Vincristine/Volasertib polymersome injection enables high-efficiency synergistic treatment of acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL), one of the most frequently diagnosed malignancies in children, is associated with a high relapse rate and drug resistance, even with intensive multidrug chemotherapy regimens. The rational combination with molecular targeted agents holds promise for sensitizing patients to chemotherapies and overcoming drug resistance. However, precise codelivery of different drugs in vivo is challenging, often leading to suboptimal therapeutic effects. Herein, we report a vincristine/volasertib polymersome (Ps-VCR/Vol)-based nanocombo for synergistic inhibition of microtubules and polo-like kinase 1, enabling high-efficacy treatment of ALL in vivo. Ps-VCR/Vol, which has a small size (∼26 nm) and tailored VCR/Vol mass ratios from 1:12 to 1:48, exhibited strong synergy in different ALL cells, with 3.3-6.8-fold greater anti-ALL activity than the free VCR/Vol combination. Intriguingly, treatment with Ps-VCR/Vol at a VCR/Vol dosage of 0.25/6 mg/kg markedly inhibited leukemia progression and invasion in orthotopic CCRF-CEM, Nalm-6-Luc and patient-derived xenograft ALL mouse models without inducing toxicity, resulting in a significantly prolonged survival time compared with that of the free drug combination and single-drug polymersome formulations. Ps-VCR/Vol polymersome injection provides a powerful synergistic combination therapy for ALL. STATEMENT OF SIGNIFICANCE: Multidrug combination therapies have increased the remission rates of acute lymphoblastic leukemia (ALL) patients. However, the therapeutic efficacy remains suboptimal due to the dissimilar physicochemical properties of the different drugs involved, and overlapping toxicities pose a critical concern. Herein, we show that intelligent polymersomes mediate the precise codelivery of vincristine sulfate (VCR), a frontline drug for ALL, and volasertib (Vol), a polo-like kinase 1 inhibitor, enabling synergistic treatment of ALL. Compared with free VCR/Vol, VCR/Vol polymersomes with tailored drug ratios substantially inhibited leukemia progression in both cell line- and patient-derived orthotopic ALL models without inducing toxicity, leading to a significant survival benefit. This synergistic polymersome injection may provide a powerful and safe combination therapy for ALL patients.