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Nanospermidine in Combination with Nanofenretinide Induces Cell Death in Neuroblastoma Cell Lines

A new strategy to cause cell death in tumors might be the increase of intracellular polyamines at concentrations above their physiological values to trigger the production of oxidation metabolites at levels exceeding cell tolerance. To test this hypothesis, we prepared nanospermidine as a carrier fo...

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Autores principales: Lodeserto, Pietro, Rossi, Martina, Blasi, Paolo, Farruggia, Giovanna, Orienti, Isabella
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9229898/
https://www.ncbi.nlm.nih.gov/pubmed/35745787
http://dx.doi.org/10.3390/pharmaceutics14061215
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author Lodeserto, Pietro
Rossi, Martina
Blasi, Paolo
Farruggia, Giovanna
Orienti, Isabella
author_facet Lodeserto, Pietro
Rossi, Martina
Blasi, Paolo
Farruggia, Giovanna
Orienti, Isabella
author_sort Lodeserto, Pietro
collection PubMed
description A new strategy to cause cell death in tumors might be the increase of intracellular polyamines at concentrations above their physiological values to trigger the production of oxidation metabolites at levels exceeding cell tolerance. To test this hypothesis, we prepared nanospermidine as a carrier for spermidine penetration into the cells, able to escape the polyamine transport system that strictly regulates intracellular polyamine levels. Nanospermidine was prepared by spermidine encapsulation in nanomicelles and was characterized by size, zeta potential, loading, dimensional stability to dilution, and stability to spermidine leakage. Antitumor activity, ROS production, and cell penetration ability were evaluated in vitro in two neuroblastoma cell lines (NLF and BR6). Nanospermidine was tested as a single agent and in combination with nanofenretinide. Free spermidine was also tested as a comparison. The results indicated that the nanomicelles successfully transported spermidine into the cells inducing cell death in a concentration range (150–200 μM) tenfold lower than that required to provide similar cytotoxicity with free spermidine (1500–2000 μM). Nanofenretinide provided a cytostatic effect in combination with the lowest nanospermidine concentrations evaluated and slightly improved nanospermidine cytotoxicity at the highest concentrations. These data suggest that nanospermidine has the potential to become a new approach in cancer treatment. At the cellular level, in fact, it exploits polyamine catabolism by means of biocompatible doses of spermidine and, in vivo settings, it can exploit the selective accumulation of nanomedicines at the tumor site. Nanofenretinide combination further improves its efficacy. Furthermore, the proven ability of spermidine to activate macrophages and lymphocytes suggests that nanospermidine could inhibit immunosuppression in the tumor environment.
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spelling pubmed-92298982022-06-25 Nanospermidine in Combination with Nanofenretinide Induces Cell Death in Neuroblastoma Cell Lines Lodeserto, Pietro Rossi, Martina Blasi, Paolo Farruggia, Giovanna Orienti, Isabella Pharmaceutics Article A new strategy to cause cell death in tumors might be the increase of intracellular polyamines at concentrations above their physiological values to trigger the production of oxidation metabolites at levels exceeding cell tolerance. To test this hypothesis, we prepared nanospermidine as a carrier for spermidine penetration into the cells, able to escape the polyamine transport system that strictly regulates intracellular polyamine levels. Nanospermidine was prepared by spermidine encapsulation in nanomicelles and was characterized by size, zeta potential, loading, dimensional stability to dilution, and stability to spermidine leakage. Antitumor activity, ROS production, and cell penetration ability were evaluated in vitro in two neuroblastoma cell lines (NLF and BR6). Nanospermidine was tested as a single agent and in combination with nanofenretinide. Free spermidine was also tested as a comparison. The results indicated that the nanomicelles successfully transported spermidine into the cells inducing cell death in a concentration range (150–200 μM) tenfold lower than that required to provide similar cytotoxicity with free spermidine (1500–2000 μM). Nanofenretinide provided a cytostatic effect in combination with the lowest nanospermidine concentrations evaluated and slightly improved nanospermidine cytotoxicity at the highest concentrations. These data suggest that nanospermidine has the potential to become a new approach in cancer treatment. At the cellular level, in fact, it exploits polyamine catabolism by means of biocompatible doses of spermidine and, in vivo settings, it can exploit the selective accumulation of nanomedicines at the tumor site. Nanofenretinide combination further improves its efficacy. Furthermore, the proven ability of spermidine to activate macrophages and lymphocytes suggests that nanospermidine could inhibit immunosuppression in the tumor environment. MDPI 2022-06-07 /pmc/articles/PMC9229898/ /pubmed/35745787 http://dx.doi.org/10.3390/pharmaceutics14061215 Text en © 2022 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
Lodeserto, Pietro
Rossi, Martina
Blasi, Paolo
Farruggia, Giovanna
Orienti, Isabella
Nanospermidine in Combination with Nanofenretinide Induces Cell Death in Neuroblastoma Cell Lines
title Nanospermidine in Combination with Nanofenretinide Induces Cell Death in Neuroblastoma Cell Lines
title_full Nanospermidine in Combination with Nanofenretinide Induces Cell Death in Neuroblastoma Cell Lines
title_fullStr Nanospermidine in Combination with Nanofenretinide Induces Cell Death in Neuroblastoma Cell Lines
title_full_unstemmed Nanospermidine in Combination with Nanofenretinide Induces Cell Death in Neuroblastoma Cell Lines
title_short Nanospermidine in Combination with Nanofenretinide Induces Cell Death in Neuroblastoma Cell Lines
title_sort nanospermidine in combination with nanofenretinide induces cell death in neuroblastoma cell lines
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9229898/
https://www.ncbi.nlm.nih.gov/pubmed/35745787
http://dx.doi.org/10.3390/pharmaceutics14061215
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