Citation: Xuanbo Zhang, Feng Fang, Na Li, Huicong Zhang, Kaiyuan Wang, Zhiqiang Yu, Jin Sun. From reversible to irreversible: Albumin-hitchhiking gemcitabine prodrugs for enhanced antitumor efficacy and reduced toxicity[J]. Chinese Chemical Letters, ;2026, 37(2): 111452. doi: 10.1016/j.cclet.2025.111452 shu

From reversible to irreversible: Albumin-hitchhiking gemcitabine prodrugs for enhanced antitumor efficacy and reduced toxicity

Xuanbo Zhang ^{a, 1} ,
Feng Fang ^{c, 1} ,
Na Li ^b ,
Huicong Zhang ^{d, *,} ,
Kaiyuan Wang ^b ,
Zhiqiang Yu ^{a, *,} ,
Jin Sun ^{b, *,}

a.
The Tenth Affiliated Hospital, Southern Medical University (Dongguan People's Hospital), Dongguan 523058, China
b.
Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China
c.
Department of Obstetrics and Gynecology, Foshan Sanshui District People's Hospital (Sanshui Hospital, Zhujiang Hospital, Southern Medical University), Foshan 528100, China
d.
CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd., Shijiazhuang 050000, China

huicongzhangvip@163.com

yuzq@smu.edu.cn

sunjin@syphu.edu.cn

Received Date: 18 April 2025
Revised Date: 10 June 2025
Accepted Date: 12 June 2025
Available Online: 14 June 2025

Figures(4)

Albumin, owing to its high abundance and excellent biocompatibility, is widely used as a drug carrier to enhance delivery efficiency and reduce systemic toxicity. The Michael addition between albumin thiols and maleimide-functionalized prodrugs is a common in situ macromolecular prodrug strategy. However, the resulting reversible adducts are susceptible to retro-Michael reactions in vivo, leading to premature drug release and off-target effects. To address this limitation, a gemcitabine prodrug (GAB) bearing a chloroacetamide group was designed to form irreversible covalent bonds with albumin via nucleophilic substitution. A maleimide-based prodrug (GAM) was synthesized as a control. Compared to GAM, GAB showed faster and stronger albumin binding in plasma, enhanced blood circulation time, improved tumor accumulation, and superior in vivo antitumor efficacy. Moreover, GAB exhibited a better safety profile, with reduced cytotoxicity in normal tissues and no observable systemic toxicity. These advantages are attributed to the stable albumin-drug conjugate formed by GAB, which improves drug retention and targeted delivery. This study presents an effective and generalizable albumin-hitchhiking strategy for constructing irreversible prodrugs, offering a promising approach to enhance the therapeutic index of chemotherapeutic agents.
- Gemcitabine prodrugs,
- Albumin-hitchhiking,
- Cancer therapy,
- Macromolecular prodrug,
- Chemotherapy-associated toxicity
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