Discovery of ALA-hydroxypyridinone hybrids: novel strategies for photodynamic therapy against superficial tumours

Superficial tumours can be effectively treated with photodynamic therapy (PDT), which is characterised by its targeted approach and enhanced safety profile. 5-aminolevulinic acid (ALA), a precursor to the endogenous photosensitiser PpIX, has been widely utilised in PDT. However, its high hydrophilicity, poor permeability and stability, necessitates structural modifications to improve its drug-like properties and increase the PpIX yield. Hydroxypyridinone (HPO) iron chelators can synergistically enhance PpIX production when administered in conjunction with ALA, as well as inducing tumour cell death through iron chelation. Consequently, this study designed a series of novel ALA-HPO derivatives, functioning as dual prodrugs to elevate intracellular PpIX levels and enhance photodynamic anti-tumour effects. The optimised compound AP-8 displayed the highest phototoxicity and greatest PpIX yield, demonstrating superior photodynamic anti-tumour efficacy compared to ALA in a mouse melanoma model, with a TGI of 84.74%. These findings underscore the potent application potential of ALA-HPO derivatives in PDT.