Organelle-targeting activity-based hemicyanine derivatives for enhanced and selective type-I photodynamic therapy under hypoxia conditions†

Abstract

Type-I photosensitizers (PSs) have attracted great attention in recent years as they minimally rely on the tissue oxygen (³O₂) to generate highly cytotoxic reactive oxygen species (ROS) in the scope of photodynamic therapy (PDT). Thus, they hold great promise for effective treatment of hypoxic cancer cells, which is a challenging task for type-II PSs. However, compared to conventional type-II PSs, the number of cancer cell selective type-I PSs is quite low. Thus, there is still a need for type-I PSs that can induce photocytotoxicity only in cancer cells without causing damage to normal tissues even under light irradiation. Additionally, targeting PSs to specific organelles has lately appeared to be a promising approach to improve the therapeutic outcome of PDT. Although a few examples of organelle-targeted type-I PS cores have emerged recently, activity-based and organelle-targeted type-I PSs have remained scarce. In this study, we report two organelle-targeted and hydrogen sulfide (H₂S) responsive type-I PSs (HEHM and HEH) based on a highly modular and easily accessible heavy atom decorated hemicyanine core. HEHM localizes to mitochondria due to its cationic structure, whereas HEH targets endoplasmic reticulum (ER) as it bears an ER-targeting sulfonamide moiety, and it marks the first example of an activity-based and ER-targeted type-I PS based on a hemicyanine core. Both PSs can be selectively activated in neuroblastoma cells (SH-SY5Y) upon reacting with high levels of endogenous H₂S and induce similar photocytotoxicity through a type-I PDT mechanism under both normoxic (20% O₂) and hypoxic (1% O₂) conditions. HEHM is shown to cause PDT-induced mitochondria stress, while HEH triggers ER stress upon LED irradiation (640 nm, 66.7 mW cm⁻²). Additionally, HEH is shown to induce immunogenic cell death (ICD) followed by PDT action. In contrast, negligible ROS generation and cell death are observed in normal cells, which is a critical and challenging task for any type of therapeutic modality. They also allow fluorescence imaging of cancer cells due to their emissive nature, suggesting that they function as phototheranostic agents. This study introduces a rational approach to develop new generation activity-based and organelle-targeted type-I PDT agents towards effective and selective treatment of hypoxic tumors.