Piperazine and Morpholine Protoporphyrin IX Derivatives Intensify Biomolecules Oxidation and Phototoxicity in Triple‐Negative Breast Cancer

Abstract

Photodynamic therapy (PDT) is a clinically established approach that relies on the localized generation of reactive oxygen species (ROS) mediated by a photosensitizer (PS), light, and molecular oxygen. Protoporphyrin IX (PpIX) is an approved PS; however, its intracellular retention is limited, factor that can alter its overall photodynamic efficiency. In this study, we report how the design of PpIX derivatives bearing piperazine (PpIX‐Pip) or morpholine (PpIX‐Morp) substituents may modulate lipophilicity, cellular uptake, oxidative stress, and phototoxicity. The photodynamic activity of these derivatives was evaluated in the aggressive triple‐negative human breast cancer cell line MDA‐MB‐231. Both derivatives showed greater time‐dependent cellular retention and enhanced photodynamic activity compared to PpIX, promoting oxidative stress, and triggering loss of mitochondrial membrane potential and caspase‐3 activation. These results highlight the impact of rational structural modification of PpIX on photodynamic efficiency and provide valuable structure–activity relationship insights for the development of improved porphyrin‐based PS for PDT.