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

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 alpha4 and beta1 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.

• Authors: Manabu Fujita, Natalya M Khazenzon, Alexander V Ljubimov, Bong-Seop Lee, Ismo Virtanen, Eggehard Holler, Keith L Black, Julia Y Ljubimova
• Journal: Angiogenesis (Angiogenesis) Vol. 9 Issue 4 Pg. 183-91 ( 2006) ISSN: 0969-6970 [Print] Germany
• PMID: 17109197 (Publication Type: Journal Article)

Chemical References

• Angiogenesis Inhibitors
• Laminin
• Malates
• Polyesters
• Polymers
• laminin 8
• poly(malic acid)
• polycefin

Topics

• Angiogenesis Inhibitors (administration & dosage, pharmacology)
• Animals
• Cell Line, Tumor
• Drug Delivery Systems
• Glioma (drug therapy)
• Humans
• Laminin (antagonists & inhibitors)
• Malates
• Neovascularization, Pathologic (drug therapy)
• Polyesters (administration & dosage, pharmacology)
• Polymers
• Rats
• Rats, Nude