A polymeric colchicinoid prodrug with reduced toxicity and improved efficacy for vascular disruption in cancer therapy

Bart J Crielaard1, Steffen van der Wal1, Twan Lammers2, Huong Thu Le1, Wim E Hennink1, Raymond M Schiffelers1, Gert Storm1, Marcel HAM Fens11Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands; 2Department of Experimental Molecular...

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Autores principales:	Crielaard BJ, van der Wal S, Lammers T, Le HT, Hennink WE, Schiffelers RM, Storm G, Fens MHAM
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2011
Materias:	Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/35c8a337cef54e64bf896ec89bc1248a
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spelling	oai:doaj.org-article:35c8a337cef54e64bf896ec89bc1248a2021-12-02T07:36:58ZA polymeric colchicinoid prodrug with reduced toxicity and improved efficacy for vascular disruption in cancer therapy1176-91141178-2013https://doaj.org/article/35c8a337cef54e64bf896ec89bc1248a2011-11-01T00:00:00Zhttp://www.dovepress.com/a-polymeric-colchicinoid-prodrug-with-reduced-toxicity-and-improved-ef-a8587https://doaj.org/toc/1176-9114https://doaj.org/toc/1178-2013Bart J Crielaard1, Steffen van der Wal1, Twan Lammers2, Huong Thu Le1, Wim E Hennink1, Raymond M Schiffelers1, Gert Storm1, Marcel HAM Fens11Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands; 2Department of Experimental Molecular Imaging, RWTH Aachen University, Aachen, Germany The first two authors contributed equally to this work. 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. Keywords: colchicine, prodrug, nanomedicines, cancer, vascular disrupting agentsCrielaard BJvan der Wal SLammers TLe HTHennink WESchiffelers RMStorm GFens MHAMDove Medical PressarticleMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol 2011, Iss default, Pp 2697-2703 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine (General) R5-920
spellingShingle	Medicine (General) R5-920 Crielaard BJ van der Wal S Lammers T Le HT Hennink WE Schiffelers RM Storm G Fens MHAM A polymeric colchicinoid prodrug with reduced toxicity and improved efficacy for vascular disruption in cancer therapy
description	Bart J Crielaard1, Steffen van der Wal1, Twan Lammers2, Huong Thu Le1, Wim E Hennink1, Raymond M Schiffelers1, Gert Storm1, Marcel HAM Fens11Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands; 2Department of Experimental Molecular Imaging, RWTH Aachen University, Aachen, Germany The first two authors contributed equally to this work. 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. Keywords: colchicine, prodrug, nanomedicines, cancer, vascular disrupting agents
format	article
author	Crielaard BJ van der Wal S Lammers T Le HT Hennink WE Schiffelers RM Storm G Fens MHAM
author_facet	Crielaard BJ van der Wal S Lammers T Le HT Hennink WE Schiffelers RM Storm G Fens MHAM
author_sort	Crielaard BJ
title	A polymeric colchicinoid prodrug with reduced toxicity and improved efficacy for vascular disruption in cancer therapy
title_short	A polymeric colchicinoid prodrug with reduced toxicity and improved efficacy for vascular disruption in cancer therapy
title_full	A polymeric colchicinoid prodrug with reduced toxicity and improved efficacy for vascular disruption in cancer therapy
title_fullStr	A polymeric colchicinoid prodrug with reduced toxicity and improved efficacy for vascular disruption in cancer therapy
title_full_unstemmed	A polymeric colchicinoid prodrug with reduced toxicity and improved efficacy for vascular disruption in cancer therapy
title_sort	polymeric colchicinoid prodrug with reduced toxicity and improved efficacy for vascular disruption in cancer therapy
publisher	Dove Medical Press
publishDate	2011
url	https://doaj.org/article/35c8a337cef54e64bf896ec89bc1248a
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A polymeric colchicinoid prodrug with reduced toxicity and improved efficacy for vascular disruption in cancer therapy

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