OICC Press Journal of Nanostructure in Chemistry 2193-8865 14 5 2023 02 10 Self-assembly of thyminyl l-tryptophanamide (TrpT) building blocks for the potential development of drug delivery nanosystems 10.1007/s40097-023-00523-7 EN Pasqualina Liana Scognamiglio Centre for Advanced Biomaterial for Health Care (CABHC), Italian Institute of Technology, Naples, 80125, IT Department of Chemical, Materials and Production Engineering (DICMAPI), University of Naples Federico II, Naples, 80125, IT Claudia Riccardi Department of Chemical Sciences, University of Naples Federico II, Naples, 80126, IT Rosanna Palumbo Consiglio Nazionale delle Ricerche (CNR), Institute of Biostructure and Bioimaging (IBB), Naples, 80145, IT Thomas F. Gale School of Science, University of Greenwich, Chatham Maritime, Kent, ME4 4TB, GB Domenica Musumeci Department of Chemical Sciences, University of Naples Federico II, Naples, 80126, IT Consiglio Nazionale delle Ricerche (CNR), Institute of Biostructure and Bioimaging (IBB), Naples, 80145, IT Giovanni N. Roviello Consiglio Nazionale delle Ricerche (CNR), Institute of Biostructure and Bioimaging (IBB), Naples, 80145, IT Journal Article 2023 02 10 Abstract The design, synthesis and characterization of a novel nucleoamino acid derivative based on an l -tryptophanamide functionalised with a thymine nucleobase (named TrpT) is here described. The novel construct’s tendency to self-assemble into supramolecular networks in aqueous solution was demonstrated by dynamic light scattering (DLS), circular dichroism (CD), fluorescence and UV spectroscopic measurements. TrpT nanoaggregates showed good stability (up to 5 h) at 140 µM and proved to comprise species of mean hydrodynamic diameter 330 nm and a homogeneous size distribution; scanning electron microscopy (SEM) analysis further revealed these to be spherical-shaped assemblies. The ability of TrpT nanoaggregates to bind curcumin, selected as a model anticancer drug, was also evaluated and its release was monitored over time by confocal microscopy. Molecular docking studies were performed on both TrpT self-assembly and curcumin-loaded nanoaggregates suggesting that the phytomolecule can be accommodated in the interior of the supramolecular network via hydrophobic ( π − π and π -alkyl) interactions; the formation of TrpT-curcumin adducts may improve the polarity of the highly-hydrophobic curcumin with a resulting logP closer to the optimal values expected for a good drug bioavailability, as estimated by the ADMETlab software. Finally, the high stability of TrpT nanoassembly in human serum, and the absence of significant toxic effects on human model cells in a cell viability assay, were also demonstrated. Despite its thymine-based scaffold, TrpT was shown not to bind adenine-bearing nucleic acids, suggesting that this interaction is hindered by its intrinsic propensity to self-assemble in preference to forming A-T base pairings. Instead, TrpT was able to interact with a serum protein such as bovine serum albumin (BSA), known to improve the bloodstream transportation and bioavailability of its cargo. Collectively, our findings support the potential use of TrpT for the development of new drug delivery systems. Graphical abstract