Uptake of Self-Assembling Amphiphilic Tryptophan-Based Polymer Nanoparticles in Three-Dimensional Cell Culture Models

Synthetic polymeric nanoparticles (NPs) have been proven to be essential drug delivery systems and cancer therapy tools. However, NPs derived from traditional linear polymers often fail to provide the stability, biocompatibility, and loading efficiencies needed for clinical application. The present work explores strategically designed amino acid-based NPs formed from self-assembling amphiphilic Y and H-shaped polymers consisting of a tryptophan-based hydrophobic segment coupled to a hydrophilic block of polyethylene glycol (PEG). This study employs tryptophan due to its natural availability and abilities as a cancer immunotherapeutic agent. These amphiphilic polymers ( SM_Trp2P and SM_Trp4P ) were synthesized via a combination of Steglich esterification and “click” chemistry (azide–alkyne cycloaddition). Their resulting NPs were characterized using electron microscopy and dynamic light scattering (DLS), by which the morphologies of the NPs were confirmed. Spherical NPs possessing a tryptophan core enabled the loading of hydrophobic cargo, such as drug molecules and near-infrared dyes, demonstrating the potential for dual imaging and delivery applications. Cytotoxicity and spectroscopic analysis of the NPs supported comparative studies between the two polymers and the biological relevancy of the nanomaterials. Employing matrix-assisted laser desorption/ionization-imaging mass spectrometry (MALDI-MSI), full penetration and metabolism of irinotecan-loaded NPs were observed in three-dimensional cell cultures. Results indicate that these strategically designed polymer frameworks and their resulting NPs are exceptional candidates for biomedical applications.