FF-10850是一种基于二氢鞘磷脂的顶替卡铂治疗难治或复发性卵巢癌的脂质体拓扑替卡铂。然而，FF-10850对于快速清除和造血毒性等临床限制具实际意义。为克服这些限制并最大程度提高临床效果，我们设计了FF-10850。在细胞系基因携带的卵巢癌模型和临床相关的DF181铂难治性卵巢癌患者源性移植模型中，FF-10850显示出了优于拓扑替卡铂的抗肿瘤活性。其安全性也得到改善，使造血毒性得以缓解。增强的抗肿瘤活性和改善的安全性是通过其在肿瘤微环境中的优先积累和荷载释放所实现的。我们的数据表明，肿瘤相关巨噬细胞摄取FF-10850，导致完全的荷载释放。荷载释放机制似乎也由肿瘤代谢重编程引起的高氨浓度介导。在富含氨的条件下，FF-10850比目前批准用于卵巢癌的脂质体阿霉素更快速且更大程度释放荷载。FF-10850在小鼠移植模型中与卡铂或PARP抑制剂的联合应用显著增强了抗肿瘤活性，并且与抗PD-1抗体结合后发展出肿瘤抗原特异性免疫的协同抗肿瘤活性。这些结果支持FF-10850在固体肿瘤治疗中，包括卵巢癌（NCT04047251）的Ⅰ期临床研究，并在联合治疗方案中进行进一步评估。

Topotecan, an approved treatment for refractory or recurrent ovarian cancer, has clinical limitations such as rapid clearance and hematological toxicity. To overcome these limitations and maximize clinical benefit, we designed FF-10850, a dihydrosphingomyelin-based liposomal topotecan. FF-10850 demonstrated superior anti-tumor activity to topotecan in ovarian cancer cell line-based xenograft models, as well as in a clinically relevant DF181 platinum-refractory ovarian cancer patient-derived xenograft model. The safety profile was also improved with mitigation of hematological toxicity. The improved anti-tumor activity and safety profile are achieved via its preferential accumulation and payload release triggered in the tumor microenvironment. Our data indicate that tumor-associated macrophages internalize FF-10850, resulting in complete payload release. The release mechanism also appears to be mediated by high ammonia concentration resulting from glutaminolysis, which is activated by tumor metabolic reprogramming. In ammonia-rich conditions, FF-10850 released payload more rapidly and to a greater extent than liposomal doxorubicin, a currently approved treatment for ovarian cancer. FF-10850 significantly enhanced anti-tumor activity in combination with carboplatin or PARP inhibitor without detrimental effects on body weight in murine xenograft models, and demonstrated synergistic anti-tumor activity combined with anti-PD-1 antibody with the development of tumor antigen-specific immunity. These results support phase Ⅰ investigation of FF-10850 for the treatment of solid tumors including ovarian cancer (NCT04047251), and further evaluation in combination settings.