Abstract

PEGylated PAMAM dendrimers (PEG-PAMAM) are well-characterized biomaterials with still unexplored applications as carriers of drugs acting via membrane receptors, such as octreotide. This work confirmed the safety and negligible internalization capacity of fourth-generation 50%-PEG-PAMAM in HEK-293 cells, to then assessed their supramolecular binding to octreotide through tryptophan quenching experiments and Gaussian-accelerated molecular dynamics (GaMD) simulations. Tryptophan quenching showed that PEG-PAMAM binds octreotide with a Kbind of 6 × 106 M−1 and a complex stoichiometry of 1:1.4, unlike native PAMAM. GaMD simulations revealed that octreotide binds at the outer PEG shell of PEG-PAMAM, potentially hindering the drug from proteolytic degradation and enabling its release at a membrane level. Viability experiments on HeLa, PC-12, and HEK-293 cells incubated with increasing concentrations of octreotide in free drug solutions and equimolar mixtures with PEG-PAMAM confirmed that the PEGylated dendrimer acts as an efficient supramolecular carrier for octreotide and enhances the antiproliferative effects of the drug. Our findings highlight a novel facet for PEG-PAMAM dendrimers as macromolecular vehicles for peptide or non-peptide drugs acting via membrane receptor sites.