Liu Xiao, Zhang Lili, Yang Yueying, Yin Weiwei, Liu Yunhu, Luo Chunyi, Zhang Ruizhe, Long Zhiguo, Jiang Yanyan, Wang Bing
Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201023, China.
School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Asian J Pharm Sci. 2023 Jul;18(4):100826. doi: 10.1016/j.ajps.2023.100826. Epub 2023 Jul 7.
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 As 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 As in arsenic-nickel complex by nickel acetate gradient method. The As-loaded liposomes (AsLP) exhibited the feature of acid-sensitive release . Tf-modified AsLP (Tf-AsLP) were specifically taken up by APL cells and the acidic intracellular environment triggered liposome to release As which stimulated reactive oxygen species level and caspase-3 activity. Tf-AsLP prolonged half-life of As in blood circulation, lowered systemic toxicity, and promoted apoptosis and induced cell differentiation at lesion site . 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 CO 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 As liposome would be a novel clinical strategy to improve patient compliance, with promising translation prospects.
临床上，三氧化二砷（ATO）作为一种可靠且有效的一线药物应用于急性早幼粒细胞白血病（APL）的治疗。然而，由于其清除速度快、治疗窗口短以及毒性，砷的给药方案受到限制。基于APL细胞上CD71的过表达，在本研究中，首先通过醋酸镍梯度法构建了转铁蛋白（Tf）修饰的脂质体（LP），以将砷包裹在砷镍复合物中。载砷脂质体（AsLP）具有酸敏性释放的特性。Tf修饰的AsLP（Tf-AsLP）被APL细胞特异性摄取，酸性的细胞内环境触发脂质体释放砷，进而刺激活性氧水平和半胱天冬酶-3活性。Tf-AsLP延长了砷在血液循环中的半衰期，降低了全身毒性，并促进了病变部位的细胞凋亡和诱导细胞分化。考虑到ATO联合全反式维甲酸（RA）在临床上通常作为APL治疗的首选以提高治疗效果，因此，设计了一种Tf修饰的RA脂质体（Tf-RALP）以减少游离RA的严重副作用，并辅助Tf-AsLP提高疗效。正如预期的那样，在皮下肿瘤模型中，Tf-AsLP与Tf-RALP联合使用时，肿瘤抑制率显著提高。此外，通过钴照射和静脉注射HL-60细胞建立了APL原位NOD/SCID小鼠模型。联合给药（Tf-AsLP + Tf-RALP）的效果也得到证实，通过促进外周血和骨髓中APL细胞的凋亡和分化，显著减少循环系统中的白血病细胞数量，并延长APL小鼠的存活时间。总体而言，Tf修饰的酸敏性AsLP可大大降低游离药物的全身毒性。此外，Tf-AsLP与Tf-RALP联合使用可取得更好的疗效。因此，转铁蛋白修饰的砷脂质体将是一种改善患者依从性的新型临床策略，具有广阔的转化前景。
