Design of a dendrimeric nanomedicine pl atform for the treatment of a neuro-degenerati ve disease, x-ald

Statement of Purpose: Delivery of therapeutics acros s the blood-brain barrier (BBB) to selectively treat injured brain areas is a major challenge (Kannan, R. M. J Intern Med 2014; 276: 579– 617) and has been a limiting factor for the treat ment of several neurodevelopmental disorders. X-linked adrenoleu kodystrophy (ALD) is a rare genetic dis ease which results in the rapid demyelination of the brain, most severely occurring during childhood. With their great potential as drug/gene delivery nanovehicles, dendrimers provide lots of advantageous features like monodispersity, mu ltivalency, enhanced water solubility and functionalization by imaging agents and targeting groups. We have shown that polyamidoamine (PAMAM) dendrimers can pass through the impaired BBB without any need for additional targeting ligands and localize in the inju red site based on the extent of injury (Zhang, F. J. Neuroin flammation 2016;3-65). In a neonatal rabbit model of cerebral palsy (CP), Cy5-labeled, generation-4 PAMAM dendrimer (D-Cy5) was shown to accumulate almost 20 times more in the brains of rabbit kits with CP, co mpared to healthy controls (Figure 1) (Lesniak, W. G. Mol. Pharmaceutics 2013;10:4560-4571). In light of these findings, a novel PAMAM-based drug delivery system was designed for the delivery of ABCD2 gene regulating drug, 4-phenyl butyrate (PBA), as a brain targeting nano-vehicle with a sustained and slow drug release profile.