Redox-responsive magnetic nanoparticle for targeted convection-enhanced delivery of O 6-benzylguanine to brain tumors

Zachary R. Stephen, Forrest M. Kievit, Omid Veiseh, Peter A. Chiarelli, Chen Fang, Kui Wang, Shelby J. Hatzinger, Richard G. Ellenbogen, John R. Silber, Miqin Zhang

Research output: Contribution to journalArticle

89 Scopus citations

Abstract

Resistance to temozolomide (TMZ) based chemotherapy in glioblastoma multiforme (GBM) has been attributed to the upregulation of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). Inhibition of MGMT using O6-benzylguanine (BG) has shown promise in these patients, but its clinical use is hindered by poor pharmacokinetics that leads to unacceptable toxicity. To improve BG biodistribution and efficacy, we developed superparamagnetic iron oxide nanoparticles (NP) for targeted convection-enhanced delivery (CED) of BG to GBM. The nanoparticles (NPCP-BG-CTX) consist of a magnetic core coated with a redox-responsive, cross-linked, biocompatible chitosan-PEG copolymer surface coating (NPCP). NPCP was modified through covalent attachment of BG and tumor targeting peptide chlorotoxin (CTX). Controlled, localized BG release was achieved under reductive intracellular conditions and NPCP-BG-CTX demonstrated proper trafficking of BG in human GBM cells in vitro. NPCP-BG-CTX treated cells showed a significant reduction in MGMT activity and the potentiation of TMZ toxicity. In vivo, CED of NPCP-BG-CTX produced an excellent volume of distribution (Vd) within the brain of mice bearing orthotopic human primary GBM xenografts. Significantly, concurrent treatment with NPCP-BG-CTX and TMZ showed a 3-fold increase in median overall survival in comparison to NPCP-CTX/TMZ treated and untreated animals. Furthermore, NPCP-BG-CTX mitigated the myelosuppression observed with free BG in wild-type mice when administered concurrently with TMZ. The combination of favorable physicochemical properties, tumor cell specific BG delivery, controlled BG release, and improved in vivo efficacy demonstrates the great potential of these NPs as a treatment option that could lead to improved clinical outcomes.

Original languageEnglish (US)
Pages (from-to)10383-10395
Number of pages13
JournalACS Nano
Volume8
Issue number10
DOIs
StatePublished - Oct 28 2014

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Keywords

  • drug delivery
  • glioblastoma multiforme
  • iron oxide
  • nanomedicine
  • theranostic

ASJC Scopus subject areas

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

Cite this

Stephen, Z. R., Kievit, F. M., Veiseh, O., Chiarelli, P. A., Fang, C., Wang, K., Hatzinger, S. J., Ellenbogen, R. G., Silber, J. R., & Zhang, M. (2014). Redox-responsive magnetic nanoparticle for targeted convection-enhanced delivery of O 6-benzylguanine to brain tumors. ACS Nano, 8(10), 10383-10395. https://doi.org/10.1021/nn503735w