Open AccessMulti‐Arm PEG/Peptidomimetic Conjugate Inhibitors of DR6/APP Interaction Block Hematogenous Tumor Cell Extravasation
Author(s) -
Wang Liting,
Shen Qing,
Liao Hongze,
Fu Hao,
Wang Qi,
Yu Jian,
Zhang Wei,
Chen Chuanrong,
Dong Yang,
Yang Xupeng,
Guo Qianqian,
Zhang Jiali,
Zhang Jian,
Zhang Wei,
Lin Houwen,
Duan Yourong
Publication year - 2021
Publication title -
advanced science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.388
H-Index - 100
ISSN - 2198-3844
DOI - 10.1002/advs.202003558
Subject(s) - extravasation , necroptosis , peptidomimetic , in vivo , phage display , in vitro , conjugate , cancer research , peg ratio , chemistry , pharmacology , medicine , peptide , programmed cell death , immunology , biochemistry , biology , apoptosis , mathematical analysis , microbiology and biotechnology , mathematics , finance , economics
The binding of amyloid precursor protein (APP) expressed on tumor cells to death receptor 6 (DR6) could initiate the necroptosis pathway, which leads to necroptotic cell death of vascular endothelial cells (ECs) and results in tumor cells (TCs) extravasation and metastasis. This study reports the first inhibitor of DR6/APP interaction as a novel class of anti‐hematogenous metastatic agent. By rationally utilizing three combined strategies including selection based on phage display library, d ‐retro‐inverso modification, and multiple conjugation of screened peptidomimetic with 4‐arm PEG, the polymer–peptidomimetic conjugate PEG‐tAHP‐DRI (tetra‐(D‐retro‐inverso isomer of AHP‐12) substitued 4‐arm PEG 5k ) is obtained as the most promising agent with the strongest binding potency ( K D = 51.12 × 10 −9 m ) and excellent pharmacokinetic properties. Importantly, PEG‐tAHP‐DRI provides efficient protection against TC‐induced ECs necroptosis both in vitro and in vivo. Moreover, this ligand exhibits prominent anti‐hematogenous metastatic activity in serval different metastatic mouse models (B16F10, 4T1, CT26, and spontaneous lung metastasis of 4T1 orthotopic tumor model) and displays no apparent detrimental effects in preliminary safety evaluation. Collectively, this study demonstrates the feasibility of exploiting DR6/APP interaction to regulate hematogenous tumor cells transendothelial migration and provides PEG‐tAHP‐DRI as a novel and promising inhibitor of DR6/APP interaction for developments of anti‐hematogenous metastatic therapies.