CD71-mediated liposomal arsenic-nickel complex combined with all-trans retinoic acid for the efficacy of acute promyelocytic leukemia

Xiao Liu; Lili Zhang; Yueying Yang; Weiwei Yin; Yunhu Liu; Chunyi Luo; Ruizhe Zhang; Zhiguo Long; Yanyan Jiang; Bing Wang

doi:10.1016/j.ajps.2023.100826

CD71-mediated liposomal arsenic-nickel complex combined with all-trans retinoic acid for the efficacy of acute promyelocytic leukemia

Asian J Pharm Sci. 2023 Jul;18(4):100826. doi: 10.1016/j.ajps.2023.100826. Epub 2023 Jul 7.

Authors

Xiao Liu¹, Lili Zhang^{1

2}, Yueying Yang¹, Weiwei Yin¹, Yunhu Liu¹, Chunyi Luo¹, Ruizhe Zhang¹, Zhiguo Long³, Yanyan Jiang¹, Bing Wang^{2

4}

Affiliations

¹ Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201023, China.
² School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
³ Department of Hematology, Shanghai Pudong Hospital, Fudan University, Shanghai 201399, China.
⁴ Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.

Abstract

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^Ⅲ 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^Ⅲ in arsenic-nickel complex by nickel acetate gradient method. The As^Ⅲ-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 As^Ⅲ which stimulated reactive oxygen species level and caspase-3 activity. Tf-AsLP prolonged half-life of As^Ⅲ 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 As^Ⅲ liposome would be a novel clinical strategy to improve patient compliance, with promising translation prospects.

Keywords: Acute promyelocytic leukemia; All-trans retinoic acid; Arsenic trioxide; Liposome; Transferrin.