Synthesis of Click Chemistry Based Dendrimer-drug Conjugates for Potential Applications for the Treatment of Neurological Disorders

Neurological disorders exhibit high mortality rates and cause a tremendous burden to society. Therapeutics for neurological disorders are oftentimes inefficacious due to the inability to deliver effective drugs across the blood-brain barrier. Previous research has shown generation 4 hydroxyl-terminating polyamidoamine (PAMAM) dendrimers as a promising drug delivery platform for high functionality, biocompatibility, and versatility in drug delivery. With the introduction of click chemistry and CuAAC (copper-catalyzed azide-alkyne cycloaddition) reactions, conjugation of drugs and biocompatible small molecules onto dendrimers can be achieved in a facile and controlled fashion. CuAAC click reaction is high-yielding and wide in scope, generating regiospecific products and only simple-to-remove byproducts. It has been recognized as a suitable approach to synthesize promising dendrimer nanomedicine with a high degree of functionality and customization for the potential treatment of neurological disorders. Building on this promise, we devised a method to attach drugs of interest onto the G4 PAMAM-OH dendrimers based on CuAAC click reaction. Specifically, we investigated the implementation of click chemistry to synthesize (1) dendrimer-PBA (4-phenylbutyric acid) conjugate for the next step application for the potential treatment of ALD (adrenoleukodystrophy) and (2) dendrimer-VPA (valproic acid) conjugate for the potential treatment of Epilepsy. Here the syntheses and characterization for dendrimer-drug conjugates will be discussed