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Ultrasmall AGuIX theranostic nanoparticles for vascular-targeted interstitial photodynamic therapy of glioblastoma

Authors Thomas E, Colombeau L, Gries M, Peterlini T, Mathieu C, Thomas N, Boura C, Frochot C, Vanderesse R, Lux F, Barberi-Heyob M, Tillement O

Received 11 May 2017

Accepted for publication 1 July 2017

Published 26 September 2017 Volume 2017:12 Pages 7075—7088


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Thomas Webster

Eloïse Thomas,1 Ludovic Colombeau,2 Mickaël Gries,3,4 Thibaut Peterlini,3,4 Clélia Mathieu,1 Noémie Thomas,3,4 Cédric Boura,3,4 Céline Frochot,2 Régis Vanderesse,5 François Lux,1 Muriel Barberi-Heyob,3,4 Olivier Tillement1

1Université Lyon, Université Claude Bernard Lyon 1, Centre National de la Recherche Scientifique (CNRS), Institut Lumière Matière, Lyon, 2Laboratoire Réactions et Génie des Procédés, Université de Lorraine-CNRS, Nancy, 3Université de Lorraine, Research Center for Automatic Control of Nancy (CRAN), 4CNRS, CRAN, Vandœuvre-lès-Nancy, 5Laboratoire de Chimie Physique Macromoléculaire, Université de Lorraine-CNRS, Nancy, France

Abstract: Despite combined treatments, glioblastoma outcome remains poor with frequent local recurrences, indicating that a more efficient and local therapy is needed. In this way, vascular-targeted photodynamic therapy (VTP) could help tumor eradication by destroying its neovessels. In this study, we designed a polysiloxane-based nanoparticle (NP) combining a magnetic resonance imaging (MRI) contrast agent, a photosensitizer (PS) and a new ligand peptide motif (KDKPPR) targeting neuropilin-1 (NRP-1), a receptor overexpressed by angiogenic endothelial cells of the tumor vasculature. This structure achieves the detection of the tumor tissue and its proliferating part by MRI analysis, followed by its treatment by VTP. The photophysical properties of the PS and the peptide affinity for NRP-1 recombinant protein were preserved after the functionalization of NPs. Cellular uptake of NPs by human umbilical vein endothelial cells (HUVEC) was increased twice compared to NPs without the KDKPPR peptide moiety or conjugated with a scramble peptide. NPs induced no cytotoxicity without light exposure but conferred a photocytotoxic effect to cells after photodynamic therapy (PDT). The in vivo selectivity, evaluated using a skinfold chamber model in mice, confirms that the functionalized NPs with KDKPPR peptide moiety were localized in the tumor vessel wall.

Keywords: nanoparticles, PDT, vascular targeting strategy, brain tumor, NRP-1, peptide ligand, MRI

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