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

Nat Med. 2004 Mar;10(3):255-61. doi: 10.1038/nm1002. Epub 2004 Feb 22.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / chemistry
  • Angiogenesis Inhibitors / metabolism*
  • Angiogenesis Inhibitors / therapeutic use
  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / metabolism*
  • Antineoplastic Agents / therapeutic use
  • Blood-Brain Barrier
  • Carcinoma / drug therapy
  • Carcinoma / metabolism
  • Chick Embryo
  • Cyclohexanes
  • Endothelial Cells / metabolism
  • Humans
  • Liver / physiology
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / metabolism
  • Male
  • Melanoma / drug therapy
  • Melanoma / metabolism
  • Melanoma / pathology
  • Methacrylates / chemistry
  • Methacrylates / metabolism*
  • Methacrylates / therapeutic use
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, SCID
  • Molecular Structure
  • Neovascularization, Pathologic*
  • O-(Chloroacetylcarbamoyl)fumagillol
  • Polymers
  • Regeneration / physiology
  • Sesquiterpenes / chemistry
  • Sesquiterpenes / metabolism*
  • Sesquiterpenes / therapeutic use

Substances

  • Angiogenesis Inhibitors
  • Antineoplastic Agents
  • Cyclohexanes
  • Methacrylates
  • Polymers
  • Sesquiterpenes
  • hydroxypropyl methacrylate
  • O-(Chloroacetylcarbamoyl)fumagillol