Angiogenesis

, Volume 9, Issue 4, pp 183–191

Inhibition of laminin-8 in vivo using a novel poly(malic acid)-based carrier reduces glioma angiogenesis

  • Manabu Fujita
  • Natalya M. Khazenzon
  • Alexander V. Ljubimov
  • Bong-Seop Lee
  • Ismo Virtanen
  • Eggehard Holler
  • Keith L. Black
  • Julia Y. Ljubimova
Original Paper

DOI: 10.1007/s10456-006-9046-9

Cite this article as:
Fujita, M., Khazenzon, N.M., Ljubimov, A.V. et al. Angiogenesis (2006) 9: 183. doi:10.1007/s10456-006-9046-9

Abstract

We have previously shown that laminin-8, a vascular basement membrane component, was overexpressed in human glioblastomas multiforme and their adjacent tissues compared to normal brain. Increased laminin-8 correlated with shorter glioblastoma recurrence time and poor patient survival making it a potential marker for glioblastoma diagnostics and prediction of disease outcome. However, laminin-8 therapeutic potential was unknown because the technology of blocking the expression of multi-chain complex proteins was not yet developed. To inhibit the expression of laminin-8 constituents in glioblastoma in vitro and in vivo, we used Polycefin, a bioconjugate drug delivery system based on slime-mold Physarum polycephalum-derived poly(malic acid). It carries an attached transferrin receptor antibody to target tumor cells and to deliver two conjugated morpholino antisense oligonucleotides against laminin-8 α4 and β1 chains. Polycefin efficiently inhibited the expression of both laminin-8 chains by cultured glioblastoma cells. Intracranial Polycefin treatment of human U87MG glioblastoma-bearing nude rats reduced incorporation of both tumor-derived laminin-8 chains into vascular basement membranes. Polycefin was thus able to simultaneously inhibit the expression of two different chains of a complex protein. The treatment also significantly reduced tumor microvessel density (p  <  0.001) and area (p  <  0.001) and increased animal survival (p  <  0.0004). These data suggest that laminin-8 may be important for glioblastoma angiogenesis. Polycefin, a versatile nanoscale drug delivery system, was suitable for in vivo delivery of two antisense oligonucleotides to brain tumor cells causing a reduction of glioblastoma angiogenesis and an increase of animal survival. This system may hold promise for future clinical applications.

Keywords

Tumor angiogenesis Glioma Laminin-8 Multiple drug targeting Poly(malic acid) 

Copyright information

© Springer Science + Business Media B.V. 2006

Authors and Affiliations

  • Manabu Fujita
    • 1
  • Natalya M. Khazenzon
    • 1
  • Alexander V. Ljubimov
    • 2
    • 3
  • Bong-Seop Lee
    • 1
  • Ismo Virtanen
    • 4
  • Eggehard Holler
    • 3
    • 5
  • Keith L. Black
    • 1
    • 3
  • Julia Y. Ljubimova
    • 1
    • 3
  1. 1.Maxine Dunitz Neurosurgical InstituteCedars-Sinai Medical CenterLos AngelesUSA
  2. 2.Ophthalmology Research LaboratoriesCedars-Sinai Medical CenterLos AngelesUSA
  3. 3.Arrogene, Inc.TarzanaUSA
  4. 4.Institute of Biomedicine/AnatomyUniversity of HelsinkiHelsinkiFinland
  5. 5.Institut für Biophysik und Physikalische Biochemie der Universität RegensburgRegensburgGermany