A dual-targeting peptide-drug conjugate based on CXCR4 and FOLR1 inhibits triple-negative breast cancer.

Kun WANG; Cong WANG; Hange YANG; Gong CHEN; Ke WANG; Peihong JI; Xudong SUN; Xuegong FAN; Jie MA; Zhencun CUI; Xingkai WANG; Hao TIAN; Dengfu WU; Lu WANG; Zhimin WANG; Jiangyan LIU; Juan YI; Kuan HU; Hailong ZHANG; Rui WANG

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A dual-targeting peptide-drug conjugate based on CXCR4 and FOLR1 inhibits triple-negative breast cancer.

Author: Kun WANG ¹ ; Cong WANG ² ; Hange YANG ² ; Gong CHEN ² ; Ke WANG ² ; Peihong JI ² ; Xudong SUN ² ; Xuegong FAN ² ; Jie MA ³ ; Zhencun CUI ⁴ ; Xingkai WANG ¹ ; Hao TIAN ¹ ; Dengfu WU ¹ ; Lu WANG ³ ; Zhimin WANG ⁵ ; Jiangyan LIU ⁴ ; Juan YI ² ; Kuan HU ¹ ; Hailong ZHANG ² ; Rui WANG ¹
Author Information

1. State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100000, China.
2. Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences & Research Unit of Peptide Science, Chinese Academy of Medical Sciences, 2019RU066, Lanzhou University, Lanzhou 730000, China.
3. Center of Cyclotron and PET Radiopharmaceuticals, Department of Nuclear Medicine & Key Laboratory of Basic and Translational Research on Radiopharmaceuticals, the First Affiliated Hospital of Jinan University, Guangzhou 510630, China.
4. Department of Nuclear Medicine, Second Hospital of Lanzhou University, Lanzhou 730000, China.
5. PET/CT Center of Gansu Provincial Hospital, Lanzhou 730000, China.
Publication Type:Journal Article
Keywords: Antitumor; CXCR4; FOLR1; Monomethyl auristatin E; Peptide–drug conjugate; Radiotherapy; Triple-negative breast cancer; Tumor microenvironment
From: Acta Pharmaceutica Sinica B 2025;15(10):4995-5009
CountryChina
Language:English
Abstract: Triple-negative breast cancer is therapeutically challenging due to the low expression of tumor markers and 'cold' tumor immunosuppressive microenvironment. Here, we present a dual-targeting peptide-drug conjugate (PDC) for tumor inhibition. Our PDC efficiently and selectively delivers cytotoxic Monomethyl Auristatin E (MMAE) into tumor cells via C-X-C chemokine receptor type 4 (CXCR4) and folate receptor 1 (FOLR1) for synergistic inhibition of growth and metastasis. Our results show that the dual-targeting PDC has potent antitumor activity in cultured human cells and several murine transplanted tumor models without apparent toxicity. The combination of dual-targeting PDC and radiotherapy modulates the tumor immunosuppressive microenvironment by increasing CD8⁺ T cell infiltration and attenuating the proportion of myeloid-derived suppressor and regulatory T cells. Therefore, our dual-targeting PDC represents a promising new strategy for cancer therapy that rebalances the immune system and promotes tumor regression.