Conformation-driven fluorocarbon-powered zinc(II) phthalocyanine for photodynamic therapy in hypoxic tumors via anti-aggregation, oxygen retention, and enhanced cellular uptake

Zinc(II) phthalocyanine (ZnPc)-based photosensitizers hold great potential for photodynamic therapy (PDT), but their efficacy is often hindered by aggregation, tumor hypoxia, and limited cellular uptake. Despite extensive research, effective strategies to simultaneously address these challenges through molecular modification of ZnPc remain scarce. In this study, we designed a series of α-position-engineered ZnPc derivatives incorporating fluorocarbon chains (FCs) and tetraethylene glycol (TEG) segments to simultaneously reduce π–π stacking, improve oxygen delivery, and enhance cellular internalization. By optimizing the spatial arrangement of TEG and FCs, and systematically tuning the FC length and substitution degree, we identified ZT₄F₃₍₈₎ as an optimized compound that strikes an ideal balance between aqueous dispersibility and oxygen-carrying capacity, resulting in efficient reactive oxygen species (ROS) generation under hypoxia. Additionally, the strong hydrophobic-lipophobic character of the FCs facilitates membrane penetration, thereby promoting efficient cellular uptake of ZnPc derivatives. As a result, ZT₄F₃₍₈₎ exhibited excellent tumor accumulation and potent tumor inhibition (78.5%) in vivo. Molecular dynamics simulations revealed that the compound maintains a partially anti-aggregated structure, stabilized by steric shielding and intra-cluster FC folding. The results position ZT₄F₃₍₈₎ as a promising candidate for next-generation PDT agents, offering robust therapeutic efficacy and favorable safety profiles.