Cationic Materials for Gene Therapy: A Look Back to the Birth and Development of 2,2-Bis-(hydroxymethyl)Propanoic Acid-Based Dendrimer Scaffolds

Gene therapy is extensively studied as a realistic and promising therapeutic approach for treating inherited and acquired diseases by repairing defective genes through introducing (transfection) the healthy genetic material in the diseased cells. To succeed, the proper DNA or RNA fragments need efficient vectors, and viruses are endowed with excellent transfection efficiency and have been extensively exploited. Due to several drawbacks related to their use, nonviral cationic materials, including lipidic, polymeric, and dendrimer vectors capable of electrostatically interacting with anionic phosphate groups of genetic material, represent appealing alternative options to viral carriers. Particularly, dendrimers are highly branched, nanosized synthetic polymers characterized by a globular structure, low polydispersity index, presence of internal cavities, and a large number of peripheral functional groups exploitable to bind cationic moieties. Dendrimers are successful in several biomedical applications and are currently extensively studied for nonviral gene delivery. Among dendrimers, those derived by 2,2-bis(hydroxymethyl)propanoic acid (b-HMPA), having, unlike PAMAMs, a neutral polyester-based scaffold, could be particularly good-looking due to their degradability in vivo. Here, an overview of gene therapy, its objectives and challenges, and the main cationic materials studied for transporting and delivering genetic materials have been reported. Subsequently, due to their high potential for application in vivo, we have focused on the biodegradable dendrimer scaffolds, telling the history of the birth and development of b-HMPA-derived dendrimers. Finally, thanks to a personal experience in the synthesis of b-HMPA-based dendrimers, our contribution to this field has been described. In particular, we have enriched this work by reporting about the b-HMPA-based derivatives peripherally functionalized with amino acids prepared by us in recent years, thus rendering this paper original and different from the existing reviews.

Automated summary

Gene therapy is a realistic and promising therapeutic approach for treating inherited and acquired diseases by repairing defective genes. Viruses, with their excellent transfection efficiency, have been extensively used as carriers, but nonviral cationic materials, such as dendrimers, are attractive alternative options. Among dendrimers, those derived from 2,2-bis(hydroxymethyl)propanoic acid (b-HMPA) are particularly interesting due to their biodegradability in vivo.