Department of Experimental Therapeutics, BC Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada; Department of Interdisciplinary Oncology, BC Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada.
Department of Experimental Therapeutics, BC Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada; Federal University of Pernambuco, PE CEP:50.670-901, Brazil.
J Control Release. 2021 May 10;333:246-257. doi: 10.1016/j.jconrel.2021.03.042. Epub 2021 Mar 30.
For more than 30 years, treatment of acute myeloid leukemia (AML) has remained largely unchanged and reliant on chemotherapeutic drug combinations, specifically cytarabine and daunorubicin (the 7 + 3 regimen). One broad spectrum drug, flavopiridol (also known as Alvocidib) has shown significant activity against AML through the inhibition of cyclin-dependent kinases. Flavopiridol is a semisynthetic flavonoid and our research team recently described methods to formulate another flavonoid, quercetin, through the ability of flavonoids to bind divalent metals. This method relies on use of copper-containing liposomes to enhance the apparent solubility of flavopiridol and to create formulations suitable for intravenous (i.v.) use. Similar to quercetin, flavopiridol is defined as an aqueous-insoluble compound (< 1 mg/mL in water) and this research sought to evaluate whether the copper-binding capabilities of flavopiridol could be used to prepare an injectable formulation that would exhibit enhanced exposure and improved efficacy. Flavopiridol powder was added directly to preformed copper-containing liposomes (DSPC:Chol or DSPC:DSPE-PEG2000) and the resulting formulations were characterized. Pharmacokinetic and efficacy studies were then conducted. The liposomal flavopiridol formulations were well-tolerated in mice following i.v. administration at a dose of 5 mg/kg with no apparent acute or chronic toxicities. In vivo pharmacokinetics of the optimized DSPC/DSPE-PEG2000 liposomal flavopiridol formulation demonstrated a 30-fold increase in AUC (0.804 μg-hr/mL versus 26.92 μg-hr/mL) compared to the free flavopiridol formulation. The resultant liposomal formulation also demonstrated significant therapeutic activity in MV4-11 and MOLM-13 subcutaneous AML models. Additional studies will be required to define whether formulation changes can be made to enhance flavopiridol retention in the selected composition. The results suggest that further increases in flavopiridol retention will result in improved therapeutic activity.
三十多年来，急性髓系白血病（AML）的治疗方法基本没有改变，仍然依赖于细胞毒性药物联合治疗，特别是阿糖胞苷和柔红霉素（7+3 方案）。一种广谱药物 flavopiridol（也称为 Alvocidib）通过抑制细胞周期蛋白依赖性激酶对 AML 表现出显著的活性。Flavopiridol 是一种半合成黄酮类化合物，我们的研究团队最近描述了通过黄酮类化合物与二价金属结合的能力来制备另一种黄酮类化合物 quercetin 的方法。该方法依赖于使用含有铜的脂质体来提高 flavopiridol 的表观溶解度，并制备适合静脉（i.v.）使用的制剂。与 quercetin 类似，flavopiridol 被定义为水不溶性化合物（<1mg/mL 在水中），本研究旨在评估 flavopiridol 的铜结合能力是否可用于制备可提高暴露度和改善疗效的注射制剂。将 flavopiridol 粉末直接添加到预先形成的含有铜的脂质体（DSPC：Chol 或 DSPC：DSPE-PEG2000）中，并对所得制剂进行了表征。然后进行了药代动力学和疗效研究。在静脉给予 5mg/kg 剂量后，脂质体 flavopiridol 制剂在小鼠中耐受良好，没有明显的急性或慢性毒性。与游离 flavopiridol 制剂相比，优化的 DSPC/DSPE-PEG2000 脂质体 flavopiridol 制剂的体内药代动力学显示 AUC（0.804μg-hr/mL 对 26.92μg-hr/mL）增加了 30 倍。该脂质体制剂还在 MV4-11 和 MOLM-13 皮下 AML 模型中表现出显著的治疗活性。需要进一步的研究来确定是否可以进行制剂改变以增强所选组合物中 flavopiridol 的保留。结果表明，进一步增加 flavopiridol 的保留将导致治疗活性的提高。
