Biomedical Sciences Research Institute, University of Ulster, Coleraine, Northern Ireland, UK.
Patrick G. Johnston Centre for Cancer Research , Queens University of Belfast, Belfast Northern Ireland, BT9 7AE, UK.
Eur J Pharm Biopharm. 2023 Nov;192:196-205. doi: 10.1016/j.ejpb.2023.10.012. Epub 2023 Oct 18.
Docetaxel (DTX) chemotherapy is commonly used in the treatment of patients with advanced prostate cancer demonstrating modest improvements in survival. As these patients are often elderly and the chemotherapy treatment is not targeted, it is often poorly tolerated. More targeted approaches that increase therapeutic efficacy yet reduce the amount of toxic chemotherapy administered are needed. In this manuscript, we investigate the potential of ultrasound targeted microbubble destruction (UTMD) to deliver a combination of docetaxel chemotherapy and Rose Bengal mediated sonodynamic therapy (SDT) in pre-clinical prostate cancer models. A Rose Bengal modified phospholipid was synthesized and used as a component lipid to prepare a microbubble (MB) formulation that was also loaded with DTX. The DTX-MB-RB formulation was used in the UTMD mediated treatment of androgen sensitive and androgen resistant 3D spheroid and murine models of prostate cancer. Results from the 3D spheroid experiments showed UTMD mediated DTX-MB-RB chemo-sonodynamic therapy to be significantly more effective at reducing cell viability than UTMD mediated DTX or SDT treatment alone. In an androgen sensitive murine model of prostate cancer, UTMD mediated DTX-MB-RB chemo-sonodynamic therapy was as effective as androgen deprivation therapy (ADT) at controlling tumour growth. However, when both treatments were combined, a significant improvement in tumour growth delay was observed. In an androgen resistant murine model, UTMD mediated DTX-MB-RB chemo-sonodynamic therapy was significantly more effective than standard DTX monotherapy. Indeed, the DTX dose administered using the DTX-MB-RB formulation was 91% less than standard DTX monotherapy. As a result, UTMD mediated DTX-MB-RB treatment was well tolerated while animals treated with DTX monotherapy displayed significant weight loss which was attributed to acute toxic effects. These results highlight the potential of UTMD mediated DTX-MB-RB chemo-sonodynamic therapy as a targeted, well tolerated alternative treatment for advanced prostate cancer.
多西他赛（DTX）化疗常用于治疗晚期前列腺癌患者，可适度提高生存率。由于这些患者通常年龄较大，且化疗治疗无针对性，因此通常耐受性较差。需要更具针对性的方法来提高治疗效果，同时减少给予的毒性化疗药物剂量。在本手稿中，我们研究了超声靶向微泡破坏（UTMD）在临床前前列腺癌模型中递送多西他赛化疗和孟加拉玫瑰红介导的声动力学疗法（SDT）联合治疗的潜力。合成了一种孟加拉玫瑰红修饰的磷脂，并将其用作制备微泡（MB）制剂的成分脂质，该制剂还负载有 DTX。DTX-MB-RB 制剂用于经 UTMD 介导的治疗对雄激素敏感和雄激素抵抗的 3D 球体和前列腺癌的鼠模型。3D 球体实验的结果表明，UTMD 介导的 DTX-MB-RB 化疗-声动力学治疗在降低细胞活力方面比 UTMD 介导的 DTX 或 SDT 单独治疗更有效。在雄激素敏感的前列腺癌鼠模型中，UTMD 介导的 DTX-MB-RB 化疗-声动力学治疗在控制肿瘤生长方面与雄激素剥夺疗法（ADT）一样有效。然而，当两种治疗方法联合使用时，观察到肿瘤生长延迟有显著改善。在雄激素抵抗的鼠模型中，UTMD 介导的 DTX-MB-RB 化疗-声动力学治疗比标准 DTX 单药治疗更有效。事实上，使用 DTX-MB-RB 制剂给予的 DTX 剂量比标准 DTX 单药治疗低 91%。因此，UTMD 介导的 DTX-MB-RB 治疗耐受性良好，而接受 DTX 单药治疗的动物体重明显减轻，这归因于急性毒性作用。这些结果强调了 UTMD 介导的 DTX-MB-RB 化疗-声动力学治疗作为一种有针对性、耐受性良好的晚期前列腺癌替代治疗方法的潜力。
