Transferrin-targeted stealth liposomes loaded with artemisinin: The Trojan horse to enhance its selectivity and anticancer activity

Artemisinin is a unique sesquiterpene lactone isolated from Artemisia annua L. having an endoperoxyl moiety, essential for the antimalarial activity after activation by iron [1]. The reaction forms cytotoxic free radicals which contribute to anticancer effects of artemisinin and its derivatives [2]. Transferrin receptors are over expressed on cancer cells which also contain high concentration of free iron [3]. These properties make artemisinin and its derivatives attractive cancer chemotherapeutic drug candidates, but they suffer of short plasma half-lives requiring high dosage and frequent administration to be effective for cancer treatment. The aim of our work was to develop a nanocarrier which can enhance the selectivity of artemisinin to tumour cells. Small unilamellar vesicles were prepared according to the film hydratation method from P90G, Chol and DSPE-PEG2000-COOH and following sonication. Liposomes obtained were conjugated to the lipid linker via the carboxyl residue of DSPE-PEG-COOH and characterized by particle size, zeta potential, polydispersion index, drug entrapment efficiency and transmission electron microscopy. The average amount of transferrin conjugated to the liposome was quantified with bicinchonic acid; chemical and physical stability were tested within 20 days. Cellular uptake of actively-targeted artemisinin liposomes on MCF-7 cells was determined by measuring the fluorescence activity. Tf-conjugated liposomes showed significantly uptake higher rates than their unmodified counterparts. These findings were in good agreement with levels of cytotoxicity of the formulations. The IC50 value of stealth liposomes (121µM) is comparable to that of free artemisinin in vitro (127µM). Tf-liposomes exhibit the strongest cytotoxicity (69µM) to MCF-7 breast cancer cells suggesting that Tf may play a critical role. However, further studies are necessary to test these liposomal systems in an animal xenograft model to obtain important in vivo data.

Keywords: artemisinin, anticancer activity, transferrin, actively targeted stealth liposomes, selectivity and efficacy

References:

[1] Nakase, I. et al. (2008) Int. J. Pharm. 354: 28 – 33.

[2] Firestone, GL. et al. (2009) Expert Rev. Mol. Med. 11: e32.

[3] Efferth, T. et al. (2004) Free Radic. Biol. Med. 37: 998 – 1009.