'Dendrimer-Cationized-Albumin' encrusted polymeric nanoparticle improves BBB penetration and anticancer activity of doxorubicin

Int J Pharm. 2019 Jan 30;555:77-99. doi: 10.1016/j.ijpharm.2018.11.035. Epub 2018 Nov 15.

Abstract

Glioblastoma is one of the most rapaciously growing cancer within the brain with an average lifespan of 12-15 months (5-year survival <3-4%). Doxorubicin (DOX) is clinically utilized as a first line drug in the treatment of Glioblastoma, however, its restricted entry into the brain via the blood-brain barrier (BBB), limited blood-tumor barrier (BTB) permeability, hemotoxicity, short mean half-life of 1-3 hr as well as rapid body clearance results in tremendously diminished bioactivity in glioblastoma. Dendrimer-Cationized-Albumin (dCatAlb) was synthesized following the carboxyl activation technique and the synthesized biopolymer was characterized by FTIR, MALDI-TOF and zeta potential. The prepared dCatAlb was encrusted on DOX-loaded PLGA nanoparticle core to develop a novel hybrid DOX nanoformulation (dCatAlb-pDNP; particle size: 156 ± 10.85 nm; ƺ: -10.0 ± 2.1 mV surface charge). The formulated dCatAlb-pDNP showed a unique pH-dependent DOX release profile, diminished hemolytic toxicity, higher drug uptake (<0.001) and cytotoxicity in U87MG glioblastoma cells, increase levels of caspase-3 gene in U87MG cells (approximately 5.35-fold higher) inferred that anticancer activity is primarily taking place through caspase-mediated apoptosis mechanism. The developed novel DOX nanoformulation also showed superior trans-epithelial permeation transport across monolayer bEnd.3 cells as well as notable biocompatibility and stability. The dCatAlb-pDNP showed enhanced BBB permeation efficacy as confirmed permeation assay in bEnd.3 cell-based model. The long-term formulation stability of developed nanoformulations was studied by storing them at 5 ± 2 °C and 30 ± 2 °C/60 ± 5% Relative Humidity (% RH) in the stability chamber for a period of 60 days (ICHQ1A (R2)). The outcomes of this investigation evidently indicate that dCatAlb-pDNP offers superior anticancer activity of DOX in glioblastoma cells while significantly improving its BBB permeation. The developed formulation is a biocompatible, safer and commercially viable approach to delivering DOX selectively in sustained manner glioblastoma while countering its hemolytic toxic effect, which is a major ongoing issue with conventional DOX injectable available in the market today.

Keywords: Apoptosis; Caspase activity; Cationized polymeric nanoparticle; DOX; Drug uptake; Glioblastoma; Hemolytic toxicity; Transepithelial monolayer permeability.

MeSH terms

  • Albumins / chemistry
  • Animals
  • Antibiotics, Antineoplastic / administration & dosage
  • Antibiotics, Antineoplastic / pharmacokinetics
  • Antibiotics, Antineoplastic / pharmacology
  • Apoptosis / drug effects
  • Blood-Brain Barrier / metabolism
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / pathology
  • Cations / chemistry
  • Cell Line
  • Cell Line, Tumor
  • Dendrimers / chemistry*
  • Doxorubicin / administration & dosage*
  • Doxorubicin / pharmacokinetics
  • Doxorubicin / pharmacology
  • Drug Carriers / chemistry
  • Glioblastoma / drug therapy*
  • Glioblastoma / pathology
  • Humans
  • Mice
  • Nanoparticles
  • Particle Size
  • Permeability
  • Polylactic Acid-Polyglycolic Acid Copolymer / chemistry
  • Polymers / chemistry

Substances

  • Albumins
  • Antibiotics, Antineoplastic
  • Cations
  • Dendrimers
  • Drug Carriers
  • Polymers
  • Polylactic Acid-Polyglycolic Acid Copolymer
  • Doxorubicin