Li Jinyang, Lu Jiasheng, Huang Xin, Ding Yuan, Zhou Jianfen, Chen Ruohan, Jiang Zhixuan, Fan Xingyan, Yang Yilin, Liao Chongbing, Lu Weiyue, Lu Wuyuan
Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Fudan University, Shanghai 200030, China.
Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education and PLA, Shanghai 201203, China.
J Control Release. 2025 Aug 10;384:113899. doi: 10.1016/j.jconrel.2025.113899. Epub 2025 May 29.
The combination chemotherapy of cytarabine and daunorubicin (7 + 3 standard regimen) has stood as the mainstay treatment against acute myeloid leukemia for decades. Recent advances in nanomedicine have led to the development of Vyxeos®, a liposomal formulation of cytarabine/daunorubicin fixed in a synergistic 5:1 molar ratio. The synchronized pharmacokinetics and biodistribution of the partner chemotherapeutic agents in Vyxeos® contribute to a significantly higher complete remission rate compared to the traditional 7 + 3 regimen. However, Vyxeos® did not markedly enhance the safety profile, exhibiting similar types and severities of adverse events. To mitigate adverse reactions as well as intensify 7 + 3 combination chemotherapy, we leveraged a functionalization strategy, engineering a humanized anti-CD33 antibody-modified liposome carrier to actively co-deliver cytarabine and daunorubicin. Differing from DSPC/DSPG-based liposomal formulation of Vyxeos®, we developed a PEGylated HSPC liposome with high cholesterol content to proportionally co-load the two agents. Surface reaction via maleimide-thiol chemistry realized anti-CD33 antibody functionalization, demonstrating superior in-vivo therapeutic efficacy compared to plain liposomal drug formulations (p < 0.001) and moderately reduced non-specific adverse effects in the heart and kidneys.
几十年来，阿糖胞苷和柔红霉素联合化疗（7 + 3标准方案）一直是治疗急性髓系白血病的主要方法。纳米医学的最新进展催生了Vyxeos®，这是一种阿糖胞苷/柔红霉素的脂质体制剂，其摩尔比为协同的5:1。Vyxeos®中联合化疗药物的同步药代动力学和生物分布，使其完全缓解率相比传统的7 + 3方案显著提高。然而，Vyxeos®并未显著改善安全性，其不良事件的类型和严重程度相似。为了减轻不良反应并强化7 + 3联合化疗，我们采用了一种功能化策略，设计了一种人源化抗CD33抗体修饰的脂质体载体，以主动共递送阿糖胞苷和柔红霉素。与基于DSPC/DSPG的Vyxeos®脂质体制剂不同，我们开发了一种高胆固醇含量的聚乙二醇化HSPC脂质体来按比例共负载这两种药物。通过马来酰亚胺-硫醇化学进行表面反应实现了抗CD33抗体功能化，与普通脂质体药物制剂相比，其体内治疗效果更佳（p < 0.001），且心脏和肾脏的非特异性不良反应有所减轻。
