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Local endostatin treatment of gliomas administered by microencapsulated producer cells

Nature Biotechnology volume 19, pages 29–34 (2001)Cite this article

Abstract

We describe a technique for the treatment of malignant brain tumors based on local delivery of the anti-angiogenic protein endostatin from genetically engineered cells encapsulated in ultrapure sodium alginate. Alginate consists of L-guluronic and D-mannuronic acid, which in the presence of divalent cations forms an extended gel network, in which cells reside and remain immunoisolated, when implanted into the rat brain. Here, we show that endostatin-transfected cells encapsulated in alginate maintain endostatin secretion for at least four months after intracerebral implantation in rats. During the implantation period 70% of the encapsulated cells remained viable, as opposed to 85% in in vitro-cultured capsules. Rats that received transplants of BT4C glioma cells, together with endostatin-producing capsules (0.2 μg/ml per capsule), survived 84% longer than the controls. The endostatin released from the capsules led to an induction of apoptosis, hypoxia, and large necrotic avascular areas within 77% of the treated tumors, whereas all the controls were negative. The encapsulation technique may be used for many different cell lines engineered to potentially interfere with the complex microenvironment in which tumor and normal cells reside. The present work may thus provide the basis for new therapeutic approaches toward brain tumors.

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Figure 1: Confocal image of bioreactors viewed by Hoffman optics.
Figure 2: Endostatin release from the bioreactors.
Figure 3: Local endostatin treatment results in prolonged survival of animals bearing intracranial tumors.
Figure 4: Encapsulated endostatin-producing 293 cells survive for several months in vivo and induce large necrotic areas in the treated tumors.
Figure 5: Biological effects of local endostatin treatment on intracranial tumors.
Figure 6: Endostatin induces apoptosis in tumor cells.

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Acknowledgements

We thank the Norwegian Cancer Society, the National Gene Therapy Program, the Norwegian Research Counsel and Innovest, and the University of Bergen for financial support toward this study. Furthermore, we thank Bodil Hansen, Tove Drange Johannsen, and Tore Jacob Raa for excellent technical assistance. Finally we thank Dr. Rupert Timpl at the Max-Planck institute, Martinsried, Germany for supplying the endostatin antiserum.

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Authors and Affiliations

  1. Department of Anatomy and Cell Biology, University of Bergen, Norway

    Tracy-Ann Read, Rupavathana Mahesparan, Per Ø. Enger & Rolf Bjerkvig

  2. Department of Comparative Medicine, The National Hospital University of Oslo, Norway

    Dag R. Sorensen

  3. Max-Planck-Institut für Biochemie, Martinsried, Germany

    Rupert Timpl

  4. Harvard Medical School, Boston, MA, USA

    Bjørn R. Olsen

  5. SINTEF Unimed, MR Center, Trondheim, 7565, Norway

    Mari H.B Hjelstuen

  6. Department of Anaesthesia and Medical Imaging, The Norwegian University of Science and Technology, Trondheim, Norway

    Olav Haraldseth

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  1. Tracy-Ann Read
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Correspondence to Tracy-Ann Read.

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Read, TA., Sorensen, D., Mahesparan, R. et al. Local endostatin treatment of gliomas administered by microencapsulated producer cells. Nat Biotechnol 19, 29–34 (2001). https://doi.org/10.1038/83471

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