Cholesterol‐Conjugated <scp>PAMAM</scp> Dendrimers: Enhancing Stability, Drug Delivery Efficiency, and In Vitro Anticancer Performance

ABSTRACT Nanomaterials offer great potential in cancer treatment, particularly in drug delivery, where their unique properties allow for targeted therapy, increasing treatment efficacy while minimizing side effects. Dendrimers, with their highly branched structure, are ideal candidates for drug delivery. However, polyamidoamine (PAMAM) dendrimers, despite their versatility, exhibit cytotoxicity. Modifying PAMAM dendrimers with cholesterol through p‐nitrophenyl chloroformate (NPC) mediation enhances their biocompatibility and targeting ability, especially toward cancer cells. In this study, PAMAM G3.0 was successfully synthesized and conjugated with cholesterol to form G3C nanogels, with a nanoscale size of 83.8 ± 21.9 nm. The study of cholesterol conjugation revealed that at 25% surface functionalization of G3.0, G3C exhibited stable behavior in PBS buffer for up to 8 days. The system's capacity to load single or dual drugs was also explored, demonstrating controlled drug release for over 96 h. Moreover, cholesterol modification on G3.0 significantly enhanced cell compatibility. The G3C@QU/PTX system exhibited improved targeting toward HeLa cancer cells in vitro compared to healthy fibroblast cells. This research provides a strong foundation for developing nanomaterials for targeted cancer treatment.