Hong R L, Huang C J, Tseng Y L, Pang V F, Chen S T, Liu J J, Chang F H
Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.
Clin Cancer Res. 1999 Nov;5(11):3645-52.
Sterically stabilized liposome is characterized by a surface coating of polyethylene glycol (PEG) or other polymers that can reduce opsonization of the liposome by plasma proteins. It has a higher plasma area under the concentration-time curve (AUC), which is believed to correlate with better therapeutic efficacy. However, the presence of large molecules on the liposomal surface may reduce the interactions of liposomes with cells and hinder entry of liposomes into the tumor tissue. Using a stable liposomal system composed of distearoyl phosphatidylcholine/cholesterol, we examined the effect of PEG (Mr 2000) on the pharmacokinetics and on the efficacy of liposomal doxorubicin with C-26 syngeneic tumor model in BALB/c mice. The plasma AUC of liposomal doxorubicin with 6 mol-% PEG-modified distearoyl phosphatidylethanolamine (PEG-DSPE) was approximately twice that of liposomal doxorubicin without PEG at various dosages, regardless of whether the mice were tumor-bearing. Paradoxically, the group of mice treated with liposomal doxorubicin without PEG had higher tumor doxorubicin concentrations. The 72-h tumor AUC was 1.44 times that of liposomal doxorubicin with 6% PEG-DSPE. The tumor-accumulation efficiency (AUC(Tumor)/AUC(Plasma)) of liposomal doxorubicin without PEG was 0.87, and this was more than twice that of the liposomal doxorubicin with 6% PEG-DSPE (0.31). At a dose of 10 mg/kg, although both liposomal groups were better than the free drug group in terms of clinically relevant parameters, including toxicity, tumor shrinkage, and survival, there was no difference between the two liposomal drug groups. In this stable liposome system, surface coating with PEG offered no benefit for liposomal doxorubicin in the C-26 tumor model. To enhance the therapeutic index of liposomal doxorubicin, simply increasing plasma AUC by surface coating with PEG may not be satisfactory.
空间稳定脂质体的特征在于其表面包被有聚乙二醇（PEG）或其他聚合物，这些聚合物可以减少血浆蛋白对脂质体的调理作用。它在浓度-时间曲线下的血浆面积（AUC）更高，据信这与更好的治疗效果相关。然而，脂质体表面存在大分子可能会减少脂质体与细胞的相互作用，并阻碍脂质体进入肿瘤组织。我们使用由二硬脂酰磷脂酰胆碱/胆固醇组成的稳定脂质体系统，在BALB/c小鼠的C-26同基因肿瘤模型中研究了PEG（分子量2000）对脂质体阿霉素药代动力学和疗效的影响。无论小鼠是否荷瘤，在不同剂量下，含有6摩尔%PEG修饰的二硬脂酰磷脂酰乙醇胺（PEG-DSPE）的脂质体阿霉素的血浆AUC约为不含PEG的脂质体阿霉素的两倍。矛盾的是，用不含PEG的脂质体阿霉素治疗的小鼠组肿瘤阿霉素浓度更高。72小时肿瘤AUC是含有6%PEG-DSPE的脂质体阿霉素的1.44倍。不含PEG的脂质体阿霉素的肿瘤蓄积效率（AUC(肿瘤)/AUC(血浆)）为0.87，是含有6%PEG-DSPE的脂质体阿霉素（0.31）的两倍多。在剂量为10mg/kg时，尽管两个脂质体组在包括毒性、肿瘤缩小和生存等临床相关参数方面均优于游离药物组，但两个脂质体药物组之间没有差异。在这个稳定的脂质体系统中，在C-26肿瘤模型中，用PEG进行表面包被对脂质体阿霉素没有益处。为了提高脂质体阿霉素的治疗指数，仅通过用PEG进行表面包被来增加血浆AUC可能并不令人满意。
