and photocages. In the latter, a bioactive molecule is rendered inactive by chemical modification; upon illumination, the active drug is released.
We have recently developed photocaged derivatives of the autophagy inhibitor chloroquine. Our lead molecule (caged-CQ) efficiently releases active chloroquine upon blue-light irradiation within less than one minute. Caged-CQ displayed a light-dependent effect in breast and head and neck cancer cell lines, showing activity only after illumination, but not in the dark. Moreover, in CSC-enriched sphere models, caged-CQ disrupted sphere formation exclusively following illumination. Finally, to demonstrate translational potential, we showed that caged-CQ can be uncaged within tumours in an orthotopic breast cancer mouse model.
