Multiscale Selectivity and in vivo Biodistribution of NRP-1-Targeted Theranostic AGuIX Nanoparticles for PDT of Glioblastoma

Mickaël Gries, 1 Noémie Thomas, 1 Joël Daouk, 1 Paul Rocchi, 2 Laurence Choulier, 3 Justine Jubréaux, 1 Julien Pierson, 1 Aurélie Reinhard, 1 Valérie Jouan-Hureaux, 1 Alicia Chateau, 1 Samir Acherar, 4 Céline Frochot, 5 Fran&am...

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Main Authors: Gries M, Thomas N, Daouk J, Rocchi P, Choulier L, Jubréaux J, Pierson J, Reinhard A, Jouan-Hureaux V, Chateau A, Acherar S, Frochot C, Lux F, Tillement O, Barberi-Heyob M
Format: Article
Language:English
Published: Dove Medical Press 2020-11-01
Series:International Journal of Nanomedicine
Subjects:
Online Access:https://www.dovepress.com/multiscale-selectivity-and-in-vivo-biodistribution-of-nrp-1-targeted-t-peer-reviewed-article-IJN
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author Gries M
Thomas N
Daouk J
Rocchi P
Choulier L
Jubréaux J
Pierson J
Reinhard A
Jouan-Hureaux V
Chateau A
Acherar S
Frochot C
Lux F
Tillement O
Barberi-Heyob M
author_facet Gries M
Thomas N
Daouk J
Rocchi P
Choulier L
Jubréaux J
Pierson J
Reinhard A
Jouan-Hureaux V
Chateau A
Acherar S
Frochot C
Lux F
Tillement O
Barberi-Heyob M
author_sort Gries M
collection DOAJ
description Mickaël Gries, 1 Noémie Thomas, 1 Joël Daouk, 1 Paul Rocchi, 2 Laurence Choulier, 3 Justine Jubréaux, 1 Julien Pierson, 1 Aurélie Reinhard, 1 Valérie Jouan-Hureaux, 1 Alicia Chateau, 1 Samir Acherar, 4 Céline Frochot, 5 François Lux, 2– 6 Olivier Tillement, 2 Muriel Barberi-Heyob 1 1Université de Lorraine, Centre National de la Recherche Scientifique (CNRS), Research Center for Automatic Control of Nancy (CRAN), Nancy, France; 2Université de Lyon, CNRS, Institut Lumière Matière, Lyon, France; 3Université de Strasbourg, CNRS, Biotechnologie et Signalisation Cellulaire, Illkirch, France; 4Université de Lorraine, CNRS, Laboratoire de Chimie-Physique Macromoléculaire, Nancy, France; 5Université de Lorraine, CNRS, Laboratoire Réactions et Génie des Procédés, Nancy, France; 6Institut Universitaire de France, Paris, FranceCorrespondence: Muriel Barberi-Heyob Email muriel.barberi@univ-lorraine.frBackground: Local recurrences of glioblastoma (GBM) after heavy standard treatments remain frequent and lead to a poor prognostic. Major challenges are the infiltrative part of the tumor tissue which is the ultimate cause of recurrence. The therapeutic arsenal faces the difficulty of eradicating this infiltrating part of the tumor tissue while increasing the targeting of tumor and endogenous stromal cells such as angiogenic endothelial cells. In this aim, neuropilin-1 (NRP-1), a transmembrane receptor mainly overexpressed by endothelial cells of the tumor vascular system and associated with malignancy, proliferation and migration of GBM, highlighted to be a relevant molecular target to promote the anti-vascular effect of photodynamic therapy (VTP).Methods: The multiscale selectivity was investigated for KDKPPR peptide moiety targeting NRP-1 and a porphyrin molecule as photosensitizer (PS), both grafted onto original AGuIX design nanoparticle. AGuIX nanoparticle, currently in Phase II clinical trials for the treatment of brain metastases with radiotherapy, allows to achieve a real-time magnetic resonance imaging (MRI) and an accumulation in the tumor area by EPR (enhanced permeability and retention) effect. Using surface-plasmon resonance (SPR), we evaluated the affinities of KDKPPR and scramble free peptides, and also peptides-conjugated AGuIX nanoparticles to recombinant rat and human NRP-1 proteins. For in vivo selectivity, we used a cranial window model and parametric maps obtained from T2*-weighted perfusion MRI analysis.Results: The photophysical characteristics of the PS and KDKPPR molecular affinity for recombinant human NRP-1 proteins were maintained after the functionalization of AGuIX nanoparticle with a dissociation constant of 4.7 μM determined by SPR assays. Cranial window model and parametric maps, both revealed a prolonged retention in the vascular system of human xenotransplanted GBM. Thanks to the fluorescence of porphyrin by non-invasive imaging and the concentration of gadolinium evaluated after extraction of organs, we checked the absence of nanoparticle in the brains of tumor-free animals and highlighted elimination by renal excretion and hepatic metabolism.Conclusion: Post-VTP follow-ups demonstrated promising tumor responses with a prolonged delay in tumor growth accompanied by a decrease in tumor metabolism.Keywords: vascular photodynamic therapy, AGuIX nanoparticle, NRP-1, peptide, brain tumors, glioblastoma, radiation therapies
