Accelerated Synthesis of Internally Functionalized Dendrimers

Abstract Poly(amidoamine) (PAMAM) dendrimers have been extensively investigated as drug delivery vectors and building blocks for biosensors, catalysts, and nanoelectronics. High-generation PAMAMs can mimic the phase behavior of biomacromolecules, while the chemical modification of their core and the addition of terminal functionalities can impart desired physicochemical and biomedical attributes. However, the high cost and molecular polydispersity of PAMAMs, as well as the complexity of post-synthesis modifications, limit their widespread application. Addressing these challenges, we previously developed a divergent approach for constructing poly(amidoamine) dendrimers hybridized with amino acid residues (DendriPeps). Unlike low-generation PAMAMs, DendriPeps in dilute solutions self-assemble into discrete nanoparticles whose size and phase behavior depend on the identity and generational placement of the “guest” amino acids and on the composition of the medium. The original synthesis method for DendriPeps, however, is laborious and provides limited product yield and purity. In this study, we developed a rapid and robust solution-phase synthesis that integrates microwave reactions and optimized synthesis conditions to afford step yields of ∼80% and increase productivity while safeguarding molecular purity, as demonstrated by LC-MS. Four guest amino acids—lysine, phenylalanine, tyrosine, and tryptophan—were integrated into Generation 2 DendriPeps with comparable yields and purities. Notably, tryptophan-hybridized DendriPeps self-assembled into intrinsically luminescent nanoparticles. This method broadens the chemical diversity and accessibility of DendriPeps, supporting further exploration of their physicochemical and functional properties.