A Novel Carrier-Free Spherical Nanomedicine for Acute Myeloid Leukemia.

内容摘要

Objective To develop a novel carrier-free spherical nanomedicine with daunorubicin(DNR)for combined chemotherapy of leukemia and systematically study its physicochemical properties,drug release behavior,and in vitro and in vivo therapeutic efficacy. Methods DNR was chemically conjugated with 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine(DOPE)for the self-assembly of nanoparticles,which were further loaded with cytarabine(Ara-C)to form DOPE-DNR Ara-C nanomedicine(DDA NPs)for combined chemotherapy of acute myeloid leukemia.The particle size and surface potential of DDA NPs were characterized by dynamic light scattering and zeta potential analysis.The drug release behavior in high-concentration glutathione(GSH)was studied through reduction-responsive drug release experiments.In vitro cytotoxicity assays were conducted to evaluate the inhibitory effect on leukemia cells,while a rat model of leukemia was used to assess the antitumor efficacy in vivo. Results DDA NPs exhibited a spherical nanostructure with a particle size of(123.67±0.11)nm and the zeta potential of(-25.60±0.67)mV,showing good stability under physiological conditions.High-concentration GSH effectively triggered disulfide bond cleavage,facilitating targeted drug release.In vitro,DDA NPs significantly enhanced drug accumulation in the nuclei of LT-12 leukemia cells and improved the cytotoxicity of DNR.The animal experiment showed that compared with free drugs,DDA NPs significantly reduced the number of leukemia cells in rat bone marrow,prolonged the survival,and effectively inhibited leukemia cell infiltration while alleviating organ damage. Conclusions DDA NPs as a novel carrier-free nanomedicine significantly enhanced drug delivery efficiency and synergistic therapeutic effects.It demonstrates good clinical translation potential and may provide a new therapeutic strategy for the treatment of acute myeloid leukemia. 目的 采用柔红霉素构建一种新型自载体球形纳米药物,用于白血病的联合化疗,并对其物理化学性质、药物释放行为以及体内外疗效进行系统研究。 方法 通过化学连接1,2-二油酰-sn-甘油-3-磷酸乙醇胺(DOPE)与柔红霉素(DNR),自组装形成纳米颗粒,并进一步负载阿糖胞苷(Ara-C)形成DOPE-DNR Ara-C 纳米药物(DDA NPs),以对急性髓系白血病进行联合化疗。通过动态光散射和Zeta电位分析对纳米药物的粒径和表面电位进行表征;采用还原响应的药物释放实验研究其在高浓度谷胱甘肽(GSH)下的药物释放行为;通过体外细胞实验评估其对白血病细胞的药物抑制效果;同时开展大鼠体内白血病模型实验,评估其抗肿瘤效果。 结果 DDA NPs粒径为(123.67±0.11)nm,Zeta电位为(-25.60±0.67)mV,在生理条件下表现出良好的稳定性。高浓度GSH能有效触发二硫键断裂,促进药物靶向释放。体外实验表明,DDA NPs显著促进了药物在LT-12白血病细胞核内的富集,并提高了柔红霉素对细胞杀伤作用。体内研究中,与游离药物组相比,DDA NPs处理组能够显著减少大鼠骨髓中白血病细胞的数量,延长生存期,并有效抑制白血病细胞浸润,减轻器官损伤。 结论 构建的DDA NPs作为一种新型无载体纳米药物,能够有效提高药物的递送效率及协同治疗效果,具有良好的临床转化潜力,有望为急性髓系白血病治疗提供一种新的治疗策略。.