Therapeutic efficacy of a lipid-based prodrug of mitomycin C in pegylated liposomes: studies with human gastro-entero-pancreatic ectopic tumor models

J Control Release. 2012 Jun 10;160(2):245-53. doi: 10.1016/j.jconrel.2011.11.019. Epub 2011 Nov 26.


Background: A mitomycin-C lipid-based prodrug (MLP) formulated in pegylated liposomes (PL-MLP) was previously reported to have significant antitumor activity and reduced toxicity in mouse tumor models (Clin Cancer Res 12:1913-20, 2006). MLP is activated by thiolysis releasing mitomycin-C (MMC) which rapidly dissociates from liposomes. The purpose of this study was to examine the plasma stability, pharmacokinetics, and antitumor activity of PL-MLP in mouse models of human gastroentero-pancreatic tumors.

Methods: MLP was incorporated with almost 100% efficiency in pegylated liposomes composed of hydrogenated phosphatidylcholine, with or without cholesterol (Chol). Mean vesicle size was 45-65 nm for liposome preparations downsized by homogenization, and 80-100 nm when downsized by extrusion, the latter displaying narrower polydispersity. MLP to phospholipid mole ratio was 5% (~20 μg MMC-equivalents/μmol). Therapeutic studies were carried out in the N87 gastric carcinoma (Ca), HCT15 colon Ca, and Panc-1 pancreatic Ca models implanted s.c. in CD1 nude mice. Treatment was administered i.v. in mice with established tumors.

Results: PL-MLP was very stable when incubated in plasma, and whole blood with a maximum of 5% release and activation to free MMC after 24 h. In the presence of a strong reducing agent (dithiotreitol), MLP was almost entirely activated to free MMC. Pharmacokinetic studies revealed major differences in plasma clearance between free MMC and PL-MLP. The longest half-lives were observed for extruded and Chol-containing preparations. Using a liposome radiolabel, it was found that the plasma levels of liposomes and prodrug were nearly superimposable confirming the absence of drug leakage in circulation. In vivo prodrug activation was significantly increased by co-injection of a large dose of a biocompatible reducing agent, N-acetylcysteine. PL-MLP was significantly more effective in delaying tumor growth and resulted in more tumor regressions than irinotecan in the N87 and HCT15 models, and than gemcitabine in the Panc-1 model. PL-MLP was ~3-fold less toxic than free MMC at MMC-equivalent doses, and displayed mild myelosuppression at therapeutic doses.

Conclusions: Delivery of MLP in pegylated liposomes is more effective than conventional chemotherapy in the treatment of gastroentero-pancreatic ectopic tumor models, and may represent an effective tool for treatment of these malignancies in the clinical setting with improved safety over free MMC. Reducing agents offer a tool for controlling in vivo prodrug release.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / administration & dosage
  • Antibiotics, Antineoplastic / pharmacokinetics
  • Antibiotics, Antineoplastic / therapeutic use*
  • Cholesterol / chemistry
  • Colonic Neoplasms / drug therapy*
  • Drug Carriers / chemistry*
  • Drug Stability
  • Female
  • Humans
  • Lipids / chemistry*
  • Liposomes
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Microscopy, Electron, Transmission
  • Mitomycin / administration & dosage
  • Mitomycin / pharmacokinetics
  • Mitomycin / therapeutic use*
  • Pancreatic Neoplasms / drug therapy*
  • Particle Size
  • Phosphatidylcholines / chemistry
  • Polyethylene Glycols / chemistry*
  • Prodrugs / administration & dosage
  • Prodrugs / pharmacokinetics
  • Prodrugs / therapeutic use*
  • Stomach Neoplasms / drug therapy*
  • Surface Properties
  • Xenograft Model Antitumor Assays


  • Antibiotics, Antineoplastic
  • Drug Carriers
  • Lipids
  • Liposomes
  • Phosphatidylcholines
  • Prodrugs
  • Polyethylene Glycols
  • Mitomycin
  • Cholesterol