Multifunctional silica-coated mixed polymeric micelles for integrin-targeted therapy of pediatric patient-derived glioblastoma

Prakram Singh Chauhan, Murali Kumarasamy, Angel M. Carcaboso, Alejandro Sosnik*, Dganit Danino

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Glioblastoma multiforme (GBM) remains a major cause of mortality because treatments are precluded by to the limited transport and penetration of chemotherapeutics across the blood–brain barrier. Pitavastatin (PTV) is a hydrophobic Food and Drug Administration (FDA)-approved anticholesterolemic agent with reported anti-GBM activity. In the present study, we encapsulate PTV in silica-coated polymeric micelles (SiO2 PMs) surface-modified with the cyclic peptide Arg-Gly-Asp-Phe-Val (cRGDfV) that actively targets the αvβ3 integrin overexpressed in the BBB endothelium and GBM. A central composite design is utilized to optimize the preparation process and improve the drug encapsulation ratio from 131 to 780 μg/mL. The silica shell provides full colloidal stability upon extreme dilution and enables a better control of the release kinetics in vitro with 28% of the cargo released after 12 h. Furthermore, SiO2 PMs show excellent compatibility and are internalized by human BBB endothelial cells, astrocytes and pericytes, as shown by confocal laser scanning fluorescence microscopy and flow cytometry. Finally, the anticancer efficacy is assessed in a pediatric patient-derived glioma cell line expressing high levels of the integrin subunits αv, β3 and β5. This PTV-loaded nanocarrier triggers apoptosis by reducing the mRNA level of anti-apoptotic genes NF-kβ, IL-6, BIRC1 and BIRC5 by 89%, 33%, 81% and 63%, respectively, and the cell viability by >60%. Overall, our results suggest the potential of these hybrid nanocarriers for the targeted therapy of GBM and other tumors overexpressing integrin receptors.

Original languageEnglish
Article number112261
JournalMaterials Science and Engineering C
Volume128
DOIs
StatePublished - Sep 2021

Keywords

  • Blood-brain barrier
  • Glioblastoma
  • Mixed polymeric micelles
  • Pediatric cancer
  • Pluronic® F127 and Tetronic® 1307
  • Silica shell
  • αvβ3 integrin receptor

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