Related Experiment Video
Updated: Jun 3, 2025
Photodynamic Therapy with Blended Conducting Polymer/Fullerene Nanoparticle Photosensitizers
Published on: October 28, 2015
BRD4-targeted photodegradation nanoplatform for light activatable melanoma therapy
Shiman Lu1, Zhaoqing Shi1, Chendi Ding1
1State Key Laboratory of Advanced Medical Materials and Devices, Tianjin Key Laboratory of Biomedical Materials, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300192, China.
Abstract:
The targeted protein degradation (TPD) strategy modulates tumor growth pathways by degrading proteins of interest (POIs) and has reshaped anti-tumor drug research and development. Recently, the emergence of photodegradation-targeting chimeras (PDTACs) and laser irradiation at specific sites enables precise spatiotemporal controllability of TPD. Capitalizing on the advances of PDTACs, herein, we report a nanoplatform for efficiently delivering PDTAC molecule for photodegradation of bromodomain-containing protein 4 (BRD4) proteins, the key activators of oncogenic transcription. The PDTAC molecule, named as PPa-JQ1, is synthesized through the covalent attachment of the BRD4-targeting ligand JQ1-acid, to the photosensitizer pyropheophorbide-a (PPa), utilizing a 1,6-hexanediamine linker. The PPa-JQ1 is further encapsulated by human serum albumin (HSA) to obtain the HSA@PPa-JQ1 nanoplatform, which facilitates targeted and efficacious delivery to melanoma lesions. Both in vitro and in vivo therapeutic outcomes demonstrate that HSA@PPa-JQ1 can efficiently generate reactive oxygen species (ROS) to degrade BRD4 upon light irradiation, which eventually induces tumor death. Our study represents the first case to validate the anti-tumor therapeutic efficacy of PDTACs by systemic administration, providing the foundation for further application of PDTACs.
Insights
This study introduces a novel nanoplatform for targeted protein degradation, effectively degrading bromodomain-containing protein 4 (BRD4) in melanoma using light-activated drug delivery for cancer therapy.
Area of Science:
- Biochemistry
- Nanotechnology
- Oncology
Background:
- Targeted protein degradation (TPD) is a novel therapeutic strategy for cancer.
- Photodegradation-targeting chimeras (PDTACs) offer precise control over TPD.
- Bromodomain-containing protein 4 (BRD4) is a key activator of oncogenic transcription.
Purpose of the Study:
- To develop a nanoplatform for efficient delivery of PDTACs for BRD4 photodegradation.
- To evaluate the anti-tumor efficacy of the nanoplatform in melanoma.
- To establish the potential of systemically administered PDTACs for cancer therapy.
Main Methods:
- Synthesized a PDTAC molecule (PPa-JQ1) by conjugating a BRD4-targeting ligand (JQ1-acid) to a photosensitizer (pyropheophorbide-a).
- Encapsulated PPa-JQ1 within human serum albumin (HSA) to create the HSA@PPa-JQ1 nanoplatform.
- Evaluated in vitro and in vivo therapeutic effects, including reactive oxygen species (ROS) generation and BRD4 degradation upon light irradiation.
Main Results:
- The HSA@PPa-JQ1 nanoplatform demonstrated efficient delivery to melanoma lesions.
- Light irradiation of HSA@PPa-JQ1 induced ROS generation and subsequent BRD4 degradation.
- Significant tumor cell death was observed, indicating therapeutic efficacy.
Conclusions:
- The HSA@PPa-JQ1 nanoplatform effectively targets and degrades BRD4 in melanoma via light-activated TPD.
- This study is the first to validate the anti-tumor efficacy of systemically administered PDTACs.
- The findings provide a foundation for the clinical application of PDTACs in cancer treatment.
