Open AccessScalable synthesis and validation of PAMAM dendrimer‐ N ‐acetyl cysteine conjugate for potential translation
Author(s) -
Sharma Rishi,
Sharma Anjali,
Kambhampati Siva P.,
Reddy Rajsekar Rami,
Zhang Zhi,
Cleland Jeffrey L.,
Kannan Sujatha,
Kannan Rangaramanujam M.
Publication year - 2018
Publication title -
bioengineering and translational medicine
Language(s) - English
Resource type - Journals
ISSN - 2380-6761
DOI - 10.1002/btm2.10094
Subject(s) - dendrimer , conjugate , cysteine , combinatorial chemistry , chemistry , translation (biology) , reagent , covalent bond , organic chemistry , biochemistry , messenger rna , enzyme , mathematics , mathematical analysis , gene
Dendrimer‐ N ‐acetyl cysteine (D‐NAC) conjugate has shown significant promise in multiple preclinical models of brain injury and is undergoing clinical translation. D‐NAC is a generation‐4 hydroxyl‐polyamidoamine dendrimer conjugate where N ‐acetyl cysteine (NAC) is covalently bound through disulfide linkages on the surface of the dendrimer. It has shown remarkable potential to selectively target and deliver NAC to activated microglia and astrocytes at the site of brain injury in several animal models, producing remarkable improvements in neurological outcomes at a fraction of the free drug dose. Here we present a highly efficient, scalable, greener, well‐defined route to the synthesis of D‐NAC, and validate the structure, stability and activity to define the benchmarks for this compound. This newly developed synthetic route has significantly reduced the synthesis time from three weeks to one week, uses industry‐friendly solvents/reagents, and involves simple purification procedures, potentially enabling efficient scale up.