title: A polymeric colchicinoid prodrug with reduced toxicity and improved efficacy for vascular disruption in cancer therapy.
abstract: Colchicinoids are very potent tubulin-binding compounds, which interfere with microtubule formation, giving them strong cytotoxic properties, such as cell mitosis inhibition and induction of microcytoskeleton depolymerization. While this makes them promising vascular disrupting agents (VDAs) in cancer therapy, their dose-limiting toxicity has prevented any clinical application for this purpose. Therefore, colchicinoids are considered attractive lead molecules for the development of novel vascular disrupting nanomedicine. In a previous study, a polymeric colchicinoid prodrug that showed favorable hydrolysis characteristics at physiological conditions was developed. In the current study, this polymeric colchicinoid prodrug was evaluated in vitro and in vivo for its toxicity and vascular disrupting potential. Cell viability studies with human umbilical vein endothelial cells, as an in vitro measure for colchicine activity, reflected the degradation kinetics of the prodrug accordingly. Upon intravenous treatment, in vivo, of B16F10 melanoma-bearing mice with colchicine or with the polymeric colchicinoid prodrug, apparent vascular disruption and consequent tumor necrosis was observed for the prodrug but not for free colchicine at an equivalent dose. Moreover, a five-times-higher dose of the prodrug was well tolerated, indicating reduced toxicity. These findings demonstrate that the polymeric colchicinoid prodrug has a substantially improved efficacy/toxicity ratio compared with that of colchicine, making it a promising VDA for cancer therapy.
authors: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors: Bart J
authors: BJ
authors: Crielaard
authors: Steffen
authors: S
authors: van der Wal
authors: Twan
authors: T
authors: Lammers
authors: Huong Thu
authors: HT
authors: Le
authors: Wim E
authors: WE
authors: Hennink
authors: Raymond M
authors: RM
authors: Schiffelers
authors: Gert
authors: G
authors: Storm
authors: Marcel Ham
authors: MH
authors: Fens
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D002470:Cell Survival / Q000187:drug effects*; D003078:Colchicine / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D005260:Female; D006651:Histocytochemistry; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D011355:Prodrugs; D003078:Colchicine