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A self-delivery photodynamic sensitizer for enhanced DNA damage by PARP inhibition
Ren-Jiang Kong1, Xin-Yu Li1, Jia-Qi Huang1
1School of Biomedical Engineering & Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Southern Medical University, Guangzhou 510515, P. R. China. chengh@smu.edu.cn.
Abstract:
Tumor cells activate DNA repair pathways to combat the oxidative damage induced by reactive oxygen species (ROS), contributing to their resistance to photodynamic therapy (PDT). Herein, a self-delivery photodynamic sensitizer is developed to enhance oxidative damage by blocking the DNA repair pathway through poly(ADP-ribose) polymerase (PARP) inhibition. Specifically, the photodynamic sensitizer (CeOla) is constructed based on the self-assembly of the photosensitizer chlorine e6 (Ce6) and the PARP inhibitor olaparib (Ola). Of note is that carrier free CeOla has a high drug content and favorable water stability, which could be effectively internalized by tumor cells for robust PDT upon light irradiation. Moreover, CeOla could inhibit the activation of PARP, promote the upregulation of γ-H2AX and reduce the expression of Rad51, thereby blocking the DNA repair pathway to sensitize tumor cells for PDT. As a consequence, the self-delivery CeOla greatly promotes the tumor cell apoptosis and shows a high antitumor performance with low side effects. It serves as a novel platform for the development of self-delivery nanomedicine to overcome oxidative resistance in tumor treatment.
Insights
This study developed a self-delivery photodynamic sensitizer (CeOla) that inhibits DNA repair by blocking poly(ADP-ribose) polymerase (PARP). This approach enhances photodynamic therapy (PDT) effectiveness against tumors.
Area of Science:
- Biomedical Engineering
- Nanomedicine
- Cancer Therapy
Background:
- Tumor cells resist photodynamic therapy (PDT) by activating DNA repair pathways against reactive oxygen species (ROS).
- Inhibiting DNA repair mechanisms presents a strategy to overcome this therapeutic resistance.
Purpose of the Study:
- To develop a self-delivery photodynamic sensitizer that enhances oxidative damage by inhibiting DNA repair via poly(ADP-ribose) polymerase (PARP) inhibition.
- To evaluate the efficacy of this novel nanomedicine in sensitizing tumor cells to PDT and improving antitumor performance.
Main Methods:
- Constructed a self-delivery photodynamic sensitizer (CeOla) through self-assembly of chlorine e6 (Ce6) and olaparib (Ola).
- Investigated CeOla's internalization by tumor cells, its effect on PARP activation, DNA repair markers (γ-H2AX, Rad51), and PDT-induced oxidative damage.
- Assessed the antitumor efficacy and side effects of CeOla-mediated PDT in vitro and in vivo.
Main Results:
- Carrier-free CeOla exhibited high drug content and water stability, facilitating tumor cell internalization.
- CeOla effectively inhibited PARP activation, upregulated γ-H2AX, and reduced Rad51 expression, thus blocking DNA repair.
- CeOla-mediated PDT significantly promoted tumor cell apoptosis and demonstrated high antitumor activity with minimal side effects.
Conclusions:
- The self-delivery CeOla acts as a potent nanomedicine platform for overcoming tumor oxidative resistance in PDT.
- This strategy effectively sensitizes cancer cells to PDT by concurrently inducing oxidative damage and inhibiting DNA repair.
- CeOla holds promise for developing advanced nanotherapeutics for enhanced cancer treatment.
