title: A small-molecule drug conjugate for the treatment of carbonic anhydrase IX expressing tumors.
abstract: Antibody-drug conjugates are a very promising class of new anticancer agents, but the use of small-molecule ligands for the targeted delivery of cytotoxic drugs into solid tumors is less well established. Here, we describe the first small-molecule drug conjugates for the treatment of carbonic anhydrase IX expressing solid tumors. Using ligand-dye conjugates we demonstrate that such molecules can preferentially accumulate inside antigen-positive lesions, have fast targeting kinetics and good tumor-penetrating properties, and are easily accessible by total synthesis. A disulfide-linked drug conjugate with the maytansinoid DM1 as the cytotoxic payload and a derivative of acetazolamide as the targeting ligand exhibited a potent antitumor effect in SKRC52 renal cell carcinoma in vivo. It was furthermore superior to sunitinib and sorafenib, both small-molecule standard-of-care drugs for the treatment of kidney cancer.
authors.affiliation: Institute of Pharmaceutical Sciences, ETH Zurich, HCI, G391.4, Vladimir-Prelog-Weg 1-5/10, 8093 Zurich (Switzerland).
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Krall
authors.forename: Francesca
authors.initials: F
authors.lastname: Pretto
authors.forename: Willy
authors.initials: W
authors.lastname: Decurtins
authors.forename: Gonçalo J L
authors.initials: GJ
authors.lastname: Bernardes
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
authors.forename: Dario
authors.initials: D
authors.lastname: Neri
mesh_terms: D000818:Animals; D002256:Carbonic Anhydrases / Q000737:chemistry*; D016503:Drug Delivery Systems; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000628:therapy*; D051379:Mice; D015394:Molecular Structure; D011355:Prodrugs
chemical_list: D011355:Prodrugs; D002256:Carbonic Anhydrases
keywords: cancer therapy; carbonic anhydrase IX; drug conjugates; drug delivery; prodrugs