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Folic Acid-Targeted Paclitaxel-Polymer Conjugates Exert Selective Cytotoxicity and Modulate Invasiveness of Colon Cancer Cells

Although selective tumor delivery of anticancer drugs has been sought by exploiting either passive targeting or by ligand-mediated targeting, a selective anticancer therapy remains an unmet medical need. Despite the advances which have been achieved by nanomedicines, nanosystems such as polymer-drug...

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Autores principales: Grigoletto, Antonella, Martinez, Gabriele, Gabbia, Daniela, Tedeschini, Tommaso, Scaffidi, Michela, Martin, Sara De, Pasut, Gianfranco
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8309175/
https://www.ncbi.nlm.nih.gov/pubmed/34201494
http://dx.doi.org/10.3390/pharmaceutics13070929
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author Grigoletto, Antonella
Martinez, Gabriele
Gabbia, Daniela
Tedeschini, Tommaso
Scaffidi, Michela
Martin, Sara De
Pasut, Gianfranco
author_facet Grigoletto, Antonella
Martinez, Gabriele
Gabbia, Daniela
Tedeschini, Tommaso
Scaffidi, Michela
Martin, Sara De
Pasut, Gianfranco
author_sort Grigoletto, Antonella
collection PubMed
description Although selective tumor delivery of anticancer drugs has been sought by exploiting either passive targeting or by ligand-mediated targeting, a selective anticancer therapy remains an unmet medical need. Despite the advances which have been achieved by nanomedicines, nanosystems such as polymer-drug conjugates still miss the goal of clinical efficacy. In this study, we demonstrated that polymer-drug conjugates require a thoroughly chemical design and the right targeting agent/polymer ratio to be selective and effective towards cancer cells. In particular, two PEG conjugates carrying paclitaxel and targeted with different folic acid (FA)/PEG ratios (one or three) were investigated. The cytotoxicity study in positive (HT-29) and negative (HCT-15) FA receptor (FR)-cell lines demonstrated that the conjugates with one or three FAs were 4- or 28-fold more active in HT-29 cells, respectively. The higher activity of the 3-FA conjugate was confirmed by its strong impact on cell cycle arrest. Furthermore, FA targeting had a clear effect on migration and invasiveness of HT-29 cells, which were significantly reduced by both conjugates. Interestingly, the 3-FA conjugate showed also an improved pharmacokinetic profile in mice. The results of this study indicate that thorough investigations are needed to optimize and tune drug delivery and achieve the desired selectivity and activity towards cancer cells.
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spelling pubmed-83091752021-07-25 Folic Acid-Targeted Paclitaxel-Polymer Conjugates Exert Selective Cytotoxicity and Modulate Invasiveness of Colon Cancer Cells Grigoletto, Antonella Martinez, Gabriele Gabbia, Daniela Tedeschini, Tommaso Scaffidi, Michela Martin, Sara De Pasut, Gianfranco Pharmaceutics Article Although selective tumor delivery of anticancer drugs has been sought by exploiting either passive targeting or by ligand-mediated targeting, a selective anticancer therapy remains an unmet medical need. Despite the advances which have been achieved by nanomedicines, nanosystems such as polymer-drug conjugates still miss the goal of clinical efficacy. In this study, we demonstrated that polymer-drug conjugates require a thoroughly chemical design and the right targeting agent/polymer ratio to be selective and effective towards cancer cells. In particular, two PEG conjugates carrying paclitaxel and targeted with different folic acid (FA)/PEG ratios (one or three) were investigated. The cytotoxicity study in positive (HT-29) and negative (HCT-15) FA receptor (FR)-cell lines demonstrated that the conjugates with one or three FAs were 4- or 28-fold more active in HT-29 cells, respectively. The higher activity of the 3-FA conjugate was confirmed by its strong impact on cell cycle arrest. Furthermore, FA targeting had a clear effect on migration and invasiveness of HT-29 cells, which were significantly reduced by both conjugates. Interestingly, the 3-FA conjugate showed also an improved pharmacokinetic profile in mice. The results of this study indicate that thorough investigations are needed to optimize and tune drug delivery and achieve the desired selectivity and activity towards cancer cells. MDPI 2021-06-23 /pmc/articles/PMC8309175/ /pubmed/34201494 http://dx.doi.org/10.3390/pharmaceutics13070929 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Grigoletto, Antonella
Martinez, Gabriele
Gabbia, Daniela
Tedeschini, Tommaso
Scaffidi, Michela
Martin, Sara De
Pasut, Gianfranco
Folic Acid-Targeted Paclitaxel-Polymer Conjugates Exert Selective Cytotoxicity and Modulate Invasiveness of Colon Cancer Cells
title Folic Acid-Targeted Paclitaxel-Polymer Conjugates Exert Selective Cytotoxicity and Modulate Invasiveness of Colon Cancer Cells
title_full Folic Acid-Targeted Paclitaxel-Polymer Conjugates Exert Selective Cytotoxicity and Modulate Invasiveness of Colon Cancer Cells
title_fullStr Folic Acid-Targeted Paclitaxel-Polymer Conjugates Exert Selective Cytotoxicity and Modulate Invasiveness of Colon Cancer Cells
title_full_unstemmed Folic Acid-Targeted Paclitaxel-Polymer Conjugates Exert Selective Cytotoxicity and Modulate Invasiveness of Colon Cancer Cells
title_short Folic Acid-Targeted Paclitaxel-Polymer Conjugates Exert Selective Cytotoxicity and Modulate Invasiveness of Colon Cancer Cells
title_sort folic acid-targeted paclitaxel-polymer conjugates exert selective cytotoxicity and modulate invasiveness of colon cancer cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8309175/
https://www.ncbi.nlm.nih.gov/pubmed/34201494
http://dx.doi.org/10.3390/pharmaceutics13070929
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