Drug carriers created based on the natural components can achieve targeted drug delivery through the inherent pathways, overcome the complicated in vivo environment and multiple internal barriers, improve the efficacy of approved drugs and expand the indications. Recently, Prof. Ding Ma group from Peking University collaborated with researchers from the Institute of Process Engineering (IPE) of the Chinese Academy of Sciences and Zhujiang Hospital of Southern Medical University, have confirmed that different forms of leukemia featured stable and strong expression of CD71, and developed a drug carrier with CD71 ligand ferritin (Fn), accomplished leukemia drug arsenic trioxide (ATO) efficiently loading in Fn (As@Fn) and targeted delivery to leukemia cells, which significantly inhibited a variety of leukemias and reduced the side effects of ATO. The study was published in Nature Nanotechnology (Ferritin-based targeted delivery of arsenic to diverse leukaemia types confers strong anti-leukaemia therapeutic effects，DOI: 10.1038//s41565-021-00980-7).
Leukemia is a severe threat to human health, with poor survival rates for both adults and children. In the clinic, chemotherapy is still the main therapeutic modality for all types of leukemia such as alkylating agents, antimetabolites, alkaloids and ATO, however inevitably induces off-target distribution and toxic side effects. Different therapeutic modalities have been established in clinic, but the overall treatment effect still needs to be improved.
New biomimetic delivery strategy was designed based on the endogenous feature of Fn and the FDA approval of AsIII. Through screening large numbers of clinical samples, researchers confirmed that CD71 expression was very low (positive expression ratio < 10%) among healthy red blood cells, lymphocytes, monocytes and granulocytes, while CD71 was highly expressed by leukemia cells (positive expression ratio > 90%). Leukemia cells featured stably elevated CD71 expression, thus CD71 can be used as a new and reliable target for the development of anti-leukemia precision therapies. On this basis, as CD71 ligand, Fn was used as a drug carrier for ATO targeted Leukemia therapy, which significantly enhanced the killing effect on leukemia cells while reducing the toxicity to normal tissues. As@Fn exhibit much superior anti-leukemia efficacies over ATO and other chemotherapy combination treatment, while few abnormalities were observed.
Current results are still pre-clinical studies, and the clinical efficacy still needs to be further verified. Given that Fn is an endogenous protein and ATO has been approved for clinical anti-leukemia use, As@Fn nanomedicine has the potential for clinical translation. The following R&D and transformation is still ongoing according to the relevant requirements.
Fig. 1 Potent anti-leukemia activity of As@Fn in patient-derived xenograft model: a) Schematic illustration of the experimental design used to evaluate anti-leukemia activity in vivo using ALL-PDX mice, b) WBC counting of leukemia-bearing mice, c) Body weight change curves of mice, d) Quantification of the frequency of leukemic blasts as a percentage of live cells in peripheral blood(PB), bone marrow (BM), and Spleen, e) Survival of mice from different treatment groups.
Current study is based on a new leukemia target, which is a potent carrier for targeted leukemia therapy with potential clinical translation. Prof. Ding Ma group fabricated the Ferritin-based Nanomedicine (As@Fn) and performed anti-leukemia cell attempts. Prof. Guanghui Ma and Prof. Wei Wei group systematically investigated As@Fn leukemia therapeutic efficacies both in vitro and in vivo, and collaborated with Prof. Yuhua Li did the clinical samples analysis. Changlong Wang from IPE of the Chinese Academy of Sciences, Dr. Wei Zhang from Peking University, and Yanjie He from Zhujiang Hospital of Southern Medical University contributed equally as first authors. Prof. Guanghui Ma, Prof. Ding Ma, Prof. Wei Wei and Prof. Yuhua Li are corresponding authors. This work is supported by the National Natural Science Foundation of China, the Strategic Priority Research Program of the Chinese Academy of Sciences, the National Key R&D Program of China, the Beijing National Laboratory for Molecular Sciences, the Open Funding Project of the State Key Laboratory of Biochemical Engineering, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, and the Natural Science Foundation of Guangdong Province.
Original link for the paper: https://www.nature.com/articles/s41565-021-00980-7
