TAT-Modified Gold Nanoparticles Enhance the Antitumor Activity of PAD4 Inhibitors

Songlin Song,1,2 Lin Gui,1,2 Qiqi Feng,1,2 Ayijiang Taledaohan,1,2 Yuanming Li,3 Wei Wang,4 Yanming Wang,5 Yuji Wang1,2 1School of Pharmaceutical Sciences of Capital Medical University, Beijing 100069, People’s Republic of China; 2Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Beijing 100069, People’s Republic of China; 3Minimally Invasive Tumor Therapies Center, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, 100730, People’s Republic of China; 4Department of Chemistry, University of Bergen, Bergen, Norway; 5School of Life Sciences, Henan University, Kaifeng 475004, People’s Republic of ChinaCorrespondence: Yuji WangSchool of Pharmaceutical Sciences of Capital Medical University, Beijing 100069, People’s Republic of ChinaTel +86 10 83950236Email wangyuji@ccmu.edu.cnPurpose: Histone citrullination by peptidylarginine deiminases 4 (PAD4) regulates the gene expression of tumor suppressor. In our previously study, YW3-56 (356) was developed as a potent PAD4 inhibitor for cancer therapy with novel function in the autophagy pathway. To enhance the antitumor activity, the PAD4 inhibitor 356 was modified by the well-established cationic penetrating peptide RKKRRQRRR (peptide TAT) and gold nanoparticles to obtain 356-TAT-AuNPs which could enhance the permeability of chemical drug in solid tumor.Methods: 356-TAT-AuNPs were prepared, and their morphology were characterized. The antitumor activity of 356-TAT-AuNPs was evaluated in vitro and in vivo.Results: 356-TAT-AuNPs exhibited higher anticancer activity against HCT-116, MCF-7 and A549 cells than 356 and 356-AuNPs. Compared with 356 and 356-AuNPs, 356-TAT-AuNPs entered the cytoplasm and nuclear, exhibited stronger anticancer activity by increasing apoptosis, inducing autophagy and inhib