CAFs Homologous Biomimetic Liposome Bearing BET Inhibitor and Pirfenidone Synergistically Promoting Antitumor Efficacy in Pancreatic Ductal Adenocarcinoma

Author:

Zhang Yin12ORCID,Yu Ranran3,Zhao Cheng1,Liang Jiawei12,Zhang Yixuan12ORCID,Su Haochen24,Zhao Jing12,Wu Hao12,Xu Shijin25,Zhang Ziying25,Wang Lei12,Zou Xiaoping12,Zhu Yun167,Zhang Shu12ORCID,Lv Ying12ORCID

Affiliation:

1. Department of Gastroenterology Nanjing Drum Tower Hospital The Affiliated Hospital of Nanjing University Medical School Nanjing Jiangsu Province 210008 P. R. China

2. Institute of Pancreatology Nanjing University Nanjing Jiangsu Province 210008 P. R. China

3. State Key Laboratory of Pharmaceutical Biotechnology School of Life Sciences Nanjing University Nanjing Jiangsu Province 210008 P. R. China

4. Department of Gastroenterology Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University Nanjing Jiangsu Province 210008 P. R. China

5. Department of Gastroenterology Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine Nanjing Jiangsu Province 210008 P. R. China

6. Department of Pharmacy Nanjing Drum Tower Hospital Drum Tower Clinical Medical College of Nanjing Medical University Nanjing Jiangsu Province 210008 P. R. China

7. Nanjing Medical Center for Clinical Pharmacy Nanjing Jiangsu Province 210008 P. R. China

Abstract

AbstractBRD4 is a member of the BET protein family involved in chromatin remodeling and transcriptional regulation. Several BET inhibitors (BETi) have entered clinical trials, demonstrating potential in inducing cancer cell apoptosis and tumor regression. However, resistance to BETi is common in solid tumors. In pancreatic cancer, it is found that cancer‐associated fibroblasts (CAFs) in the tumor microenvironment reduce the BET inhibitor JQ1 sensitivity by inducing BRD4 expression. Moreover, CAFs play a crucial role in the formation of a dense stromal barrier. Therefore, targeting CAFs in the tumor microenvironment of pancreatic cancer not only enhances cancer cells sensitivity to JQ1 but also increases drug perfusion and improves oxygen supply, thus reducing glycolysis and limiting energy supply. To address this challenge, a homologous targeting mechanism utilizing activated fibroblast membrane‐coated liposomes is proposed for specific drug precise target to CAFs‐rich pancreatic cancer. Additionally, TAT peptides enable liposomes penetration, delivering PFD for targeted anti‐fibrotic therapy, reducing extracellular matrix generation and glycolysis, and enhancing JQ1 delivery and sensitivity. In conclusion, the findings indicate the tremendous potential of this CAFs‐targeting liposomal delivery system in pancreatic cancer.

Funder

National Natural Science Foundation of China

Publisher

Wiley

Subject

General Physics and Astronomy,General Engineering,Biochemistry, Genetics and Molecular Biology (miscellaneous),General Materials Science,General Chemical Engineering,Medicine (miscellaneous)

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