Experimental Therapeutics, British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada.
Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver, BC, V6T 1Z3, Canada.
Drug Deliv Transl Res. 2018 Feb;8(1):239-251. doi: 10.1007/s13346-017-0455-7.
Clioquinol (CQ) is an FDA-approved topical antifungal agent known to kill cancer cells. This facilitated the initiation of clinical trials in patients with refractory hematologic malignancies. These repurposing efforts were not successful; this was likely due to low intracellular levels of the drug owing to poor absorption and rapid metabolism upon oral administration. CQ forms a sparingly soluble copper complex (Cu(CQ)) that exhibits enhanced anticancer activity in some cell lines. We have utilized a novel method to synthesize Cu(CQ) inside liposomes, an approach that maintains the complex suspended in solution and in a format suitable for intravenous administration. The complex was prepared inside 100-nm liposomes composed of 1,2-distearoyl-sn-glycero-3-phosphocholine/cholesterol (55:45). The therapeutic activity of the resultant formulation was evaluated in two subcutaneous tumor models (glioblastoma and ovarian cancers) but was not active. We also assessed the ability of the Cu(CQ) formulation to increase copper delivery to cancer cells in vitro and its potential to be used in combination with disulfiram (DSF). The results suggested that addition of Cu(CQ) enhanced cellular copper levels and the activity of DSF in vitro; however, this combination did not result in a statistically significant reduction in tumor growth in vivo. These studies demonstrate that a Cu(CQ) formulation suitable for intravenous use can be prepared, but this formulation used alone or in combination with DSF was not efficacious. The methods described are suitable for development formulations of other analogues of 8-hydroxyquinoline which could prove to be more potent.
卤倍他索（CQ）是一种获得美国食品药品监督管理局（FDA）批准的外用抗真菌药物，已知其可杀死癌细胞。这促成了在难治性血液恶性肿瘤患者中开展临床试验。这些重新定位的努力并未取得成功；这可能是由于药物的细胞内水平较低，这是由于口服后吸收不良和快速代谢所致。CQ 形成一种难溶的铜配合物（Cu（CQ）），在某些细胞系中表现出增强的抗癌活性。我们利用一种新方法在脂质体内部合成 Cu（CQ），这种方法可使该复合物保持悬浮在溶液中，并具有适合静脉内给药的形式。该复合物是由 1,2-二硬脂酰-sn-甘油-3-磷酸胆碱/胆固醇（55:45）组成的 100nm 脂质体内部制备的。评估了该制剂在两种皮下肿瘤模型（胶质母细胞瘤和卵巢癌）中的治疗活性，但无效。我们还评估了 Cu（CQ）制剂增加癌细胞内铜输送的能力及其与双硫仑（DSF）联合使用的潜力。结果表明，添加 Cu（CQ）可增强细胞内铜水平和 DSF 的体外活性；然而，这种组合并未导致体内肿瘤生长的统计学显著减少。这些研究表明，可以制备适合静脉使用的 Cu（CQ）制剂，但该制剂单独使用或与 DSF 联合使用均无效。所描述的方法适用于其他 8-羟基喹啉类似物的制剂开发，这些类似物可能更有效。
