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Targeting angiogenesis with a conjugate of HPMA copolymer and TNP-470

Nature Medicine volume 10, pages 255–261 (2004)Cite this article

Abstract

Angiogenesis is crucial for tumor growth. Angiogenesis inhibitors, such as O-(chloracetyl-carbamoyl) fumagillol (TNP-470), are thus emerging as a new class of anticancer drugs. In clinical trials, TNP-470 slowed tumor growth in patients with metastatic cancer. However, at higher doses necessary for tumor regression, many patients experienced neurotoxicity. We therefore synthesized and characterized a water-soluble conjugate of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer, Gly-Phe-Leu-Gly linker and TNP-470. This conjugate accumulated selectively in tumor vessels because of the enhanced permeability and retention (EPR) effect. HPMA copolymer–TNP-470 substantially enhanced and prolonged the activity of TNP-470 in vivo in tumor and hepatectomy models. Polymer conjugation prevented TNP-470 from crossing the blood-brain barrier (BBB) and decreased its accumulation in normal organs, thereby avoiding drug-related toxicities. Treatment with TNP-470 caused weight loss and neurotoxic effects in mice, whereas treatment with the conjugate did not. This new approach for targeting angiogenesis inhibitors specifically to the tumor vasculature may provide a new strategy for the rational design of cancer therapies.

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Figure 1: Synthesis and characterization of HPMA copolymer–TNP-470 conjugate.
Figure 2: TNP-470 and HPMA copolymer–TNP-470 conjugate selectively inhibit endothelial cell proliferation.
Figure 3: Once-weekly administration of HPMA copolymer–TNP-470 conjugate inhibits angiogenesis in liver regeneration model.
Figure 4: HPMA copolymer–TNP-470 inhibits A2058 human melanoma and LLC growth.
Figure 5: HPMA copolymer–TNP-470 conjugate accumulates at higher concentrations in tumors and has a longer half-life in circulation than free TNP-470.
Figure 6: HPMA copolymer–TNP-470 does not affect neurological function.

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Acknowledgements

We thank R. Duncan, H. Ringsdorf, C. Barnes and T. Udagawa for helpful discussions; G. Jackson, R. Winter and A. T. Lee for excellent technical assistance; A. Kaipainen and D. Panigrahy for their help with LLC implantation; K. Gullage for photography; and M. Moses, D. Ingber and D. Freedman for critical appraisal of the manuscript. This work was supported by The Fulbright and The Rothschild Foundations, and a grant from the Breast Cancer Research Foundation.

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Authors and Affiliations

  1. Vascular Biology Program and Department of Surgery, Boston Children's Hospital and Harvard Medical School, 1 Blackfan Circle, New Research Building, Boston, 02115, Massachusetts, USA

    Ronit Satchi-Fainaro, Mark Puder, David A Sampson, Arin K Greene & Judah Folkman

  2. Polymer Laboratories, Essex Road, Church Stretton, SY6 6EA, Shropshire, UK

    John W Davies

  3. Divisions of Cancer Medicine and Pharmacy, University of Texas, MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 432, Houston, 77030, Texas, USA

    Hai T Tran

  4. Department of Neurology, Boston Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, 02115, Massachusetts, USA

    Gabriel Corfas

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Correspondence to Judah Folkman.

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The authors filed a patent application under the PCT (WO 031086382AI) on 23 October 2003.

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Satchi-Fainaro, R., Puder, M., Davies, J. et al. Targeting angiogenesis with a conjugate of HPMA copolymer and TNP-470. Nat Med 10, 255–261 (2004). https://doi.org/10.1038/nm1002

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