Direct comparison of liposomal doxorubicin with or without polyethylene glycol coating in C-26 tumor-bearing mice: Is surface coating with polyethylene glycol beneficial?

Sterically stabilized liposome is characterized by a surface coating of pol yethylene glycol (PEG) or other polymers that can reduce opsonization of th e liposome by plasma proteins. It has a higher plasma area under the concen tration-time curve (AUC), which is believed to correlate with better therap eutic efficacy. However, the presence of large molecules on the liposomal s urface may reduce the interactions of liposomes with cells and hinder entry of liposomes into the tumor tissue. Using a stable liposomal system compos ed of distearoyl phosphatidylcholine/cholesterol, we examined the effect of PEG (M-r 2000) on the pharmacokinetics and on the efficacy of liposomal do xorubicin with C-26 syngeneic tumor model in BALB/c mice. The plasma AUC of liposomal doxorubicin with 6 mol-% PEG-modified distearoyl phosphatidyleth anolamine (PEG-DSPE) was approximately twice that of liposomal doxorubicin without PEG at various dosages, regardless of whether the mice were tumor-b earing. Paradoxically, the group of mice treated with liposomal doxorubicin without PEG had higher tumor doxorubicin concentrations. The 72-h tumor AU C was 1.44 times that of liposomal doxorubicin with 6% PEG-DSPE, The tumor- accumulation efficiency (AUC(Tumor)/AUC(Plasma)) of liposomal doxorubicin w ithout PEG was 0.87, and this was more than twice that of the liposomal dox orubicin with 6% PEG-DSPE (0.31), At a dose of 10 mg/kg, although both lipo somal groups were better than the free drug group in terms of clinically re levant parameters, including toxicity, tumor shrinkage, and survival, there was no difference between the two liposomal drug groups. In this stable li posome system, surface coating with PEG offered no benefit for liposomal do xorubicin in the C-26 tumor model. To enhance the therapeutic index of lipo somal doxorubicin, simply increasing plasma AUC by surface coating with PEG may not be satisfactory.