Zhang Yumei, Wang Shunli, Duan Xiaofan, Xu Xiaoxiao, Gao Yuan, Zhou Jiuli, Xu Xiaolin, Li Jin
Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.
Department of VIP Clinic, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.
Front Pharmacol. 2022 Apr 6;13:861938. doi: 10.3389/fphar.2022.861938. eCollection 2022.
Ovarian cancer is the second most common cause of gynecological cancer death in women. It is usually diagnosed late and accompanied by peritoneal metastasis. For ovarian cancer with peritoneal metastasis, intraperitoneal (IP) chemotherapy can maintain a high drug concentration in the abdominal cavity and reduce local and systemic toxicity. Recently, docetaxel (DTX) has shown broad-spectrum antitumor activity against various malignant tumors, including ovarian cancer with peritoneal metastasis. However, DTX has limited clinical applications due to its poor water solubility, predisposition to hypersensitivity, fluid retention, and varying degrees of neurotoxicity. In this study, we prepared methoxy-poly(ethylene glycol)-block-poly(D,L-lactide) (mPEG-PDLLA) micelles loaded with DTX and developed an alternative, less toxic, more effective DTX formulation, without Tween 80, and evaluated its pharmacokinetics in the abdominal cavity and its efficacy in ovarian cancer with peritoneal metastasis. The mean diameter of DTX-mPEG-PDLLA was about 25 nm, and the pharmacokinetics of BALB/c mice IP showed that the plasma exposure of DTX-mPEG-PDLLA was about four times lower than that of DTX. Importantly, DTX-mPEG-PDLLA was significantly more effective than DTX and prolonged the survival period in a SKOV-3 ovarian cancer peritoneal metastasis model. Moreover, the apoptosis rate was significantly increased . Based on these findings, it is expected that DTX-mPEG-PDLLA can enhance efficacy against ovarian cancer peritoneal metastasis, while reducing toxic side effects, and has the potential to be used in the clinical treatment of peritoneal metastatic cancer.
卵巢癌是女性妇科癌症死亡的第二大常见原因。它通常在晚期被诊断出来，并伴有腹膜转移。对于伴有腹膜转移的卵巢癌，腹腔内（IP）化疗可在腹腔内维持高药物浓度，并降低局部和全身毒性。最近，多西他赛（DTX）已显示出对包括伴有腹膜转移的卵巢癌在内的各种恶性肿瘤具有广谱抗肿瘤活性。然而，由于其水溶性差、易发生超敏反应、液体潴留以及不同程度的神经毒性，DTX的临床应用有限。在本研究中，我们制备了负载DTX的甲氧基聚（乙二醇）-嵌段-聚（D，L-丙交酯）（mPEG-PDLLA）胶束，并开发了一种不含吐温80的毒性更小、更有效的DTX替代制剂，并评估了其在腹腔内的药代动力学及其对伴有腹膜转移的卵巢癌的疗效。DTX-mPEG-PDLLA的平均直径约为25 nm，BALB/c小鼠腹腔注射后的药代动力学表明，DTX-mPEG-PDLLA的血浆暴露量比DTX低约四倍。重要的是，在SKOV-3卵巢癌腹膜转移模型中，DTX-mPEG-PDLLA比DTX显著更有效，并延长了生存期。此外，凋亡率显著增加。基于这些发现，预计DTX-mPEG-PDLLA可增强对卵巢癌腹膜转移的疗效，同时减少毒副作用，并具有用于腹膜转移性癌临床治疗的潜力。
