A TME-enlightened protein-binding photodynamic nanoinhibitor for highly effective oncology treatment
Zepeng Cui1, Baoxuan Huang1, Jiahao Zheng1
1Shanghai Key Laboratory of Functional Materials Chemistry, School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai 200237, People's Republic of China.
Abstract:
The efficiency of photodynamic therapy (PDT) is greatly dependent on intrinsic features of photosensitizers (PSs), but most PSs suffer from narrow diffusion distances and short life span of singlet oxygen (1O2). Here, to conquer this issue, we propose a strategy for in situ formation of complexes between PSs and proteins to deactivate proteins, leading to highly effective PDT. The tetrafluorophenyl bacteriochlorin (FBC), a strong near-infrared absorbing photosensitizer, can tightly bind to intracellular proteins to form stable complexes, which breaks through the space-time constraints of PSs and proteins. The generated singlet oxygen directly causes the protein dysfunction, leading to high efficiency of PSs. To enable efficient delivery of PSs, a charge-conversional and redox-responsive block copolymer POEGMA-b-(PAEMA/DMMA-co-BMA) (PB) was designed to construct a protein-binding photodynamic nanoinhibitor (FBC@PB), which not only prolongs blood circulation and enhances cellular uptake but also releases FBC on demand in tumor microenvironment (TME). Meanwhile, PDT-induced destruction of cancer cells could produce tumor-associated antigens which were capable to trigger robust antitumor immune responses, facilitating the eradication of residual cancer cells. A series of experiments in vitro and in vivo demonstrated that this multifunctional nanoinhibitor provides a promising strategy to extend photodynamic immunotherapy.
Insights
This study introduces a novel photodynamic therapy (PDT) approach using photosensitizers (PSs) that form complexes with proteins. This strategy enhances PDT efficiency and triggers antitumor immune responses for improved cancer treatment.
Area of Science:
- Biomedical Engineering
- Photochemistry
- Immunology
Background:
- Photodynamic therapy (PDT) efficacy is limited by photosensitizer (PS) diffusion and singlet oxygen (¹O₂) lifespan.
- Developing strategies to overcome these limitations is crucial for enhancing PDT effectiveness.
Purpose of the Study:
- To develop a novel protein-binding photodynamic nanoinhibitor for enhanced PDT.
- To investigate the potential of this nanoinhibitor in triggering antitumor immune responses.
Main Methods:
- Synthesized a tetrafluorophenyl bacteriochlorin (FBC) photosensitizer.
- Designed a charge-conversional, redox-responsive block copolymer (PB) for nanoinhibitor construction (FBC@PB).
- Evaluated FBC@PB performance in vitro and in vivo for PDT and immunomodulation.
Main Results:
- FBC forms stable complexes with intracellular proteins, overcoming space-time constraints.
- The FBC@PB nanoinhibitor demonstrated efficient delivery, enhanced cellular uptake, and on-demand FBC release in the tumor microenvironment (TME).
- PDT induced by FBC@PB triggered robust antitumor immune responses via tumor-associated antigens.
Conclusions:
- In situ protein-PS complex formation offers a highly effective PDT strategy.
- The developed multifunctional nanoinhibitor shows promise for photodynamic immunotherapy.
- This approach addresses key limitations of traditional PDT, paving the way for advanced cancer treatments.
