Selective occlusion of tumor blood vessels by targeted delivery of an antibody-photosensitizer conjugate.
The irregular vasculature and high interstitial pressure of solid tumors hinder the delivery of cytotoxic agents to cancer cells. As a consequence, the doses of chemotherapy necessary to achieve complete tumor eradication are associated with unacceptably high toxicities. The selective thrombosis of tumor blood vessels has been postulated as an alternative avenue for combating cancer, depriving tumors of nutrients and oxygen and causing an avalanche of tumor cell deaths. The human antibody L19, specific to the EDB domain of fibronectin, a marker of angiogenesis, is capable of selective in vivo localization around tumor blood vessels and is thus a suitable agent for delivering toxic payloads to the tumor neovasculature. Here we show that a chemical conjugate of the L19 antibody with the photosensitizer bis(triethanolamine)Sn(IV) chlorin e(6), after intravenous injection and irradiation with red light, caused an arrest of tumor growth in mice with subcutaneous tumors. By contrast, a photosensitizer conjugate obtained with an antibody of identical pharmacokinetic properties but irrelevant specificity did not exhibit a significant therapeutic effect. These results confirm that vascular targeting strategies, aimed at the selective occlusion/disruption of tumor blood vessels, have a significant anticancer therapeutic potential and encourage the use of antibody-photosensitizer conjugates for the therapy of superficial tumors and possibly other angiogenesis-related pathologies.
Fabbrini
Monica
M
Department of Molecular Biology, University of Siena, Siena, Italy.
Trachsel
Eveline
E
Soldani
Patrizia
P
Bindi
Stefano
S
Alessi
Patrizia
P
Bracci
Luisa
L
Kosmehl
Hartwig
H
Zardi
Luciano
L
Neri
Dario
D
Neri
Paolo
P
D000230:Adenocarcinoma / Q000098:blood supply / Q000188:drug therapy; D000818:Animals; D000906:Antibodies; D003110:Colonic Neoplasms / Q000098:blood supply / Q000188:drug therapy; D007135:Immunoglobulin Variable Region; D051379:Mice; D009389:Neovascularization, Pathologic; D017319:Photosensitizing Agents / Q000008:administration & dosage / Q000494:pharmacology*; D010789:Phototherapy / Q000379:methods*; D051381:Rats; D012039:Regional Blood Flow; D012509:Sarcoma / Q000098:blood supply / Q000188:drug therapy; D018243:Teratocarcinoma / Q000098:blood supply / Q000188:drug therapy; D014183:Transplantation, Heterologous
D000906:Antibodies; D007135:Immunoglobulin Variable Region; D017319:Photosensitizing Agents