Enhanced delivery of artemisinin and its analogues to cancer cells by their adducts with human serum transferrin.

Artemisinin (ART) and its analogues, such as dihydroartesunate (DHA) and artesunate (ATS), are sesquiterpene lactones with anticancer activities. Transferrin (Tf) receptor is frequently overexpressed in cancer cells. In order to improve the delivery and the anticancer activity of ART and its analogues, adducts of Tf with ART, DHA or ATS were fabricated by simply combining ART, DHA or ATS with Tf. Increased antitumor effects of these adducts were observed on human liver hepatocellular carcinoma (HepG2) and lung adenocarcinoma (A549) cells. Meanwhile, only a low level of toxic effect was observed on normal human liver cells (HL-7702). Improved cellular uptake of ATS-Tf adduct compared to ATS alone was confirmed by HPLC analysis. UV-vis, fluorescence spectroscopy and docking study further confirmed the formation of the adducts with relatively high binding constants at neutral pH (7.4×10(4), 4.2×10(5) and 3.4×10(5)M(-1), for ART-Tf, DHA-Tf and ATS-Tf, respectively, at pH 7.4). However, the adducts became less stable with reduced binding constants under an acidic condition (2.6×10(4), 1.9×10(4) and 1.7×10(4)M(-1), for ART-Tf, DHA-Tf and ATS-Tf, respectively, at pH 5.5). A possible mechanism of the anticancer effect by these adducts was proposed. The short term and long term stability of ART-Tf in the presence of human serum albumin (HSA) was also studied. Our results showed that adducts of ART and its analogues with Tf, especially ATS-Tf and DHA-Tf, have significant anticancer effects to cancer cells, with minimal side effects on normal cells, therefore, are promising as potential novel anticancer agents.