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Continuous release of endostatin from microencapsulated engineered cells for tumor therapy

Nature Biotechnology volume 19, pages 35–39 (2001)Cite this article

Abstract

Research studies suggest that tumor-related angiogenesis contributes to the phenotype of malignant gliomas. We assessed the effect of local delivery of the angiogenesis inhibitor endostatin on human glioma cell line (U-87MG) xenografts. Baby hamster kidney (BHK) cells were stably transfected with a human endostatin (hES) expression vector and were encapsulated in alginate-poly L-lysine (PLL) microcapsules for long-term delivery of hES. The release of biologically active endostatin was confirmed using assays of bovine capillary endothelial (BCE) proliferation and of tube formation. Human endostatin released from the microcapsules brought about a 67.2% inhibition of BCE proliferation. Furthermore, secreted hES was able to inhibit tube formation in KDR/PAE cells (porcine aortic endothelial cells stably transfected with KDR, a tyrosine kinase) treated with conditioned U-87MG medium. A single local injection of encapsulated endostatin-secreting cells in a nude mouse model resulted in a 72.3% reduction in subcutaneous U87 xenografts' weight 21 days post treatment. This inhibition was achieved by only 150.8 ng/ml human endostatin secreted from 2 × 105 encapsulated cells. Encapsulated endostatin-secreting cells are effective for the treatment of human glioblastoma xenografts. Continuous local delivery of endostatin may offer an effective therapeutic approach to the treatment of a variety of tumor types.

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Figure 1: Endostatin encapsulation.
Figure 2: The biological activity of endostatin on endothelial cells.
Figure 3: The effect of encapsulated BHK-endo on tumor growth in vivo.
Figure 4: Western blot analysis of recombinant endostatin.
Figure 5: Immunochemistry of tumors treated with BHK-neo or BHK-endo encapsulated cells.

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Acknowledgements

We wish to thank Dr. Judah Folkman for his helpful suggestions in the preparation of the manuscript. This work is supported by a grant from the Boston Neurosurgical Foundation. T.J. is a recipient of a fellowship from Jikei University School of Medicine.

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Author notes

  1. Tatsuhiro Joki and Marcelle Machluf: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery Department of Surgery, Brain Tumor Laboratory, Brigham Women's Hospital, Harvard Medical School, Boston, 02115, MA

    Tatsuhiro Joki, Jianhong Zhu, Nicholas T. Seyfried, Ian F. Dunn, Rona S. Carroll & Peter McL. Black

  2. Children's Hospital, Harvard Medical School, Boston, 02115, MA

    Tatsuhiro Joki, Jianhong Zhu, Nicholas T. Seyfried, Ian F. Dunn, Rona S. Carroll & Peter McL. Black

  3. Department of Neurosurgery, Jikei University School of Medicine, Tokyo, Japan

    Tatsuhiro Joki & Toshiaki Abe

  4. Department of Urology, The Children's Hospital, Harvard Medical School, Boston, 02115, MA

    Marcelle Machluf & Anthony Atala

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Correspondence to Rona S. Carroll.

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Joki, T., Machluf, M., Atala, A. et al. Continuous release of endostatin from microencapsulated engineered cells for tumor therapy. Nat Biotechnol 19, 35–39 (2001). https://doi.org/10.1038/83481

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