Cargando…

Methotrexate-Loaded Solid Lipid Nanoparticles: Protein Functionalization to Improve Brain Biodistribution

Glioblastoma is the most common and invasive primary tumor of the central nervous system and normally has a negative prognosis. Biodistribution in healthy animal models is an important preliminary study aimed at investigating the efficacy of chemotherapy, as it is mainly addressed towards residual c...

Descripción completa

Detalles Bibliográficos
Autores principales: Muntoni, Elisabetta, Martina, Katia, Marini, Elisabetta, Giorgis, Marta, Lazzarato, Loretta, Salaroglio, Iris Chiara, Riganti, Chiara, Lanotte, Michele, Battaglia, Luigi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6409770/
https://www.ncbi.nlm.nih.gov/pubmed/30717376
http://dx.doi.org/10.3390/pharmaceutics11020065
_version_ 1783402061864370176
author Muntoni, Elisabetta
Martina, Katia
Marini, Elisabetta
Giorgis, Marta
Lazzarato, Loretta
Salaroglio, Iris Chiara
Riganti, Chiara
Lanotte, Michele
Battaglia, Luigi
author_facet Muntoni, Elisabetta
Martina, Katia
Marini, Elisabetta
Giorgis, Marta
Lazzarato, Loretta
Salaroglio, Iris Chiara
Riganti, Chiara
Lanotte, Michele
Battaglia, Luigi
author_sort Muntoni, Elisabetta
collection PubMed
description Glioblastoma is the most common and invasive primary tumor of the central nervous system and normally has a negative prognosis. Biodistribution in healthy animal models is an important preliminary study aimed at investigating the efficacy of chemotherapy, as it is mainly addressed towards residual cells after surgery in a region with an intact blood–brain barrier. Nanoparticles have emerged as versatile vectors that can overcome the blood–brain barrier. In this experimental work, solid lipid nanoparticles, prepared using fatty acid coacervation, have been loaded with an active lipophilic ester of cytotoxic drug methotrexate, and functionalized with either transferrin or insulin, two proteins whose receptors are abundantly expressed on the blood–brain barrier. Functionalization has been achieved by grafting a maleimide moiety onto the nanoparticle’s surface and exploiting its reactivity towards thiolated proteins. The nanoparticles have been tested in vitro on a blood–brain barrier cellular model and in vivo for biodistribution in Wistar rats. Drug metabolites, in particular 7-hydroxymethotrexate, have also been investigated in the animal model. The data obtained indicate that the functionalization of the nanoparticles improved their ability to overcome the blood–brain barrier when a PEG spacer between the proteins and the nanoparticle’s surface was used. This is probably because this method provided improved ligand–receptor interactions and selectivity for the target tissue.
format Online
Article
Text
id pubmed-6409770
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-64097702019-03-29 Methotrexate-Loaded Solid Lipid Nanoparticles: Protein Functionalization to Improve Brain Biodistribution Muntoni, Elisabetta Martina, Katia Marini, Elisabetta Giorgis, Marta Lazzarato, Loretta Salaroglio, Iris Chiara Riganti, Chiara Lanotte, Michele Battaglia, Luigi Pharmaceutics Article Glioblastoma is the most common and invasive primary tumor of the central nervous system and normally has a negative prognosis. Biodistribution in healthy animal models is an important preliminary study aimed at investigating the efficacy of chemotherapy, as it is mainly addressed towards residual cells after surgery in a region with an intact blood–brain barrier. Nanoparticles have emerged as versatile vectors that can overcome the blood–brain barrier. In this experimental work, solid lipid nanoparticles, prepared using fatty acid coacervation, have been loaded with an active lipophilic ester of cytotoxic drug methotrexate, and functionalized with either transferrin or insulin, two proteins whose receptors are abundantly expressed on the blood–brain barrier. Functionalization has been achieved by grafting a maleimide moiety onto the nanoparticle’s surface and exploiting its reactivity towards thiolated proteins. The nanoparticles have been tested in vitro on a blood–brain barrier cellular model and in vivo for biodistribution in Wistar rats. Drug metabolites, in particular 7-hydroxymethotrexate, have also been investigated in the animal model. The data obtained indicate that the functionalization of the nanoparticles improved their ability to overcome the blood–brain barrier when a PEG spacer between the proteins and the nanoparticle’s surface was used. This is probably because this method provided improved ligand–receptor interactions and selectivity for the target tissue. MDPI 2019-02-02 /pmc/articles/PMC6409770/ /pubmed/30717376 http://dx.doi.org/10.3390/pharmaceutics11020065 Text en © 2019 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Muntoni, Elisabetta
Martina, Katia
Marini, Elisabetta
Giorgis, Marta
Lazzarato, Loretta
Salaroglio, Iris Chiara
Riganti, Chiara
Lanotte, Michele
Battaglia, Luigi
Methotrexate-Loaded Solid Lipid Nanoparticles: Protein Functionalization to Improve Brain Biodistribution
title Methotrexate-Loaded Solid Lipid Nanoparticles: Protein Functionalization to Improve Brain Biodistribution
title_full Methotrexate-Loaded Solid Lipid Nanoparticles: Protein Functionalization to Improve Brain Biodistribution
title_fullStr Methotrexate-Loaded Solid Lipid Nanoparticles: Protein Functionalization to Improve Brain Biodistribution
title_full_unstemmed Methotrexate-Loaded Solid Lipid Nanoparticles: Protein Functionalization to Improve Brain Biodistribution
title_short Methotrexate-Loaded Solid Lipid Nanoparticles: Protein Functionalization to Improve Brain Biodistribution
title_sort methotrexate-loaded solid lipid nanoparticles: protein functionalization to improve brain biodistribution
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6409770/
https://www.ncbi.nlm.nih.gov/pubmed/30717376
http://dx.doi.org/10.3390/pharmaceutics11020065
work_keys_str_mv AT muntonielisabetta methotrexateloadedsolidlipidnanoparticlesproteinfunctionalizationtoimprovebrainbiodistribution
AT martinakatia methotrexateloadedsolidlipidnanoparticlesproteinfunctionalizationtoimprovebrainbiodistribution
AT marinielisabetta methotrexateloadedsolidlipidnanoparticlesproteinfunctionalizationtoimprovebrainbiodistribution
AT giorgismarta methotrexateloadedsolidlipidnanoparticlesproteinfunctionalizationtoimprovebrainbiodistribution
AT lazzaratoloretta methotrexateloadedsolidlipidnanoparticlesproteinfunctionalizationtoimprovebrainbiodistribution
AT salaroglioirischiara methotrexateloadedsolidlipidnanoparticlesproteinfunctionalizationtoimprovebrainbiodistribution
AT rigantichiara methotrexateloadedsolidlipidnanoparticlesproteinfunctionalizationtoimprovebrainbiodistribution
AT lanottemichele methotrexateloadedsolidlipidnanoparticlesproteinfunctionalizationtoimprovebrainbiodistribution
AT battaglialuigi methotrexateloadedsolidlipidnanoparticlesproteinfunctionalizationtoimprovebrainbiodistribution