Trapped in Cells: A Selective Accumulation Approach for Type-I Photodynamic Ablation of Cancer Stem–like Cells

Aldehyde dehydrogenase (ALDH) is an enzyme responsible for converting aldehyde functional groups into carboxylate metabolites. Elevated ALDH activity is a characteristic feature of cancer stem-like cells (CSCs). As a novel approach to target the CSC trait of overexpressing ALDH, we aimed to utilize ALDH activity for the selective accumulation of a photosensitizer in ALDH^High CSCs. A novel ALDH substrate photosensitizer, <b>SCHO</b>, with thionylated coumarin and <i>N</i>-ethyl-4-(aminomethyl)benzaldehyde was developed to achieve this goal. Our study demonstrated the efficient metabolism of the aldehyde unit of <b>SCHO</b> into carboxylate, leading to its accumulation in ALDH^High MDA-MB-231 cells. Importantly, we established the selectivity of <b>SCHO</b> as an ALDH^High cell photosensitizer as it is not a substrate for ABC transporters. <b>SCHO</b>-based photodynamic therapy triggers apoptosis and pyroptosis in MDA-MB-231 cells and further reduces the characteristics of CSCs. Our study presents a novel strategy to target CSCs by exploiting their cellular metabolism to enhance photosensitizer accumulation, highlighting the potential of photodynamic therapy as a powerful tool for eliminating ALDH^High CSCs.