Cationic Engineering of Photosensitizers Drives Mitochondrial Targeting and Enhanced ROS-Based Tumor Phototherapy

Area of Science:

• Biochemistry
• Materials Science
• Oncology

Background:

• Photodynamic therapy (PDT) shows promise for cancer treatment but faces challenges with inefficient reactive oxygen species (ROS) generation and poor subcellular targeting.
• Developing strategies to enhance ROS production and direct therapeutic agents to specific cellular components is crucial for improving PDT efficacy.

Purpose of the Study:

• To investigate cationic engineering of aggregation-induced emission (AIE) photosensitizers (PS) for enhanced mitochondrial targeting and ROS-amplified photodynamic tumor therapy.
• To precisely regulate molecular charge density to optimize excited-state energetics and ROS generation.

Main Methods:

• Stepwise conversion of a neutral AIE photosensitizer into monocationic (PS-Bu) and dicationic (PS-PPh) derivatives.
• Evaluation of cationic modification effects on excited-state energetics, intersystem crossing, and Type I/II ROS generation under visible-light irradiation.
• Assessment of mitochondrial accumulation, membrane depolarization, intracellular ROS levels, cell-cycle arrest, and apoptosis in HepG2 cells.

Main Results:

• Cationic modification of the photosensitizer enhanced intersystem crossing and promoted both Type I and Type II ROS generation.
• Increased positive charge led to preferential mitochondrial accumulation, causing membrane depolarization and amplified intracellular ROS.
• PS-PPh demonstrated significantly enhanced phototoxicity against HepG2 cells with minimal dark toxicity, and superior in vivo tumor growth suppression in xenograft models.

Conclusions:

• Cationic engineering effectively enhances mitochondrial targeting and ROS amplification for improved photodynamic cancer therapy.
• The developed photosensitizers show potential for effective and safe tumor treatment with reduced proliferation, enhanced apoptosis, and alleviated tumor hypoxia.
• This study presents cationic modulation as a valuable molecular design strategy for developing advanced mitochondria-targeted PDT agents.