PROTAC-loaded nanocapsules degrading BRD4 for radio-chemotherapy sensitization in glioblastoma.
10.1016/j.apsb.2025.03.018
- Author:
Yun GUO
1
;
Mingzhu FANG
1
;
Shilin ZHANG
1
;
Zheng ZHOU
1
;
Zonghua TIAN
1
;
Haoyu YOU
1
;
Yun CHEN
1
;
Jingyi ZHOU
1
;
Xiaobao YANG
2
;
Yunke BI
3
;
Chen JIANG
1
;
Tao SUN
1
Author Information
1. Key Laboratory of Smart Drug Delivery/Innovative Center for New Drug Development of Immune Inflammatory Diseases (Ministry of Education), Minhang Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, China.
2. Gluetacs Therapeutics (Shanghai) Co., Ltd., Shanghai 201306, China.
3. Department of Neurosurgery, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200025, China.
- Publication Type:Journal Article
- Keywords:
BRD4;
DNA damage repair;
GSH responsive;
Glioblastoma;
Nanocapsules;
Nanosensitizer;
PROTAC;
Radiotherapy
- From:
Acta Pharmaceutica Sinica B
2025;15(10):5050-5070
- CountryChina
- Language:English
-
Abstract:
Glioblastoma (GBM) is a highly aggressive primary brain tumor characterized by poor prognosis. Conventional chemo-radiotherapy demonstrates limited therapeutic efficacy and is often accompanied by significant side effects, largely due to factors such as drug resistance, radiation resistance, the presence of the blood-brain barrier (BBB), and the activation of DNA damage repair mechanisms. There is a pressing need to enhance treatment efficacy, with BRD4 identified as a promising target for increasing GBM sensitivity to therapy. Lacking small molecule inhibitors, BRD4 can be degraded using PROteolysis Targeting Chimera (PROTAC), thereby inhibiting DNA damage repair. To deliver PROTAC, SIAIS171142 (SIS) effectively, we designed a responsive nanocapsule, MPL(SS)P@SIS, featuring GBM-targeting and GSH-responsive drug release. Modified with 1-methyl-l-tryptophan (MLT), nanocapsules facilitate targeted delivery of SIS, downregulating BRD4 and sensitizing GBM cells to radiotherapy and chemotherapy. After intravenous administration, MPL(SS)P@SIS selectively accumulates in tumor tissue, enhancing the effects of radiotherapy and temozolomide (TMZ) by increasing DNA damage and oxidative stress. GSH activates the nanocapsules, triggering BRD4 degradation and hindering DNA repair. In mouse models, the nanosensitizer, combined with TMZ and X-ray irradiation, efficiently inhibited the growth of GBM. These findings demonstrate a novel PROTAC-based sensitization strategy targeting BRD4, offering a promising approach for effective GBM therapy.
