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Carrier-Free Nano-PROTACs to Amplify Photodynamic Therapy Induced DNA Damage through BRD4 Degradation
Lin-Ping Zhao1,2, Xiao-Na Rao3, Rong-Rong Zheng3
1Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou 510700, People's Republic of China.
Abstract:
Therapy-induced DNA damage is the most common strategy to inhibit tumor cell proliferation, but the therapeutic efficacy is limited by DNA repair machinery. Carrier-free nanoproteolysis targeting chimeras (PROTACs), designed as SDNpros, have been developed to enhance photodynamic therapy (PDT) by blocking the DNA damage repair pathway through BRD4 degradation. Specifically, SDNpros are constructed through noncovalent interactions between the photosensitizer of chlorine e6 (Ce6) and PROTACs of BRD4 degrader (dBET57) via self-assembly. SDNpro has favorable dispersibility and a uniform nanosize distribution without drug excipients. Upon light irradiation, SDNpro produces abundant reactive oxygen species (ROS) to induce DNA oxidative damage. Meanwhile, the DNA repair pathway would be interrupted by the concurrent degradation of BRD4, which could intensify the oxidative DNA damage and elevate PDT efficiency. Beneficially, SDNpro suppresses tumor growth and avoids systemic side effects, providing a promising strategy to promote the clinical translation of PROTACs for tumor treatment.
Insights
New nanomedicine combines photodynamic therapy with proteolysis targeting chimeras (PROTACs) to degrade BRD4, blocking DNA repair and enhancing cancer treatment. This approach improves photodynamic therapy (PDT) efficacy by inhibiting tumor cell proliferation.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Therapy
Background:
- Therapy-induced DNA damage is a common cancer treatment, but its efficacy is limited by DNA repair mechanisms.
- Photodynamic therapy (PDT) uses light-activated compounds to generate reactive oxygen species (ROS) for cancer treatment.
- Proteolysis targeting chimeras (PROTACs) offer a novel approach to degrade specific proteins, including those involved in DNA repair.
Purpose of the Study:
- To develop carrier-free nanoproteolysis targeting chimeras (SDNpros) to enhance PDT by inhibiting DNA damage repair.
- To investigate the self-assembly of chlorine e6 (Ce6) and a BRD4 degrader (dBET57) into SDNpros.
- To evaluate the efficacy of SDNpros in inducing DNA oxidative damage and suppressing tumor growth.
Main Methods:
- SDNpros were synthesized via self-assembly of Ce6 and dBET57.
- Nanoparticle characterization included dispersibility and size distribution analysis.
- The combined effect of ROS generation and BRD4 degradation on DNA damage and tumor suppression was assessed in vitro and in vivo.
Main Results:
- SDNpros exhibited favorable dispersibility and uniform nanosize distribution without excipients.
- Light irradiation of SDNpros generated ROS, inducing DNA oxidative damage.
- Concurrent BRD4 degradation by SDNpros interrupted DNA repair pathways, enhancing PDT efficiency and suppressing tumor growth.
- SDNpros demonstrated reduced systemic side effects compared to conventional therapies.
Conclusions:
- SDNpros represent a promising strategy for enhancing PDT by simultaneously inducing DNA damage and inhibiting DNA repair.
- The developed nanomedicine effectively suppresses tumor growth with minimal side effects.
- This approach holds potential for advancing the clinical translation of PROTACs in cancer therapy.
