Nose-to-brain delivery of temozolomide-loaded PLGA nanoparticles functionalized with anti-EPHA3 for glioblastoma targeting

Drug Deliv. 2018 Nov;25(1):1634-1641. doi: 10.1080/10717544.2018.1494226.

Abstract

Glioblastoma is the most common malignant brain tumor. Efficient delivery of drugs targeting glioblastomas remains a challenge. Ephrin type-A receptor 3 (EPHA3) tyrosine kinase antibody-modified polylactide-co-glycolide (PLGA) nanoparticles (NPs) were developed to target glioblastoma via nose-to-brain delivery. Anti-EPHA3-modified, TBE-loaded NPs were prepared using an emulsion-solvent evaporation method, showed a sustained in vitro release profile up to 48 h and a mean particle size of 145.9 ± 8.7 nm. The cellular uptake of anti-EPHA3-modified NPs by C6 cells was significantly enhanced compared to that of nontargeting NPs (p < .01). In vivo imaging and distribution studies on the glioma-bearing rats showed that anti-EPHA3-modified NPs exhibited high fluorescence intensity in the brain and effectively accumulated to glioma tissues, indicating the targeting effect of anti-EPHA3. Glioma-bearing rats treated with anti-EPHA3-modified NPs resulted in significantly higher tumor cell apoptosis (p < .01) than that observed with other formulations and prolonged the median survival time of glioma-bearing rats to 26 days, which was 1.37-fold longer than that of PLGA NPs. The above results indicated that anti-EPHA3-modified NPs may potentially serve as a nose-to-brain drug carrier for the treatment of glioblastoma.

Keywords: EPHA3 antibody; Glioblastoma; nanoparticles; nose-to-brain delivery; temozolomide butyl ester.

MeSH terms

  • Animals
  • Antibodies, Monoclonal* / chemistry
  • Antibodies, Monoclonal* / immunology
  • Antibodies, Monoclonal* / pharmacology
  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / immunology
  • Antineoplastic Agents* / pharmacology
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / immunology
  • Cell Line, Tumor
  • Drug Carriers* / chemistry
  • Glioblastoma / drug therapy*
  • Glioblastoma / immunology
  • Humans
  • Male
  • Molecular Targeted Therapy
  • Nanoparticles* / chemistry
  • Polyglactin 910* / chemistry
  • Rats
  • Rats, Sprague-Dawley
  • Receptor Protein-Tyrosine Kinases / immunology
  • Receptor, EphA3
  • Temozolomide / pharmacology

Substances

  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • Drug Carriers
  • Polyglactin 910
  • EPHA3 protein, human
  • Receptor Protein-Tyrosine Kinases
  • Receptor, EphA3
  • Temozolomide

Grants and funding

This study was funded by the Natural Science Foundation of Shandong Province (ZR2017LH076 and ZR2016HB58).