Sustained and Step-Wise Drug Release by a Novel Double Responsive Dendrimer-<i>N</i>-Acetylcysteine Conjugate

Polyamidoamine (PAMAM) dendrimers have emerged as promising vehicles for targeting the brain due to their intrinsic ability to penetrate through the injured blood-brain barrier. Herein, we present a novel drug delivery system based on a fourth generation PAMAM dendrimer as a brain targeting nanomedicine for the delivery of an anti-inflammatory drug <i>N</i>-acetyl cysteine with a sustained drug release profile. This D_"ester"(NAC_"ss"NAC) design enables NACs conjugated to the periphery of PAMAM dendrimers in the dimer form with ester and disulfide bonds to be sequentially released in a stepwise manner, responding to environmental pH and redox potential. Moreover, in vitro studies were conducted with a fluorescently labeled conjugate to confirm its nontoxic behavior and time-dependent cellular uptake, together with improved anti-inflammatory and antioxidative effects over endotoxin-activated microglia. These findings demonstrate that the DNACNAC conjugate has a high potential to be utilized as a promising dendrimer-based nanomedicine platform for prolonged treatment of neuroinflammation-related CNS disorders.