CD38-Directed Vincristine Nanotherapy for Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Although intensive chemotherapy greatly improved the survival rate, it is often accompanied by severe and lifelong side effects as a result of weak ALL selectivity. The intensive and poorly selective chemotherapy is also detrimental to patients' immune system. There is an urgent need to develop more selective and less toxic chemotherapy for ALL. Here, we report daratumumab-polymersome-vincristine (DP-VCR) as a CD38-directed nanotherapy for ALL. DP-VCR showed selective uptake in CD38-positive 697 and Nalm-6-Luc ALL cells and potent anti-ALL activity with an IC₅₀ as low as 0.06 nM VCR, which was 13.7-fold more potent than free VCR. In contrast, no toxicity to human peripheral blood mononuclear cells was detected for DP-VCR even at 108.3 nM VCR. The apoptotic assays confirmed a high selectivity of DP-VCR to CD38-positive ALL cells. DP-VCR exhibited superior treatment of both 697 and Nalm-6-Luc orthotopic ALL models to all controls, as revealed by significant survival benefit and marked reduction of leukemia burden in bone marrow, blood, spleen, and liver. Importantly, DP-VCR induced few side effects. DP-VCR emerges as a safe and potent nanotherapy for CD38-positive ALL.