Angiopep‐2 and cyclic RGD dual‐targeting ligand modified micelles across the blood–brain barrier for improved anti‐tumor activity

Abstract In this paper, three polymers of Angiopep‐2 conjugated polyethylene glycol (PEG)‐β‐cyclodextrin (Ang‐2‐PEG‐βCD), cyclic RGD (cRGD)‐PEG‐βCD, Ad‐PCL‐FITC and corresponding double‐targeted polymer micelles (D‐T micelles) were successfully prepared by host–guest self‐assembly. Transmission electron microscope images showed that uniformly dispersed spherical supermolecular micelles could be formed. The colloidal stability of D‐T micelles in 5% glucose and 10% FBS solution were good within 24 h, which was fine in distilled water at room temperature within 2 weeks. The results of fluorescence microscope and flow cytometry demonstrating the prepared double‐targeted micells showed high intracellular delivery efficiency in both brain microvascular endothelial cells (bEnd.3 cell) and glioma cells (C6 cell). As expected, based on the specific recognition between the peptides and the receptors, the D‐T micelles exhibited better anti‐tumor efficacy than free chemotherapy drug and non‐targeted micelles both in vitro and in vivo, indicating the great potential of D‐T micelles developed here as promising vehicle for glioma targeted drug delivery.