Polymer nanoparticles for nano diagnostic and brain targeting

Krabbe disease (KD) is a lysosomal storage disorder (LSD) caused by a deficient activity of the enzyme galactosylceramidase (GALC). An impaired GALC activity causes increased psycosine (PSY) levels in neural tissues, leading to a widespread degeneration of glial cells and demyelination. While KD causes early mortality (within 2 years after birth), an effective cure is still lacking. The ideal therapeutic approach would be the systemic administration of the enzyme. This approach fails because of the blood brain barrier (BBB) hampering GALC translocation toward the central nervous system (CNS). A winning strategy is to exploit targeted nanovectors capable of inducing GALC transcytosis across the BBB. In the present work, we developed a new delivery platform based on polymeric degradable reversed micelles (RMs) loaded with GALC and targeted to cross the BBB. RMs are produced with the amphiphilic di-block copolymer methoxy polyethylene glycol-block-poly(lactide-co-glycolide) (mPEG-b-PLGA). The copolymer is functionalized with chemical units suitable for the application. RMs are externally crosslinked to improve their physical stability and GALC retention without affecting degradation and biocompatibility. The conjugation of the ligand Angiopep-2 endows RMs with targeting capabilities toward the CNS. RMs opportunely formulated are administered in vivo in the murine model of KD, the Twitcher (TWI) mouse, via retro-orbital administration. Mice are sacrificed at fixed times after the treatment to evaluate the enzymatic activity recovery. Results show high RMs stability, and a good biocompatibility of the administered formulation. Enzymatic activity recovery is around 10% in respect to that measured in healthy mice. This is a suitable value for KD treatment. In conclusion, the developed system shows some potential and could be considered a good candidate for the KD treatment.

For information, please contact:

Fabio Taddei (9038) - fabio.taddei@nano.cnr.it
Stefan Heun (9472) - stefan.heun@nano.cnr.it