Citation: Menghua Xiang, Fen Yang, Peng Chen, Jiaoyu Chen, Jianzhong Zhang, Jiayi Yang, Yilin Liu, Qianqian Zhang, Jiang Pi, Peiyan Yuan, Shao Q Yao, Liqian Gao. Tumor microenvironment-responsive self-assembled nanomedicine for reversible covalent targeting of BCR-ABL kinase[J]. Chinese Chemical Letters, ;2026, 37(2): 111423. doi: 10.1016/j.cclet.2025.111423 shu

Tumor microenvironment-responsive self-assembled nanomedicine for reversible covalent targeting of BCR-ABL kinase

Menghua Xiang ^{a, 1} ,
Fen Yang ^{b, 1} ,
Peng Chen ^c ,
Jiaoyu Chen ^a ,
Jianzhong Zhang ^a ,
Jiayi Yang ^b ,
Yilin Liu ^b ,
Qianqian Zhang ^b ,
Jiang Pi ^{b, *,} ,
Peiyan Yuan ^{a, *,} ,
Shao Q Yao ^{c, *,} ,
Liqian Gao ^{a, *,}

a.
School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China
b.
Dongguan Key Laboratory of Pathogenesis and Experimental Diagnosis of Infectious Diseases, School of Medical Technology, Guangdong Medical University, Dongguan 523808, China
c.
Department of Chemistry, National University of Singapore, Singapore 117543, Singapore

jiangpi@gdmu.edu.cn

yuanpy3@mail.sysu.edu.cn

chmyaosq@nus.edu.sg

gaolq@mail.sysu.edu.cn

Received Date: 25 March 2025
Revised Date: 4 June 2025
Accepted Date: 6 June 2025
Available Online: 7 June 2025

Figures(4)

Lysine-targeting reversible covalent inhibitors, particularly salicylaldehyde-based compounds such as the Food and Drug Administration (FDA)-approved drug Voxelotor, exhibit significant therapeutic potential but are limited by challenges including instability and off-target effects. To overcome these limitations in kinase inhibitor A5, we devised a pH-responsive prodrug strategy by masking its reactive aldehyde group with an acid-labile hydrazone linkage and enhancing intracellular delivery through conjugation with FK506. The optimized prodrug demonstrated robust antitumor efficacy in K562 tumor-bearing mice. Furthermore, the incorporation of the photosensitizer chlorin e6 (Ce6) led to the formation of self-assembled nanoparticles (AKNP), which not only improved physiological stability and prolonged tumor retention but also enabled light-triggered release of A5 in conjunction with photodynamic therapy (PDT). Our study thus presents a promising prodrug self-assembly strategy that combines the on-demand release of a novel lysine-targeting, reversible covalent kinase inhibitor with PDT in clinical cancer therapy.
- Reversible covalent inhibitor,
- Lysine-targeting,
- Prodrug,
- Self-assembled nanoparticle,
- Photodynamic therapy
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