Arsenic–ferritin delivery system displays strong anti-leukaemia effect

Using a specifically developed arsenic–ferritin complex, researchers have potentially developed a new targeted delivery system for the treatment of several leukaemias.

Leukaemia can be either acute i.e., fast-growing or chronic (slow growing) and there are two main subgroups of acute leukaemia; acute lymphoblastic leukaemia (ALL), frequently diagnosed in children and young adults and acute myeloid leukaemia (AML), which is the most common type in adults.¹

Treatments for AML have increased in recent years, although the cancer has a number of phenotypes and both primary and secondary drug resistance is a problem for many patients.² One form of treatment for promyelocytic leukaemia, which is a subtype of AML, is trivalent arsenic (arsenic trioxide, ATO) which is an apoptosis-inducing agent.³ However, while ATO appears to be effective, a potential difficulty is that the intracellular concentration of the ion within cancerous cells has been found to vary between different form of leukaemia, making it is a less reliable treatment in practice.⁴ 

In previous work, a team from China had shown that one common feature of different leukaemia cell lines, is over-expression of cell surface receptor termed ‘human transferrin receptor 1’ (or CD71) and which facilitates the supply of iron into cells upon binding with iron-loaded ferritin. The ferritin molecule itself is a spherical shaped and can serve as a nanocarrier for encapsulated iron oxide particles into peripheral tumours and be used as a treatment for cancer.⁵ For the latest study, the Chinese team used the ferritin carrier into which they inserted trivalent arsenic and tested whether this arsenic-ferritin complex, was able to deliver the ion into leukaemia cells.⁶ 

In their study, the team used animal models to confirm that CD71 was preferentially over expressed on the surface of the cells from different forms of leukaemia, i.e., AML, ALL and chronic myeloid leukaemia in comparison with normal lymphocytes. Secondly, they explored whether the trivalent arsenic could be easily released from the ferritin complex once bound and endocytosed by leukaemia cells. Using HL60 cells, the half-maximum inhibitory concentration value for the arsenic–ferritin complex was 4.9-fold lower than that of conventional arsenic trioxide. Once this had been confirmed, the team measured the concentration of arsenic within cells derived from 167 patients with different leukaemias, it was shown that the arsenic–ferritin complex, released the trivalent ion and led to its accumulation within leukaemia cells. 

In their conclusion, the authors noted that the results demonstrated how CD71 was a suitable target because it was preferentially over-expressed in all the forms of leukaemias, even at different stages of the disease. 

They suggested that the arsenic–ferritin complex has the potential to become a useful therapy that requires further clinical evaluation in different forms of leukaemia.

References

1. Lhermitte LL et al. Automated database-guided expert-supervised orientation for immunophenotypic diagnosis and classification of acute leukemia. Leukemia 2018;32:874–81. 
2. Advances in the treatment of acute myeloid leukemia: new drugs and new challenges. Cancer Discov 2020;10:506–25.
3. Yedjou C et al. Basic mechanisms of arsenic trioxide (ATO)-induced apoptosis in human leukemia (HL-60) cells. J Hematol Oncol 2010;3:28. 
4. Sahu GR, Jena RK. Significance of intracellular arsenic trioxide for therapeutic response in acute promyelocytic leukemia. Am J Hematol 2005;78:113–16.
5. Fan K et al. Ferritin nanocarrier traverses the blood brain barrier and kills glioma. ACS Nano 2018;12:4105–15.
6. Wang C et al. Ferritin-based targeted delivery of arsenic to diverse leukaemia types confers strong anti-leukaemic therapeutic effects. Nat Nanotechnol 2021 doi.org/10.1038/s41565-021-00980-7