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

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 canc...

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Autores principales: Crielaard, Bart J, van der Wal, Steffen, Lammers, Twan, Le, Huong Thu, Hennink, Wim E, Schiffelers, Raymond M, Storm, Gert, Fens, Marcel HAM
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove Medical Press 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3218583/
https://www.ncbi.nlm.nih.gov/pubmed/22114500
http://dx.doi.org/10.2147/IJN.S24450
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author Crielaard, Bart J
van der Wal, Steffen
Lammers, Twan
Le, Huong Thu
Hennink, Wim E
Schiffelers, Raymond M
Storm, Gert
Fens, Marcel HAM
author_facet Crielaard, Bart J
van der Wal, Steffen
Lammers, Twan
Le, Huong Thu
Hennink, Wim E
Schiffelers, Raymond M
Storm, Gert
Fens, Marcel HAM
author_sort Crielaard, Bart J
collection PubMed
description 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.
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spelling pubmed-32185832011-11-23 A polymeric colchicinoid prodrug with reduced toxicity and improved efficacy for vascular disruption in cancer therapy Crielaard, Bart J van der Wal, Steffen Lammers, Twan Le, Huong Thu Hennink, Wim E Schiffelers, Raymond M Storm, Gert Fens, Marcel HAM Int J Nanomedicine Original Research 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. Dove Medical Press 2011 2011-11-02 /pmc/articles/PMC3218583/ /pubmed/22114500 http://dx.doi.org/10.2147/IJN.S24450 Text en © 2011 Crielaard et al, publisher and licensee Dove Medical Press Ltd This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.
spellingShingle Original Research
Crielaard, Bart J
van der Wal, Steffen
Lammers, Twan
Le, Huong Thu
Hennink, Wim E
Schiffelers, Raymond M
Storm, Gert
Fens, Marcel HAM
A polymeric colchicinoid prodrug with reduced toxicity and improved efficacy for vascular disruption in cancer therapy
title 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_short 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
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3218583/
https://www.ncbi.nlm.nih.gov/pubmed/22114500
http://dx.doi.org/10.2147/IJN.S24450
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