Cargando…

Tumor-selective peptide-carrier delivery of Paclitaxel increases in vivo activity of the drug

Taxanes are highly effective chemotherapeutic drugs against proliferating cancer and an established option in the standard treatment of ovarian and breast cancer. However, treatment with paclitaxel is associated with severe side effects, including sensory axonal neuropathy, and its poor solubility i...

Descripción completa

Detalles Bibliográficos
Autores principales: Brunetti, Jlenia, Pillozzi, Serena, Falciani, Chiara, Depau, Lorenzo, Tenori, Eleonora, Scali, Silvia, Lozzi, Luisa, Pini, Alessandro, Arcangeli, Annarosa, Menichetti, Stefano, Bracci, Luisa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4667195/
https://www.ncbi.nlm.nih.gov/pubmed/26626158
http://dx.doi.org/10.1038/srep17736
_version_ 1782403797834792960
author Brunetti, Jlenia
Pillozzi, Serena
Falciani, Chiara
Depau, Lorenzo
Tenori, Eleonora
Scali, Silvia
Lozzi, Luisa
Pini, Alessandro
Arcangeli, Annarosa
Menichetti, Stefano
Bracci, Luisa
author_facet Brunetti, Jlenia
Pillozzi, Serena
Falciani, Chiara
Depau, Lorenzo
Tenori, Eleonora
Scali, Silvia
Lozzi, Luisa
Pini, Alessandro
Arcangeli, Annarosa
Menichetti, Stefano
Bracci, Luisa
author_sort Brunetti, Jlenia
collection PubMed
description Taxanes are highly effective chemotherapeutic drugs against proliferating cancer and an established option in the standard treatment of ovarian and breast cancer. However, treatment with paclitaxel is associated with severe side effects, including sensory axonal neuropathy, and its poor solubility in water complicates its formulation. In this paper we report the in vitro and in vivo activity of a new form of paclitaxel, modified for conjugation with a tumor-selective tetrabranched peptide carrier (NT4). NT4 selectively targets tumor cells by binding to membrane sulfated glycosaminoglycans (GAG) and to endocytic receptors, like LRP1 and LRP6, which are established tumor markers. Biological activity of NT4-paclitaxel was tested in vitro on MDA-MB 231 and SKOV-3 cell lines, representing breast and ovarian cancer, respectively, and in vivo in an orthotopic mouse model of human breast cancer. Using in vivo bioluminescence imaging, we found that conjugation of paclitaxel with the NT4 peptide led to increased therapeutic activity of the drug in vivo. NT4-paclitaxel induced tumor regression, whereas treatment with unconjugated paclitaxel only produced a reduction in tumor growth. Moreover, unlike paclitaxel, NT4-paclitaxel is very hydrophilic, which may improve its pharmacokinetic profile and allow the use of less toxic dilution buffers, further decreasing its general chemotherapic toxicity.
format Online
Article
Text
id pubmed-4667195
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher Nature Publishing Group
record_format MEDLINE/PubMed
spelling pubmed-46671952015-12-08 Tumor-selective peptide-carrier delivery of Paclitaxel increases in vivo activity of the drug Brunetti, Jlenia Pillozzi, Serena Falciani, Chiara Depau, Lorenzo Tenori, Eleonora Scali, Silvia Lozzi, Luisa Pini, Alessandro Arcangeli, Annarosa Menichetti, Stefano Bracci, Luisa Sci Rep Article Taxanes are highly effective chemotherapeutic drugs against proliferating cancer and an established option in the standard treatment of ovarian and breast cancer. However, treatment with paclitaxel is associated with severe side effects, including sensory axonal neuropathy, and its poor solubility in water complicates its formulation. In this paper we report the in vitro and in vivo activity of a new form of paclitaxel, modified for conjugation with a tumor-selective tetrabranched peptide carrier (NT4). NT4 selectively targets tumor cells by binding to membrane sulfated glycosaminoglycans (GAG) and to endocytic receptors, like LRP1 and LRP6, which are established tumor markers. Biological activity of NT4-paclitaxel was tested in vitro on MDA-MB 231 and SKOV-3 cell lines, representing breast and ovarian cancer, respectively, and in vivo in an orthotopic mouse model of human breast cancer. Using in vivo bioluminescence imaging, we found that conjugation of paclitaxel with the NT4 peptide led to increased therapeutic activity of the drug in vivo. NT4-paclitaxel induced tumor regression, whereas treatment with unconjugated paclitaxel only produced a reduction in tumor growth. Moreover, unlike paclitaxel, NT4-paclitaxel is very hydrophilic, which may improve its pharmacokinetic profile and allow the use of less toxic dilution buffers, further decreasing its general chemotherapic toxicity. Nature Publishing Group 2015-12-02 /pmc/articles/PMC4667195/ /pubmed/26626158 http://dx.doi.org/10.1038/srep17736 Text en Copyright © 2015, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Brunetti, Jlenia
Pillozzi, Serena
Falciani, Chiara
Depau, Lorenzo
Tenori, Eleonora
Scali, Silvia
Lozzi, Luisa
Pini, Alessandro
Arcangeli, Annarosa
Menichetti, Stefano
Bracci, Luisa
Tumor-selective peptide-carrier delivery of Paclitaxel increases in vivo activity of the drug
title Tumor-selective peptide-carrier delivery of Paclitaxel increases in vivo activity of the drug
title_full Tumor-selective peptide-carrier delivery of Paclitaxel increases in vivo activity of the drug
title_fullStr Tumor-selective peptide-carrier delivery of Paclitaxel increases in vivo activity of the drug
title_full_unstemmed Tumor-selective peptide-carrier delivery of Paclitaxel increases in vivo activity of the drug
title_short Tumor-selective peptide-carrier delivery of Paclitaxel increases in vivo activity of the drug
title_sort tumor-selective peptide-carrier delivery of paclitaxel increases in vivo activity of the drug
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4667195/
https://www.ncbi.nlm.nih.gov/pubmed/26626158
http://dx.doi.org/10.1038/srep17736
work_keys_str_mv AT brunettijlenia tumorselectivepeptidecarrierdeliveryofpaclitaxelincreasesinvivoactivityofthedrug
AT pillozziserena tumorselectivepeptidecarrierdeliveryofpaclitaxelincreasesinvivoactivityofthedrug
AT falcianichiara tumorselectivepeptidecarrierdeliveryofpaclitaxelincreasesinvivoactivityofthedrug
AT depaulorenzo tumorselectivepeptidecarrierdeliveryofpaclitaxelincreasesinvivoactivityofthedrug
AT tenorieleonora tumorselectivepeptidecarrierdeliveryofpaclitaxelincreasesinvivoactivityofthedrug
AT scalisilvia tumorselectivepeptidecarrierdeliveryofpaclitaxelincreasesinvivoactivityofthedrug
AT lozziluisa tumorselectivepeptidecarrierdeliveryofpaclitaxelincreasesinvivoactivityofthedrug
AT pinialessandro tumorselectivepeptidecarrierdeliveryofpaclitaxelincreasesinvivoactivityofthedrug
AT arcangeliannarosa tumorselectivepeptidecarrierdeliveryofpaclitaxelincreasesinvivoactivityofthedrug
AT menichettistefano tumorselectivepeptidecarrierdeliveryofpaclitaxelincreasesinvivoactivityofthedrug
AT bracciluisa tumorselectivepeptidecarrierdeliveryofpaclitaxelincreasesinvivoactivityofthedrug