Poly(ethylene glycol)-block-poly(d,l-lactide acid) micelles anchored with angiopep-2 for brain-targeting delivery

Abstract

In this study, angiopep with high transcytosis capacity and parenchymal accumulation was used as a novel ligand for the brain-targeting delivery of poly(ethylene glycol)-block-poly(d,l-lactide acid) (PEG-PLA) micelles. Angiopep-2 was synthesized by solid-phase peptide synthesis, and then conjugated with maleimide-PEG-PLA to form angiopep-PEG-PLA. The micelles composed of methoxy-PEG-PLA (mPEG-PLA) and angiopep-PEG-PLA was prepared by film-hydration method. Near-infrared fluorescence dye, DiR was loaded into micelles to evaluate the brain-targeting ability of micelles with or without angiopep modification by near-infrared fluorescence imaging in vivo and ex vivo. Significant near-infrared (NIR) fluorescent signal was detected in the brain after angiopep-anchored micelles administration and further confirmed by imaging the whole brain and brain slices, compared with that of the micelles without modification. ¹²⁵I-radiolabeled angiopep-PEG-PLA micelles after intravenous administration in mice showed high brain accumulation for up to 24 h. These results indicate that angiopep-modified PEG-PLA micelle is a promising brain-targeting nanocarrier for lipophilic drugs.

Keywords::

• Brain targeting
• angiopep
• PEG-PLA micelles
• blood-brain barrier
• near-infrared fluorescence imaging

Acknowledgements

The authors acknowledged Prof. Jianhua Zhu and Jun Qian (Fudan University, China) for their help in radiolabeled experiment. We also greatly acknowledged Prof. Jiandong Ding and Doctor Guangtao Chang for their help in the synthesis of PEG-PLA copolymers.

Declaration of interest

This work was supported by National Basic Research Program of China (973 Program) 2007CB935800, the “National Science and Technology Major Project” 2009ZX09310-006 and “Shanghai Postdoctoral Scientific Program” 10R21410800.