title: A Combined Approach Employing Chlorotoxin-Nanovectors and Low Dose Radiation To Reach Infiltrating Tumor Niches in Glioblastoma.
abstract: Glioblastoma multiforme (GBM) is the most aggressive form of glioma, with life expectancy of around 2 years after diagnosis, due to recidivism and to the blood-brain barrier (BBB) limiting the amount of drugs which reach the residual malignant cells, thus contributing to the failure of chemotherapies. To bypass the obstacles imposed by the BBB, we investigated the use of nanotechnologies combined with radiotherapy, as a potential therapeutic strategy for GBM. We used poly(lactic-co-glycolic acid) (PLGA) nanoparticles (PNP) conjugated to chlorotoxin (CTX), a peptide reported to bind selectively to glioma cells. Silver nanoparticles were entrapped inside the functionalized nanoparticles (Ag-PNP-CTX), to allow detection and quantification of the cellular uptake by confocal microscopy, both in vitro and in vivo. In vitro experiments performed with different human glioblastoma cell lines showed higher cytoplasmic uptake of Ag-PNP-CTX, with respect to nonfunctionalized nanoparticles. In vivo experiments showed that Ag-NP-CTX efficiently targets the tumor, but are scarcely effective in crossing the blood brain barrier in the healthy brain, where dispersed metastatic cells are present. We show here that single whole brain X-ray irradiation, performed 20 h before nanoparticle injection, enhances the expression of the CTX targets, MMP-2 and ClC-3, and, through BBB permeabilization, potently increases the amount of internalized Ag-PNP-CTX even in dispersed cells, and generated an efficient antitumor synergistic effect able to inhibit in vivo tumor growth. Notably, the application of Ag-PNP-CTX to irradiated tumor cells decreases the extracellular activity of MMP-2. By targeting dispersed GBM cells and reducing MMP-2 activity, the combined use of CTX-nanovectors with radiotherapy may represent a promising therapeutic approach toward GBM.
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, Via Vanvitelli 32, 20129 Milano, Italy.|CNR Institute of Neuroscience, Via Vanvitelli 32, 20129 Milano, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Tamborini
authors.affiliation: Department of Industrial Chemistry "Toso Montanari", University of Bologna , Viale Risorgimento 4, 40136 Bologna, Italy.
authors.forename: Erica
authors.initials: E
authors.lastname: Locatelli
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, Via Vanvitelli 32, 20129 Milano, Italy.|Laboratory of Pharmacology and Brain Pathology, Humanitas Research Hospital , Via Manzoni 56, Rozzano, 20089 Milano, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Rasile
authors.affiliation: Department of Industrial Chemistry "Toso Montanari", University of Bologna , Viale Risorgimento 4, 40136 Bologna, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Monaco
authors.affiliation: Fondazione Filarete, Viale Ortles 22/4, 20139 Milano, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Rodighiero
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, Via Vanvitelli 32, 20129 Milano, Italy.|CNR Institute of Neuroscience, Via Vanvitelli 32, 20129 Milano, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Corradini
authors.affiliation: Department of Industrial Chemistry "Toso Montanari", University of Bologna , Viale Risorgimento 4, 40136 Bologna, Italy.
authors.forename: Mauro Comes
authors.initials: MC
authors.lastname: Franchini
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, Via Vanvitelli 32, 20129 Milano, Italy.|Fondazione Filarete, Viale Ortles 22/4, 20139 Milano, Italy.
authors.forename: Lorena
authors.initials: L
authors.lastname: Passoni
authors.affiliation: CNR Institute of Neuroscience, Via Vanvitelli 32, 20129 Milano, Italy.|Laboratory of Pharmacology and Brain Pathology, Humanitas Research Hospital , Via Manzoni 56, Rozzano, 20089 Milano, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Matteoli
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001932:Brain Neoplasms / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D059248:Chemoradiotherapy / Q000379:methods*; D018118:Chloride Channels / Q000378:metabolism; D005909:Glioblastoma / Q000473:pathology / Q000628:therapy*; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D053768:Metal Nanoparticles / Q000737:chemistry*; D051379:Mice; D009362:Neoplasm Metastasis; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011485:Protein Binding; D012604:Scorpion Venoms / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012834:Silver / Q000737:chemistry; D059016:Tumor Microenvironment; D014964:X-Ray Therapy
chemical_list: D018118:Chloride Channels; C115376:ClC-3 channel; D012604:Scorpion Venoms; C091539:Chlorotoxin; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D012834:Silver; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2
keywords: MMP-2; chlorotoxin-targeted nanovectors; drug delivery; glioblastoma; ionizing radiation