Reduced toxicity and superior therapeutic activity of a mitomycin C lipid-based prodrug incorporated in pegylated liposomes

Clin Cancer Res. 2006 Mar 15;12(6):1913-20. doi: 10.1158/1078-0432.CCR-05-1547.

Abstract

Purpose: A lipid-based prodrug of mitomycin C [MMC; 2,3-(distearoyloxy)propane-1-dithio-4'-benzyloxycarbonyl-MMC] was designed for liposome formulation. The purpose of this study was to examine the in vitro cytotoxicity, pharmacokinetics, in vivo toxicity, and in vivo antitumor activity of this new lipid-based prodrug formulated in polyethylene glycol-coated (pegylated) liposomes.

Experimental design: MMC was released from the MMC lipid-based prodrug (MLP) by thiolytic-induced cleavage with a variety of thiol-containing reducing agents. MLP was incorporated with nearly 100% efficiency in cholesterol-free pegylated liposomes with hydrogenated phosphatidylcholine as the main component and a mean vesicle size of approximately 90 nm. This formulation was used for in vitro and in vivo tests in rodents.

Results: In vitro, the cytotoxic activity of pegylated liposomal MLP (PL-MLP) was drastically reduced compared with free MMC. However, in the presence of reducing agents, such as cysteine or N-acetyl-cysteine, its activity increased to nearly comparable levels to those of free MMC. Intravenous administration of PL-MLP in rats resulted in a slow clearance indicating stable prodrug retention in liposomes and long circulation time kinetics, with a pharmacokinetic profile substantially different from that of free MMC. In vivo, PL-MLP was approximately 3-fold less toxic than free MMC. The therapeutic index and absolute antitumor efficacy of PL-MLP were superior to that of free MMC in the three tumor models tested. In addition, PL-MLP was significantly more active than a formulation of doxorubicin in pegylated liposomes (DOXIL) in the M109R tumor model, a mouse tumor cell line with a multidrug-resistant phenotype.

Conclusions: Delivery of MLP in pegylated liposomes is a potential approach for effective treatment of multidrug-resistant tumors while significantly buffering the toxicity of MMC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Female
  • Inhibitory Concentration 50
  • Liposomes / chemistry*
  • Mice
  • Mice, Inbred BALB C
  • Mitomycins / pharmacokinetics
  • Mitomycins / pharmacology*
  • Mitomycins / therapeutic use
  • Molecular Structure
  • Neoplasms, Experimental / drug therapy*
  • Neoplasms, Experimental / pathology
  • Polyethylene Glycols / chemistry
  • Prodrugs / pharmacokinetics
  • Prodrugs / pharmacology*
  • Prodrugs / therapeutic use
  • Rats
  • Rats, Sprague-Dawley
  • Time Factors
  • Treatment Outcome

Substances

  • 2,3-(distearoyloxy)propane-1-dithio-4'-benzyloxycarbonyl-mitomycin C
  • Antineoplastic Agents
  • Liposomes
  • Mitomycins
  • Prodrugs
  • Polyethylene Glycols