PAMAM-calix-dendrimers as carriers for 5-fluorouracil: complexation, aggregation, and in vitro antitumor activity

Abstract

Despite a number of serious challenges and limitations in clinical use, drug therapy is considered one of the most common approaches to treating cancer. However, many types of cancer become resistant to antitumor drugs. Modern supramolecular chemistry provides a variety of compounds and materials that can be used to develop targeted drug delivery approaches, thereby enhancing therapeutic efficacy. Dendrimers are one example of such materials. This study presents an approach to creating supramolecular systems based on poly(amidoamine) dendrimers with a thiacalix[4]arene core (PAMAM-calix-dendrimers), capable of binding and delivering 5-fluorouracil (5-Fu). Fluorescence spectroscopy has demonstrated the good binding of 5-Fu by G1–G3 PAMAM-calix-dendrimers (logKa = 3.15–3.62) regardless of the macrocyclic core conformation. Self-assembly of the PAMAM-calix-dendrimers/5-Fu supramolecular systems was studied by dynamic light scattering and transmission electron microscopy. Loading and release of 5-Fu were evaluated by UV-Vis spectroscopy. The encapsulation efficiency and loading capacity increased slightly in the following order: G3-cone G3-paco G3-alt. For all dendrimers studied, 95% release of 5-Fu was observed within 4 h. An in vitro HeLa tumor cell model showed a positive trend (up to 20%) toward overcoming resistance to 5-Fu chemotherapy when G3-alt is used. These results provide proof of concept for using macrocyclic dendrimers to create anticancer drug delivery systems.