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spelling doaj.art-29f4bf6d46be45c79f388ccc4227819d2022-12-21T23:38:53ZengDove Medical PressInternational Journal of Nanomedicine1178-20132020-11-01Volume 158739875859064Multiscale Selectivity and in vivo Biodistribution of NRP-1-Targeted Theranostic AGuIX Nanoparticles for PDT of GlioblastomaGries MThomas NDaouk JRocchi PChoulier LJubréaux JPierson JReinhard AJouan-Hureaux VChateau AAcherar SFrochot CLux FTillement OBarberi-Heyob MMickaël Gries, 1 Noémie Thomas, 1 Joël Daouk, 1 Paul Rocchi, 2 Laurence Choulier, 3 Justine Jubréaux, 1 Julien Pierson, 1 Aurélie Reinhard, 1 Valérie Jouan-Hureaux, 1 Alicia Chateau, 1 Samir Acherar, 4 Céline Frochot, 5 François Lux, 2– 6 Olivier Tillement, 2 Muriel Barberi-Heyob 1 1Université de Lorraine, Centre National de la Recherche Scientifique (CNRS), Research Center for Automatic Control of Nancy (CRAN), Nancy, France; 2Université de Lyon, CNRS, Institut Lumière Matière, Lyon, France; 3Université de Strasbourg, CNRS, Biotechnologie et Signalisation Cellulaire, Illkirch, France; 4Université de Lorraine, CNRS, Laboratoire de Chimie-Physique Macromoléculaire, Nancy, France; 5Université de Lorraine, CNRS, Laboratoire Réactions et Génie des Procédés, Nancy, France; 6Institut Universitaire de France, Paris, FranceCorrespondence: Muriel Barberi-Heyob Email muriel.barberi@univ-lorraine.frBackground: Local recurrences of glioblastoma (GBM) after heavy standard treatments remain frequent and lead to a poor prognostic. Major challenges are the infiltrative part of the tumor tissue which is the ultimate cause of recurrence. The therapeutic arsenal faces the difficulty of eradicating this infiltrating part of the tumor tissue while increasing the targeting of tumor and endogenous stromal cells such as angiogenic endothelial cells. In this aim, neuropilin-1 (NRP-1), a transmembrane receptor mainly overexpressed by endothelial cells of the tumor vascular system and associated with malignancy, proliferation and migration of GBM, highlighted to be a relevant molecular target to promote the anti-vascular effect of photodynamic therapy (VTP).Methods: The multiscale selectivity was investigated for KDKPPR peptide moiety targeting NRP-1 and a porphyrin molecule as photosensitizer (PS), both grafted onto original AGuIX design nanoparticle. AGuIX nanoparticle, currently in Phase II clinical trials for the treatment of brain metastases with radiotherapy, allows to achieve a real-time magnetic resonance imaging (MRI) and an accumulation in the tumor area by EPR (enhanced permeability and retention) effect. Using surface-plasmon resonance (SPR), we evaluated the affinities of KDKPPR and scramble free peptides, and also peptides-conjugated AGuIX nanoparticles to recombinant rat and human NRP-1 proteins. For in vivo selectivity, we used a cranial window model and parametric maps obtained from T2*-weighted perfusion MRI analysis.Results: The photophysical characteristics of the PS and KDKPPR molecular affinity for recombinant human NRP-1 proteins were maintained after the functionalization of AGuIX nanoparticle with a dissociation constant of 4.7 μM determined by SPR assays. Cranial window model and parametric maps, both revealed a prolonged retention in the vascular system of human xenotransplanted GBM. Thanks to the fluorescence of porphyrin by non-invasive imaging and the concentration of gadolinium evaluated after extraction of organs, we checked the absence of nanoparticle in the brains of tumor-free animals and highlighted elimination by renal excretion and hepatic metabolism.Conclusion: Post-VTP follow-ups demonstrated promising tumor responses with a prolonged delay in tumor growth accompanied by a decrease in tumor metabolism.Keywords: vascular photodynamic therapy, AGuIX nanoparticle, NRP-1, peptide, brain tumors, glioblastoma, radiation therapieshttps://www.dovepress.com/multiscale-selectivity-and-in-vivo-biodistribution-of-nrp-1-targeted-t-peer-reviewed-article-IJNvascular photodynamic therapyaguix nanoparticlenrp-1peptidebrain tumorsglioblastomaradiation therapies
spellingShingle Gries M
Thomas N
Daouk J
Rocchi P
Choulier L
Jubréaux J
Pierson J
Reinhard A
Jouan-Hureaux V
Chateau A
Acherar S
Frochot C
Lux F
Tillement O
Barberi-Heyob M
Multiscale Selectivity and in vivo Biodistribution of NRP-1-Targeted Theranostic AGuIX Nanoparticles for PDT of Glioblastoma
International Journal of Nanomedicine
vascular photodynamic therapy
aguix nanoparticle
nrp-1
peptide
brain tumors
glioblastoma
radiation therapies
title Multiscale Selectivity and in vivo Biodistribution of NRP-1-Targeted Theranostic AGuIX Nanoparticles for PDT of Glioblastoma
title_full Multiscale Selectivity and in vivo Biodistribution of NRP-1-Targeted Theranostic AGuIX Nanoparticles for PDT of Glioblastoma
title_fullStr Multiscale Selectivity and in vivo Biodistribution of NRP-1-Targeted Theranostic AGuIX Nanoparticles for PDT of Glioblastoma
title_full_unstemmed Multiscale Selectivity and in vivo Biodistribution of NRP-1-Targeted Theranostic AGuIX Nanoparticles for PDT of Glioblastoma
title_short Multiscale Selectivity and in vivo Biodistribution of NRP-1-Targeted Theranostic AGuIX Nanoparticles for PDT of Glioblastoma
title_sort multiscale selectivity and in vivo biodistribution of nrp 1 targeted theranostic aguix nanoparticles for pdt of glioblastoma
topic vascular photodynamic therapy
aguix nanoparticle
nrp-1
peptide
brain tumors
glioblastoma
radiation therapies
url https://www.dovepress.com/multiscale-selectivity-and-in-vivo-biodistribution-of-nrp-1-targeted-t-peer-reviewed-article-IJN
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