Zhou Qing, Ma Hailong, Xu Hongling, Bai Yuyang, Tan Chang, Su Yangxue, Li Yang, Ying Xue, Zheng Yaxin
Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital of Chengdu Medical College, Nuclear Industry 416 Hospital, Chengdu 610051, China.
Key Laboratory of Structure-Specific Small Molecule Drugs at Chengdu Medical College of Sichuan Province, School of Pharmacy, Chengdu Medical College, Chengdu 610500, China.
Mol Pharm. 2025 Jun 2;22(6):3121-3131. doi: 10.1021/acs.molpharmaceut.5c00024. Epub 2025 Apr 28.
The aim of this study is to investigate the effects of prodrug activation rates on the in vivo drug release and antitumor activity of prodrug-entrapped liposomes. We performed such an investigation using two liposomes encapsulating hydrophilic SN38-glutathione (GSH) prodrugs (linked at 10- and 20-hydroxy of SN38) with different activation rates. The results showed that SN38-GSH was first released from liposomes and, consequently, activated into SN38. The SN38-GSH release rate from liposomes was similar, but the 10SN38-GSH activated much faster than 20SN38-GSH (, < 1 min versus ∼60 min) in plasma. Such different activation rates did not influence the prodrug's pharmacokinetics and biodistribution, but the fast prodrug activation rate resulted in 4-6-fold higher SN38 concentration in various organs and led to more potent antitumor efficacy. By contrast, the slowly activated SN38-GSH liposomes failed to exhibit potent antitumor activity, even at the maximum tolerance dose. Our data illustrated how the prodrug activation rate influences in vivo drug release and antitumor activity of prodrug-loaded liposomes, suggesting that sufficient prodrug activation is a prerequisite for potent prodrug-loaded liposomes.
本研究的目的是探讨前药活化速率对包载前药的脂质体在体内药物释放及抗肿瘤活性的影响。我们使用两种包载亲水性SN38-谷胱甘肽（GSH）前药（连接在SN38的10-和20-羟基上）且活化速率不同的脂质体进行了此项研究。结果显示，SN38-GSH首先从脂质体中释放出来，随后被活化为SN38。脂质体中SN38-GSH的释放速率相似，但在血浆中10SN38-GSH的活化速度比20SN38-GSH快得多（<1分钟对约60分钟）。这种不同的活化速率并未影响前药的药代动力学和生物分布，但前药的快速活化速率导致各器官中SN38浓度提高4至6倍，并产生更强的抗肿瘤疗效。相比之下，即使在最大耐受剂量下，活化缓慢的SN38-GSH脂质体也未能表现出强大的抗肿瘤活性。我们的数据阐明了前药活化速率如何影响包载前药的脂质体在体内的药物释放及抗肿瘤活性，表明足够的前药活化是包载前药的脂质体发挥强大作用的前提条件。
