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Direct Comparison of Liposomal Doxorubicin with or without Polyethylene Glycol Coating in C-26 Tumor-bearing Mice

Is Surface Coating with Polyethylene Glycol Beneficial?¹

Department of Oncology, National Taiwan University Hospital, Taipei 10016, Taiwan [R-L. H.]; Institute of Biochemistry, College of Medicine [Y-L. T., J-J. L., F-H. C.], and Department of Veterinary Medicine, College of Agriculture [V. F. P.], National Taiwan University, Taipei 10016, Taiwan; Institute of Biological Chemistry, Academia Sinica, Taipei 11543, Taiwan [C-J. H., S-T. C.]

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 (M_r 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.

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