依托泊苷（VP16）可导致治疗相关性白血病，长期剂量方案似乎较少发生该情况。因此，我们假设纳米载体可以通过减少VP16接触速率来减少VP16引起的白血病发生率，以实现持续缓释药物释放。为验证我们的假设，采用谷胱甘肽梯度加载法将VP16-马来酰亚胺共轭体迅速包裹入脂质体，构建了具有缓慢药物释放行为的VP16负载脂质体，并将其毒性和体内抗肿瘤效力与游离VP16在LLC肺癌异种移植动物模型中进行了比较。结果发现，多次注射游离VP16导致严重脾肿大，淋巴细胞增多，并在各种组织中出现广泛的淋巴细胞浸润，表明为VP16治疗相关性白血病症状。相比之下，脂质体VP16不仅显著缓解了白血病发生的综合征，而且与相同剂量的游离VP16相比，其抗肿瘤活性也显著增强。这些结果突出了持续缓释的脂质体VP16能够有效降低白血病发生的毒性，为开发脂质体VP16作为一种安全替代商用VP16注射剂提供了新的保证。版权所有© 2023 Elsevier B.V. 保留所有权利。

Etoposide (VP16) can induce therapy-related leukemia, which is reported to occur less frequently with a prolonged dose schedule. Therefore, we hypothesized that nanocarriers could decrease the VP16-induced leukemogenesis by reducing the rate of VP16 exposure via a sustained drug release. To test our hypothesis, the VP16-loaded liposome with a slow drug release behavior was constructed by encapsulating a rapidly-cleaved VP16-maleimide conjugate into liposomes using a glutathione-gradient loading method, and its toxicities and in vivo antitumor efficacy were compared with free VP16 in the LLC lung cancer xenograft. It was found that the repeated injection of free VP16 induced severe splenomegaly, lymphocytosis, and extensive lymphocyte infiltration in various tissues, indicating a sign of VP16 therapy-related leukemia. By contrast, the liposomal VP16 not only remarkably alleviated the syndrome of leukemogenesis, but also exhibited significantly enhanced antitumor activity as compared with free VP16 at the same dose. These results highlighted that the liposomal VP16 having a sustained drug release could effectively decrease the toxicity of leukemogenesis, which provided a new warranty to develop liposomal VP16 as a safe alternative to the commercial VP16 injection.Copyright © 2023 Elsevier B.V. All rights reserved.