title: 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.affiliation: Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, 8631 W. Third Street, Suite 800E, Los Angeles, CA, 90048, USA.
authors.forename: Manabu
authors.initials: M
authors.lastname: Fujita
authors.forename: Natalya M
authors.initials: NM
authors.lastname: Khazenzon
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Ljubimov
authors.forename: Bong-Seop
authors.initials: BS
authors.lastname: Lee
authors.forename: Ismo
authors.initials: I
authors.lastname: Virtanen
authors.forename: Eggehard
authors.initials: E
authors.lastname: Holler
authors.forename: Keith L
authors.initials: KL
authors.lastname: Black
authors.forename: Julia Y
authors.initials: JY
authors.lastname: Ljubimova
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D005910:Glioma / Q000188:drug therapy*; D006801:Humans; D007797:Laminin / Q000037:antagonists & inhibitors*; D008293:Malates; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D011091:Polyesters / Q000008:administration & dosage / Q000494:pharmacology*; D011108:Polymers; D051381:Rats; D011923:Rats, Nude
chemical_list: D020533:Angiogenesis Inhibitors; D007797:Laminin; D008293:Malates; D011091:Polyesters; D011108:Polymers; C110308:laminin 8; C121060:poly(malic acid); C511560:polycefin