临床上，三氧化二砷（ATO）被应用于急性早幼粒细胞白血病（APL）的治疗，被认为是一种可靠和有效的一线药物。然而，由于AsⅢ的快速清除、短疗程和毒性，AsⅢ的给药方案受到限制。基于APL细胞上过表达的CD71，本研究首次通过乙酸镍梯度法建立了转铁蛋白（Tf）修饰的脂质体（LP），将AsⅢ封装在砷-镍配合物中。AsⅢ负载的脂质体（AsLP）在体外表现出酸敏释放的特点。Tf修饰的AsLP（Tf-AsLP）特异性地被APL细胞摄取，并由细胞内酸性环境触发脂质体释放AsⅢ，高水平的产生活性氧和caspase-3活性。Tf-AsLP延长了AsⅢ在血液循环中的半衰期，降低了全身毒性，并在体内诱导细胞凋亡和促进病灶处细胞分化。考虑到ATO与RA常常联合应用于APL治疗的一线选择，以提高治疗效果，因此，设计了转铁蛋白修饰的RA脂质体（Tf-RALP），以减少自由RA的严重副作用，协助Tf-AsLP取得更好的疗效。预期地，Tf-RALP的结合显著提高了Tf-AsLP对皮下肿瘤模型的肿瘤抑制率。此外，通过60CO照射和HL-60细胞静脉注射建立了APL同种异种移植的NOD/SCID小鼠模型。联合给药（Tf-AsLP+Tf-RALP）的效果也被证实明显减少了循环系统中的白血病细胞数量，并通过促进外周血和骨髓中APL细胞的凋亡和分化延长了APL小鼠的生存时间。总的来说，转铁蛋白修饰的酸敏感AsLP能够大大减少自由药物的全身毒性。此外，Tf-AsLP与Tf-RALP的联合可实现更好的疗效。因此，转铁蛋白修饰的AsⅢ脂质体将成为改善患者依从性的新型临床策略，并具有可靠的转译前景。© 2023 Shenyang Pharmaceutical University，由Elsevier B.V.代表其发表。

Clinically, arsenic trioxide (ATO) was applied to the treatment of acute promyelocytic leukemia (APL) as a reliable and effective frontline drug. However, the administration regimen of AsⅢ was limited due to its fast clearance, short therapeutic window and toxicity as well. Based on CD71 overexpressed on APL cells, in present study, a transferrin (Tf)-modified liposome (LP) was established firstly to encapsulate AsⅢ in arsenic-nickel complex by nickel acetate gradient method. The AsⅢ-loaded liposomes (AsLP) exhibited the feature of acid-sensitive release in vitro. Tf-modified AsLP (Tf-AsLP) were specifically taken up by APL cells and the acidic intracellular environment triggered liposome to release AsⅢ which stimulated reactive oxygen species level and caspase-3 activity. Tf-AsLP prolonged half-life of AsⅢ in blood circulation, lowered systemic toxicity, and promoted apoptosis and induced cell differentiation at lesion site in vivo. Considering that ATO combined with RA is usually applied as the first choice in clinic for APL treatment to improve the therapeutic effect, accordingly, a Tf-modified RA liposome (Tf-RALP) was designed to reduce the severe side effects of free RA and assist Tf-AsLP for better efficacy. As expected, the tumor inhibition rate of Tf-AsLP was improved significantly with the combination of Tf-RALP on subcutaneous tumor model. Furthermore, APL orthotopic NOD/SCID mice model was established by 60CO irradiation and HL-60 cells intravenously injection. The effect of co-administration (Tf-AsLP + Tf-RALP) was also confirmed to conspicuous decrease the number of leukemia cells in the circulatory system and prolong the survival time of APL mice by promoting the APL cells' apoptosis and differentiation in peripheral blood and bone marrow. Collectively, Tf-modified acid-sensitive AsLP could greatly reduce the systemic toxicity of free drug. Moreover, Tf-AsLP combined with Tf-RALP could achieve better efficacy. Thus, transferrin-modified AsⅢ liposome would be a novel clinical strategy to improve patient compliance, with promising translation prospects.© 2023 Published by Elsevier B.V. on behalf of Shenyang Pharmaceutical University.