Citation: Qing-Hua Chen, Da-Yong Hou, Ni-Yuan Zhang, Jia-Qi Wang, Rui Zheng, Xing-Jie Hu, Xiu-Hai Wu, Li Yi, Ying-Jin Zhang, Guang-Xu Zhang, Yu-Juan Gao, Ben-Li Song, Rui Wang, Jian-Xiao Liang, Ming-Ze Cai, Yu Wang, Jia-Yuan Niu, Li-Ying Wang, Yang Yang, Hao-Ze Li, Hong-Wei An, Lei Wang, Yuliang Zhao, Hao Wang. Systemic study on anti-tumor activity of HER2 induced peptide-drug conjugate clustering in xenograft tumor models[J]. Chinese Chemical Letters, ;2026, 37(5): 111257. doi: 10.1016/j.cclet.2025.111257 shu

Systemic study on anti-tumor activity of HER2 induced peptide-drug conjugate clustering in xenograft tumor models

Qing-Hua Chen ^{a, b, d, 1} ,
Da-Yong Hou ^{a, 1} ,
Ni-Yuan Zhang ^{a, d, 1} ,
Jia-Qi Wang ^a ,
Rui Zheng ^{a, d} ,
Xing-Jie Hu ^a ,
Xiu-Hai Wu ^a ,
Li Yi ^{a, d} ,
Ying-Jin Zhang ^a ,
Guang-Xu Zhang ^a ,
Yu-Juan Gao ^a ,
Ben-Li Song ^{a, d} ,
Rui Wang ^{a, d} ,
Jian-Xiao Liang ^{a, d} ,
Ming-Ze Cai ^a ,
Yu Wang ^a ,
Jia-Yuan Niu ^a ,
Li-Ying Wang ^a ,
Yang Yang ^a ,
Hao-Ze Li ^a ,
Hong-Wei An ^{a, d} ,
Lei Wang ^{a, c, d} ,
Yuliang Zhao ^{a, b, c, d} ,
Hao Wang ^{a, b, c, d, *,}

a.
CAS Center for Excellence in Nanoscience, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), Beijing 100190, China
b.
Sino-Danish College, Sino-Danish Center for Education and Research, University of Chinese Academy of Sciences, Beijing 100049, China
c.
Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing 100049, China
d.
University of Chinese Academy of Sciences, Beijing 100049, China

wanghao@nanoctr.cn

Received Date: 7 December 2024
Revised Date: 23 April 2025
Accepted Date: 24 April 2025
Available Online: 24 April 2025

Figures(4)

Target therapy represents a paradigm shift to a precise and personalized approach. Unlike the great success of antibody-drug conjugate (ADC) in clinical practice, peptide-drug conjugate (PDC) with good tissue penetration and drug loading capacity exhibits poor stability, quick blood clearance and cellular internalization that limit their translation. In this study, a feasible approach for constructing an in vivo self-assembling peptide-drug conjugate (sPDC) was proposed by rationally designing the combination of tumor-specific targeting peptide module, responsive self-assembling peptide module, and therapeutic drug. Two optimized sPDCs (sPDC1 and sPDC2) capable of specifically targeting human epidermal growth factor receptor 2 (HER2) on the surface of tumors were reported. sPDCs could selectively target HER2-positive tumors and effectively kill HER2 overexpressing tumor cells. In addition, weak but significant efficacy of sPDCs was also observed in HER2-negative tumors, which was likely by-stander effect due to the release of monomethyl auristatin E (MMAE) in the tumor microenvironment. Finally, in HER2-positive xenograft mouse models, sPDC1 showed superior therapeutic efficacy over the clinical HER2-targeted therapeutic agents trastuzumab and lapatinib, and roughly equivalent therapeutic efficacy compared with RC48 even in large tumor-bearing mouse models. Therefore, sPDC1 was promising to serve as a lead compound for further clinical development for oncology therapy.
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沈阳化工大学材料科学与工程学院沈阳 110142