Fucosylated dendrimer mediated enhancement of solubility, stability and biological activity of genistein

Abstract

Phytochemicals derived from plants have been used as traditional medication owing to their potential therapeutic properties and gained recent attention due to their safe toxicological profiles contrary to synthetic drugs. Genistein (GEN) is a phytophenol reported to have an anticancer effect against various cancers including lung cancer, colorectal carcinoma, breast cancer, etc. However, its practical utilization is rendered by its limited aqueous solubility, slow dissolution, low oral bioavailability, poor stability, and non-specific biodistribution. Small bioactive molecules such as sugars are the most facile targeting ligands as almost all types of cancer cells are reported to exhibit the over-expression of sugar receptors in comparison to healthy cells. Sugar-based targeting of tumor sites is often mediated by surface-functionalized dendrimers which can simultaneously improve the efficacy of GEN and enable its site-specific delivery. In the present work, amine-terminated PAMAM dendrimers (DEND) have been used as a delivery carrier for improving the aqueous solubility and efficacy of GEN. Moreover, fucose (FUC) as a small sugar molecule, has been used for tumor-specific functionalization of DEND improving the lung cancer targeting of GEN. FUC conjugation also reduced the amine-terminal associated toxicity of DEND. The encapsulation of GEN in nanoscale FUC-DEND resulted 128 times enhancement in its water solubility, sustained release, improved physicochemical stability, and 22 times enhancement of anticancer activity. The greater cytotoxicity of GEN was attributed to higher cellular uptake and increased apoptosis in A549 human lung cancer cells. Hence, fucose-functionalized dendrimers could be an efficient carrier for the advanced and targeted delivery of phytochemicals.