A Combined Approach Employing Chlorotoxin-Nanovectors and Low Dose Radiation to Reach Infiltrating Tumor Niches in Glioblastoma

Matteo Tamborini, Erica Locatelli, Marco Rasile, Ilaria Monaco, Simona Rodighiero, Irene Corradini, Mauro Comes Franchini, Lorena Passoni, Michela Matteoli

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)2509-2520
Number of pages12
JournalACS Nano
Volume10
Issue number2
DOIs
Publication statusPublished - Feb 23 2016

Keywords

  • chlorotoxin-targeted nanovectors
  • drug delivery
  • glioblastoma
  • ionizing radiation
  • MMP-2

ASJC Scopus subject areas

  • Engineering(all)
  • Materials Science(all)
  • Physics and Astronomy(all)

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