Co-targeting the tumor endothelium and P-selectin-expressing glioblastoma cells leads to a remarkable therapeutic outcome

Elife. 2017 Oct 4;6:e25281. doi: 10.7554/eLife.25281.

Abstract

Glioblastoma is a highly aggressive brain tumor. Current standard-of-care results in a marginal therapeutic outcome, partly due to acquirement of resistance and insufficient blood-brain barrier (BBB) penetration of chemotherapeutics. To circumvent these limitations, we conjugated the chemotherapy paclitaxel (PTX) to a dendritic polyglycerol sulfate (dPGS) nanocarrier. dPGS is able to cross the BBB, bind to P/L-selectins and accumulate selectively in intracranial tumors. We show that dPGS has dual targeting properties, as we found that P-selectin is not only expressed on tumor endothelium but also on glioblastoma cells. We delivered dPGS-PTX in combination with a peptidomimetic of the anti-angiogenic protein thrombospondin-1 (TSP-1 PM). This combination resulted in a remarkable synergistic anticancer effect on intracranial human and murine glioblastoma via induction of Fas and Fas-L, with no side effects compared to free PTX or temozolomide. This study shows that our unique therapeutic approach offers a viable alternative for the treatment of glioblastoma.

Keywords: P/L-selectins; cancer biology; glioblastoma; human; mouse; polyglycerol; polymeric nanomedicine; targeted delivery; thrombospondin-1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacokinetics
  • Brain Neoplasms / drug therapy*
  • Drug Carriers / administration & dosage*
  • Drug Carriers / chemistry
  • Drug Carriers / pharmacokinetics
  • Drug Synergism
  • Drug Therapy / methods
  • Glioblastoma / drug therapy*
  • Glycerol / administration & dosage*
  • Glycerol / chemistry
  • Glycerol / pharmacokinetics
  • Humans
  • Mice
  • P-Selectin / metabolism
  • Paclitaxel / administration & dosage*
  • Paclitaxel / chemistry
  • Paclitaxel / pharmacokinetics
  • Polymers / administration & dosage*
  • Polymers / chemistry
  • Polymers / pharmacokinetics
  • Protein Binding
  • Thrombospondin 1 / administration & dosage*
  • Treatment Outcome

Substances

  • Antineoplastic Agents
  • Drug Carriers
  • P-Selectin
  • Polymers
  • Thrombospondin 1
  • polyglycerol
  • Paclitaxel
  • Glycerol

Grant support

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.