“Dual-boosting” strategy to enhance radical generation of photosensitizer for mitochondria-targeted phototherapy”

Background

Photodynamic therapy (PDT) uses photosensitizers that generate reactive oxygen species (ROS) upon light irradiation to kill tumor cells. Conventional type-II photosensitizers rely on oxygen to produce singlet oxygen (¹O₂), which limits their efficacy in hypoxic tumors. In contrast, type-I photosensitizers generate superoxide radicals (•O₂⁻) and hydroxyl radicals (•OH) through electron-transfer processes and are less dependent on oxygen, making them more effective under low-oxygen conditions.

Mitochondria, central organelles in cellular energy metabolism and oxidative stress regulation, are ideal targets for PDT. Enrichment of photosensitizers in mitochondria can induce in situ oxidative damage, disrupt mitochondrial function, and trigger tumor cell apoptosis, while potentially reducing the required photosensitizer dose and systemic side effects. Accordingly, developing mitochondria-targeted type-I photosensitizers is a promising strategy for improving PDT efficacy against hypoxic tumors.

Research Progress

To enhance the type-I PDT efficacy of mitochondria-targeted photosensitizers, Prof. Lin Li's team at the School of Flexible Electronics, Northwestern Polytechnical University, has constructed a series of cationic pyrido cyanines with a (D-π)_n-A architecture (n = 1,2,3), namely McL1, McL2, and McL3. Increasing the donor/π-bridge branches enhanced intramolecular charge transfer, enabling McL3 to exhibit a broader visible-light absorption range and a smaller singlet-triplet energy gap (ΔE_S1-T3 =0.24 eV). Consequently, its •O₂⁻ production was 4.2-fold higher than that of McL1.

McL3 was subsequently self-assembled with human serum albumin (HSA) to form McL3@HSA nanoparticles with an average size of approximately 40 nm. Benefiting from the confinement effect of the HSA binding pocket, the ΔE_S1-T2 value of McL3@HSA was further reduced to 0.08 eV, increasing its •O₂⁻ generation to 20.3-fold that of McL1. Mechanistic studies indicate that HSA confinement modulates molecular conformation and promotes intersystem crossing (ISC) efficiency from 33% to 52% and ultimately enabling highly efficient type-I ROS generation.

Cellular studies and investigations in a subcutaneous transplantation model in nude mice demonstrated that McL3@HSA possesses excellent mitochondrial-targeting capability. Upon white-light irradiation, it efficiently generated •O₂⁻ and •OH, induced mitochondrial structural damage, and maintained potent apoptosis and tumor growth inhibitory effects under hypoxic conditions.

Future Prospects

This study achieves a “dual-boosting” of ROS generation through multi-branched donor/π-bridge molecular design and HSA confinement, while elucidating the underlying mechanism by which these strategies cooperatively regulate excited-state dynamics. These findings offer a new approach to developing mitochondria-targeted theranostic molecules and high-performance Type-I photosensitizers, with the potential to advance their translation into biomedical applications.

Sources: https://spj.science.org/doi/10.34133/research.1279