Targeting angiogenesis with a conjugate of HPMA copolymer and TNP-470.
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.
Vascular Biology Program and Department of Surgery, Boston Children's Hospital and Harvard Medical School, 1 Blackfan Circle, New Research Building, Boston, Massachusetts 02115, USA.
Ronit
R
Satchi-Fainaro
Mark
M
Puder
John W
JW
Davies
Hai T
HT
Tran
David A
DA
Sampson
Arin K
AK
Greene
Gabriel
G
Corfas
Judah
J
Folkman
D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D001812:Blood-Brain Barrier; D002277:Carcinoma / Q000188:drug therapy / Q000378:metabolism; D002642:Chick Embryo; D003510:Cyclohexanes; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000502:physiology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008689:Methacrylates / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D015394:Molecular Structure; D009389:Neovascularization, Pathologic; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D011108:Polymers; D012038:Regeneration / Q000502:physiology; D012717:Sesquiterpenes / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D003510:Cyclohexanes; D008689:Methacrylates; D011108:Polymers; D012717:Sesquiterpenes; C032802:hydroxypropyl methacrylate; D000077609:O-(Chloroacetylcarbamoyl)fumagillol