MitoGPS: A Mitochondrial DNA G-Quadruplex-Targeting Strategy for Tumor-Preferential Type I Photodynamic Therapy

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Therapy

Background:

• Photodynamic therapy (PDT) shows promise for cancer treatment but faces challenges with tumor-specific drug accumulation and off-target toxicity.
• Preferential accumulation of photosensitizers (PSs) in tumors is crucial for enhancing therapeutic efficacy and minimizing side effects.

Purpose of the Study:

• To develop a rational design framework, mitoGPS (mitochondrial G-quadruplex-targeting photosensitizer), for creating PSs with enhanced intratumoral retention.
• To leverage mitochondrial DNA G-quadruplexes (mtDNA G4s) for targeted accumulation and action of PSs within tumor mitochondria.

Main Methods:

• Integrated molecular generation, G4-specific docking simulations, and evaluation of photosensitizing properties to discover mitoGPS compounds.
• Designed and identified A1, a lead mitoGPS compound, through a modular workflow.
• Assessed mitochondrial localization, retention influenced by mtDNA G4 interactions, and reactive oxygen species (ROS) generation of A1.

Main Results:

• The lead compound A1 demonstrated preferential mitochondrial localization in tumor cells.
• A1's retention was significantly influenced by interactions with mtDNA G4s.
• Upon light activation, A1 predominantly generated Type I ROS, inducing mitochondrial oxidative stress, apoptosis, and ferroptosis.

Conclusions:

• The mitoGPS strategy effectively targets mtDNA G4s for improved subcellular precision in PDT.
• This approach offers a generalizable framework for developing mitochondria-directed phototherapies with enhanced tumor-specific action.
• Targeting mtDNA G4s represents a viable strategy to enhance PDT efficacy and reduce toxicity.