Direct comparison of liposomal doxorubicin with or without polyethylene glycol coating in C-26 tumor-bearing mice

Is surface coating with polyethylene glycol beneficial?

Ruey Long Hong, Chang Jen Huang, Yun Long Tseng, Victor Fei Pang, Shui Tsung Chen, Jim Jen Liu, Fu Hsiung Chang

Research output: Contribution to journalArticle

192 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)3645-3652
Number of pages8
JournalClinical Cancer Research
Volume5
Issue number11
Publication statusPublished - Nov 1999
Externally publishedYes

Fingerprint

Liposomes
Neoplasms
liposomal doxorubicin
Phosphatidylcholines
Pharmaceutical Preparations
Doxorubicin
Area Under Curve
Blood Proteins
Polymers
Pharmacokinetics
Cholesterol
Therapeutics
1,2-distearoylphosphatidylethanolamine

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Direct comparison of liposomal doxorubicin with or without polyethylene glycol coating in C-26 tumor-bearing mice : Is surface coating with polyethylene glycol beneficial? / Hong, Ruey Long; Huang, Chang Jen; Tseng, Yun Long; Pang, Victor Fei; Chen, Shui Tsung; Liu, Jim Jen; Chang, Fu Hsiung.

In: Clinical Cancer Research, Vol. 5, No. 11, 11.1999, p. 3645-3652.

Research output: Contribution to journalArticle

Hong, Ruey Long ; Huang, Chang Jen ; Tseng, Yun Long ; Pang, Victor Fei ; Chen, Shui Tsung ; Liu, Jim Jen ; Chang, Fu Hsiung. / Direct comparison of liposomal doxorubicin with or without polyethylene glycol coating in C-26 tumor-bearing mice : Is surface coating with polyethylene glycol beneficial?. In: Clinical Cancer Research. 1999 ; Vol. 5, No. 11. pp. 3645-3652.
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abstract = "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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