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Angiogenesis

A helping hand

Nature Reviews Cancer volume 4, page 248 (2004)Cite this article

TNP-470 is a potent endothelial-cell inhibitor in vitro and inhibits the growth of most types of primary and metastatic tumours in mice. However, dose-limiting neurotoxicity has prevented the efficacy of these agents from being realised in the clinic. The authors conjugated TNP-470 to the HPMA copolymer, which is a water-soluble synthetic polymer that is taken up by leaky tumour vessels and accumulates there because of poor lymphatic drainage. The HPMA copolymer is also non-immunogenic and non-toxic. When the TNP-470 conjugate enters the lysosomal environment of endothelial cells, enzymes — such as cathepsin B, which is overexpressed in tumour endothelial cells — cleave a linker sequence between the polymer and the drug, so releasing the active drug. The activity of the conjugated drug was similar to that of free TNP-470 in vitro — both were cytotoxic to endothelial cells and inhibited vascular sprouting in a chick aorta Matrigel assay.

Next, the authors tested both the free and conjugated drug in a mouse hepatectomy model, because liver regeneration is dependent on angiogenesis. Whereas control mice regenerated their resesected liver to ∼1.2 g by postoperative day 8, subcutaneous drug treatment every other day inhibited growth — livers only reached 0.7 g by day 8. Unlike the free drug, HPMA-copolymer-TNP-470 even inhibited regeneration if given every 4 days or as a single dose on the day of hepatectomy, indicating that the conjugate either has a longer circulation life or accumulates more near proliferating endothelial cells.

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References

ORIGINAL RESEARCH PAPER

  1. Satchi-Fainaro, R. et al. Targeting angiogenesis with a conjugate of HPMA copolymer and TNP-470. Nature Med. 10, 255–261 (2004)

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FURTHER READING

  1. Duncan, R. The dawning era of polymer therapeutics. Nature Rev. Drug Discov. 2, 347–360 (2003)

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Authors
  1. Ezzie Hutchinson
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Hutchinson, E. A helping hand. Nat Rev Cancer 4, 248 (2004). https://doi.org/10.1038/nrc1326

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  • DOI: https://doi.org/10.1038/nrc1326

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