A nuclear targeted dual-photosensitizer for drug-resistant cancer therapy with NIR activated multiple ROS
Zhengze Yu1, Wei Pan1, Na Li1
1College of Chemistry , Chemical Engineering and Materials Science , Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong , Key Laboratory of Molecular and Nano Probes , Ministry of Education , Shandong Provincial Key Laboratory of Clean Production of Fine Chemicals , Shandong Normal University , Jinan 250014 , P. R. China .
Abstract:
Photodynamic therapy against cancer, especially multidrug resistant cancer, is limited seriously due to the efflux of photosensitizer molecules by P-glycoprotein, which leads to insufficient production of reactive oxygen species (ROS). For the purpose of abundant ROS generation and effective therapeutic response, herein, we firstly design and fabricate a nuclear targeted dual-photosensitizer for photodynamic therapy against multidrug resistant cancer. Molecule-photosensitizer Ce6 was selected and modified on the surface of core/shell structure nano-photosensitizer upconversion@TiO2 and then nuclear targeted peptides TAT were anchored for nuclear targeting. Through selective doping of rare earth elements Er and Tm, multiple ROS (˙OH, O2˙-, and 1O2) can be generated for the dual-photosensitizer and realize their functions synergistically using a single 980 nm NIR excitation. The nano-sized photosensitizer accompanied with nuclear targeting can effectively generate multiple ROS in the nucleus regardless of P-glycoprotein and directly break DNA double strands, which is considered as the most direct and serious lesion type for cytotoxic effects. Therefore, enhanced photodynamic therapy can be achieved against multidrug resistant cancer. In vitro and in vivo studies confirmed the excellent therapeutic effect of the dual-photosensitizer against cancer cells and drug-resistant cancer cells, as well as xenograft tumor models.
Insights
This study developed a nuclear-targeted dual-photosensitizer to overcome drug-resistant cancers. The novel nanoparticle generates abundant reactive oxygen species (ROS) within cancer cell nuclei, enhancing photodynamic therapy effectiveness.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Photodynamic Therapy
Background:
- Photodynamic therapy (PDT) efficacy against multidrug-resistant (MDR) cancer is hindered by photosensitizer efflux mediated by P-glycoprotein.
- Insufficient reactive oxygen species (ROS) production limits therapeutic outcomes in conventional PDT for MDR cancers.
Purpose of the Study:
- To design and fabricate a nuclear-targeted dual-photosensitizer for enhanced PDT against MDR cancer.
- To achieve abundant ROS generation within the nucleus, overcoming P-glycoprotein-mediated resistance.
Main Methods:
- A core/shell nanostructure (upconversion@TiO2) was modified with the photosensitizer Ce6 and nuclear-targeting peptide TAT.
- Rare earth elements (Er, Tm) were doped to enable synergistic generation of multiple ROS (•OH, O2•−, 1O2) under 980 nm near-infrared (NIR) excitation.
- In vitro and in vivo studies were conducted using cancer cells, drug-resistant cancer cells, and xenograft tumor models.
Main Results:
- The nuclear-targeted dual-photosensitizer effectively accumulated in cancer cell nuclei.
- Synergistic ROS generation within the nucleus was achieved, leading to direct DNA double-strand breaks.
- Significant therapeutic effects were observed against both cancer cells and drug-resistant cancer cells, including xenograft tumor models.
Conclusions:
- The developed nuclear-targeted dual-photosensitizer offers a promising strategy to overcome P-glycoprotein-mediated resistance in PDT for MDR cancer.
- This approach enhances ROS production and induces direct DNA damage, leading to improved anti-cancer therapeutic efficacy.
- The findings support the potential of this novel nanoplatform for advanced cancer treatment.
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