AIE-Active Photosensitizer APT NPs with Type I/II ROS Generating Orchestrate the DDIT4-Centric Gene-Metabolite Axis
Zhen Fang1,2,3, Mei Li2,3, Yali Mai1
1NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China.
ACS Applied Materials & Interfaces
|December 16, 2025
Summary
A novel organic photosensitizer, APT nanoparticles, effectively treats tumors via photodynamic therapy (PDT) even in low-oxygen conditions. It targets cancer cell death by disrupting gene and metabolic pathways, showing promise for hypoxia-insensitive cancer treatment.
Area of Science:
- Biochemistry
- Materials Science
- Oncology
Background:
- Photodynamic therapy (PDT) faces challenges due to photosensitizer oxygen dependence and unclear mechanisms.
- Developing novel photosensitizers is crucial for advancing tumor treatment strategies.
Purpose of the Study:
- To design and synthesize a novel aggregation-induced emission (AIE) active Schiff base photosensitizer (APT) for hypoxia-insensitive PDT.
- To elucidate the multi-omics mechanism of action for APT nanoparticles (NPs) in cancer therapy.
Main Methods:
- Synthesis and characterization of the APT photosensitizer and its nanoparticles.
- In vitro evaluation of cytotoxicity and reactive oxygen species (ROS) generation.
- Multi-omics analysis to identify molecular targets and pathways affected by APT NPs.
- In vivo antitumor efficacy assessment in a mouse model.
Main Results:
- APT NPs exhibit efficient generation of Type I and Type II ROS, leading to potent phototoxicity under hypoxic conditions.
- In vitro studies showed minimal dark toxicity and significant light-induced cytotoxicity (IC50 = 4.61 μM) in MCF-7 cells.
- APT NPs upregulate DDIT4, inhibit mTORC1 signaling, downregulate oncogenic drivers (FOS, Bcl-2), and disrupt amino acid biosynthesis, causing cell cycle arrest and apoptosis.
- In vivo studies demonstrated significant antitumor efficacy in a mouse model with no major side effects.
Conclusions:
- APT NPs represent a novel, hypoxia-insensitive photosensitizer for effective photodynamic therapy.
- The study reveals a unique mechanism involving transcriptional and metabolic regulation, highlighting the therapeutic potential of AIE-active materials in cancer treatment.
