Dose dependency of pharmacokinetics and therapeutic efficacy of pegylated liposomal doxorubicin (DOXIL) in murine models
Dose dependency of pharmacokinetics and therapeutic efficacy of pegylated liposomal doxorubicin (DOXIL) in murine models
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DOI：
10.1080/1061186021000072447
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发表时间：
2002-01-01
影响因子：
4.5
通讯作者：
Horowitz, AT
中科院分区：
文献类型：
--
作者：
Gabizon, A;Tzemach, D;Horowitz, AT
近年来，隐形（聚乙二醇化）脂质体阿霉素（Doxil）已在临床前和临床水平进行了广泛研究。然而，一个尚未解决的问题是剂量对Doxil的肿瘤定位和治疗功效的影响。尽管有报道称，无药物Stealth脂质体的药代动力学在一定范围内与剂量无关，但Doxil的临床药代动力学分析表明，当检查较宽的剂量范围时，存在剂量依赖性清除饱和现象。此外，脂质体包封的阿霉素可对肝脏巨噬细胞群体以吞噬功能受损和胶体颗粒清除能力降低的形式产生毒性作用。在荷瘤小鼠的研究中，Doxil的剂量从2.5 mg/kg递增至20 mg/kg，我们证明剂量递增导致Doxil清除饱和和脂质体药物在肿瘤中蓄积量的不成比例增加。将放射性标记的高负电荷脂质体注射到先前用Doxil处理的小鼠中的实验与网状内皮系统的部分阻断一致，肝脏摄取相对减少，脂质体循环时间更长。在Doxil后以剂量依赖性方式观察到清除饱和效应，而在无药物脂质体中类似的游离阿霉素剂量或类似的磷脂剂量后未观察到。还观察到基于较大剂量的治疗的上级疗效优于较小分次剂量的趋势，同时保持等效剂量强度。这些观察结果可能与Doxil剂量方案的选择有关，以确保最佳的抗肿瘤活性。因此，阿霉素脂质体对网状内皮系统的剂量依赖性阻断可以延长脂质体循环时间，并显著增强药物向肿瘤的递送。
Stealth (pegylated) liposomal doxorubicin (Doxil) has been extensively studied at the pre-clinical and clinical level in recent years. However, one issue not yet addressed is the effect of dose on tumor localization and therapeutic efficacy of Doxil. Although it has been reported that the pharmacokinetics of drug-free Stealth liposomes is independent of dose within a certain range, clinical pharmacokinetic analysis of Doxil suggests a dose-dependent clearance saturation phenomenon when a broad dose range is examined. In addition, liposome-encapsulated doxorubicin can exert toxic effects on the liver macrophage population in the form of impairment of the phagocytic function and reduced ability of colloid particle clearance. In studies with tumor-bearing mice in which the dose of Doxil was escalated from 2.5 to 20 mg/kg, we demonstrate that dose escalation results in a saturation of Doxil clearance and a disproportional increase of the amount of liposomal drug accumulating in tumor. Experiments with radiolabeled highly negatively-charged liposomes injected into mice previously treated with Doxil are consistent with a partial blockade of the reticulo-endothelial system with relative reduction of liver uptake and greater prolongation of liposome circulation time. The clearance saturation effect is seen after Doxil in a dose-dependent fashion, and not after a similar free doxorubicin dose or similar phospholipid dose in drug-free liposomes. A trend to superior therapeutic efficacy for treatments based on larger doses as compared to smaller split doses, while maintaining an equivalent dose intensity, was also observed. These observations may be relevant to the choice of dose-schedule of Doxil to ensure optimal anti-tumor activity. Therefore, dose-dependent liposomal doxorubicin blockade of the reticulo-endothelial system may prolong liposome circulation time and enhance significantly drug delivery to tumors.