Improved efficacy and reduced toxicity of doxorubicin encapsulated in sulfatide-containing nanoliposome in a glioma model

PLoS One. 2014 Jul 29;9(7):e103736. doi: 10.1371/journal.pone.0103736. eCollection 2014.

Abstract

As a glycosphingolipid that can bind to several extracellular matrix proteins, sulfatide has the potential to become an effective targeting agent for tumors overexpressing tenasin-C in their microenvironment. To overcome the dose-limiting toxicity of doxorubicin (DOX), a sulfatide-containing nanoliposome (SCN) encapsulation approach was employed to improve treatment efficacy and reduce side effects of free DOX. This study analysed in vitro characteristics of sulfatide-containing nanoliposomal DOX (SCN-DOX) and assessed its cytotoxicity in vitro, as well as biodistribution, therapeutic efficacy, and systemic toxicity in a human glioblastoma U-118MG xenograft model. SCN-DOX was shown to achieve highest drug to lipid ratio (0.5∶1) and a remarkable in vitro stability. Moreover, DOX encapsulated in SCN was shown to be delivered into the nuclei and displayed prolonged retention over free DOX in U-118MG cells. This simple two-lipid SCN-DOX nanodrug has favourable pharmacokinetic attributes in terms of prolonged circulation time, reduced volume of distribution and enhanced bioavailability in healthy rats. As a result of the improved biodistribution, an enhanced treatment efficacy of SCN-DOX was found in glioma-bearing mice compared to the free drug. Finally, a reduction in the accumulation of DOX in the drug's principal toxicity organs achieved by SCN-DOX led to the diminished systemic toxicity as evident from the plasma biochemical analyses. Thus, SCN has the potential to be an effective and safer nano-carrier for targeted delivery of therapeutic agents to tumors with elevated expression of tenascin-C in their microenvironment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / administration & dosage*
  • Antibiotics, Antineoplastic / pharmacokinetics
  • Antibiotics, Antineoplastic / pharmacology
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Disease Models, Animal
  • Doxorubicin / administration & dosage*
  • Doxorubicin / chemistry
  • Doxorubicin / pharmacokinetics
  • Female
  • Glioma / drug therapy*
  • Glioma / mortality
  • Humans
  • Kinetics
  • Liposomes / chemistry*
  • MCF-7 Cells
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Microscopy, Confocal
  • Nanoparticles / chemistry*
  • Particle Size
  • Rats
  • Rats, Sprague-Dawley
  • Sulfoglycosphingolipids / chemistry*
  • Tissue Distribution
  • Transplantation, Heterologous

Substances

  • Antibiotics, Antineoplastic
  • Liposomes
  • Sulfoglycosphingolipids
  • Doxorubicin

Grant support

This work was supported by a grants from National Health and Medical Research Council, Australia (#479505), www.nhmrc.gov.au and Australia-India Strategic Research Fund Programme–Indo-Australia Science and Technology Fund (#ST040007), http://www.innovation.gov.au/Science/InternationalCollaboration/aisrf/Pages/default.aspx. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.