The brain targeting mechanism of Angiopep-conjugated poly(ethylene glycol)-co-poly(ε-caprolactone) nanoparticles.

In order to evaluate the potential and mechanism of Angiopep-conjugated poly(ethylene glycol)-co-poly(ε-caprolactone)nanoparticles (ANG-PEG-NP) as brain targeting drug delivery system, Rhodamine B isothiocyanate (RBITC) was used as a fluorescent probe molecule to label ANG-PEG-NP through covalent bonding. The brain transcytosis across the blood-brain barrier (BBB) and brain delivery in mice of RBITC labeled ANG-PEG-NP were investigated in this paper. Results showed that ANG-PEG-NP enhanced significantly the uptake by BCECs compared with that of PEG-NP through caveolae- and clathrin-mediated endocytosis, involving a time-dependent, concentration-dependent and energy-dependent mode. The transport of ANG-PEG-NP across the in vitro BBB model was significantly increased than that of PEG-NP. After injection a dose of 100 mg/kg RBITC labeled ANG-PEG-NP or PEG-NP in mouse caudal vein, the brain coronal section showed a higher accumulation of ANG-PEG-NP in the cortical layer, lateral ventricle, third ventricles and hippocampus than that of PEG-NP. By using an excess of free LRP ligand (Angiopep-2 and/or Aprotinin) as a specific receptor inhibitor, it was evidenced that the uptake by BCECs in vitro, transport across in vitro BBB model and penetration into brain tissue in vivo of RBITC labeled ANG-PEG-NP could be inhibited significantly, which demonstrated the brain targeting mechanism of Angiopep-conjugated poly(ethylene glycol)-co-poly(ε-caprolactone)nanoparticles might be a LRP receptor mediated transcytosis process. Understanding these issues is important for the future development of ANG-PEG-NP as a brain targeting drug delivery system for neurodegenerative disorders including glioma and Alzheimer's disease.