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

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. & COPY; 2023 Published by Elsevier B.V. on behalf of Shenyang Pharmaceutical University. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ )

Automated summary

Arsenic trioxide (ATO) has been clinically used as a reliable and effective frontline drug for the treatment of acute promyelocytic leukemia (APL). However, its administration regimen is limited due to fast clearance, short therapeutic window, and toxicity. This study developed transferrin-modified liposomes encapsulating AsIII to improve its therapeutic efficacy. The AsIII-loaded liposomes exhibited acid-sensitive release and specifically targeted APL cells, leading to apoptosis and cell differentiation. Combining transferrin-modified retinoic acid liposomes further enhanced the tumor inhibition effect. The results suggest that transferrin-modified AsIII liposomes could be a novel clinical strategy for APL treatment with reduced systemic toxicity and improved efficacy.