Degradable Biotinylated Polyesters for Cancer Cell-Selective Targeting and Anticancer Drug Delivery

The growing demand for biodegradable polymers capable of stimuli-responsive drug release is challenged by limitations in facile synthetic methods. In this study, two biotin-functionalized amphiphilic polyesters (<b>P1</b> and <b>P2</b>) were synthesized through step-growth polymerization, aiming to achieve biotin receptor-mediated cancer cell selective uptake. In addition to polar biotin, <b>P2</b> incorporates a hydrophobic fluorescent dye, which enabled intracellular fluorescence tracking. <b>P2</b> self-assembled into highly biocompatible spherical nanoaggregates (∼120 nm) in water, which showed effective encapsulation of the hydrophobic anticancer drug doxorubicin (DOX). It displayed ∼85-90% internalization in biotin-overexpressed cancer cells (HeLa and MCF7) contrary to only ∼5-10% uptake in noncancerous cells (NIH 3T3), as determined by flow cytometry and fluorescence microscopy. Cell-selective DOX release was likely induced by the polyester degradation in the acidic cancer microenvironment and via endogenous esterases, evident from size exclusion chromatography (SEC) and dynamic light scattering (DLS) experiments. These findings highlight the potential of stimuli-responsive degradable polyester nanocarriers for targeted cancer treatment.