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

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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.

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Acknowledgements

The authors are indebted to Dr. Takako Sasaki, Max-Planck-Institut für Biochemie, Martinsried, Germany, for a gift of polyclonal antibody to laminin α4 chain.

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Authors and Affiliations

  1. Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, 8631 W. Third Street, Suite 800E, Los Angeles, CA, 90048, USA

    Manabu Fujita, Natalya M. Khazenzon, Bong-Seop Lee, Keith L. Black & Julia Y. Ljubimova

  2. Ophthalmology Research Laboratories, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA

    Alexander V. Ljubimov

  3. Arrogene, Inc., Tarzana, CA, 91356, USA

    Alexander V. Ljubimov, Eggehard Holler, Keith L. Black & Julia Y. Ljubimova

  4. Institute of Biomedicine/Anatomy, University of Helsinki, Helsinki, Finland

    Ismo Virtanen

  5. Institut für Biophysik und Physikalische Biochemie der Universität Regensburg, Regensburg, Germany

    Eggehard Holler

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  1. Manabu Fujita
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  2. Natalya M. Khazenzon
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  3. Alexander V. Ljubimov
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  4. Bong-Seop Lee
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  6. Eggehard Holler
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  7. Keith L. Black
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  8. Julia Y. Ljubimova
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Correspondence to Julia Y. Ljubimova.

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Fujita, M., Khazenzon, N.M., Ljubimov, A.V. et al. Inhibition of laminin-8 in vivo using a novel poly(malic acid)-based carrier reduces glioma angiogenesis. Angiogenesis 9, 183–191 (2006). https://doi.org/10.1007/s10456-006-9046-9

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  • DOI: https://doi.org/10.1007/s10456-006-9046-9

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