Human serum albumin and sialic acid co-modified liposome nanoreactors with tumor-specific activable cascade reactions for cooperative cancer therapy

Abstract

Herein, a new type of human serum albumin (HSA) and sialic acid (SA) co-modified liposome nanoreactor was prepared to realize chemotherapy and chemodynamic therapy cooperative treatment of tumor. Firstly, Paclitaxel (PTX) acidic sensitive prodrug with a maleimide-terminated functional group and a sialic acid-modified reduced glutathione (GSH) sensitive paclitaxel prodrug have been synthesized. Then, a liposome nanoreactor was prepared by using PTX prodrugs, lecithin, and cholesterol as membrane materials, and simultaneously encapsulating water-soluble Fe3O4 and glucose oxidase. Finally, HSA was bound to the surface of liposomes through the Michael addition between maleimide-terminated functional group of PTX prodrug and the thiol group at the cysteine 34 residue of human serum albumin. The cumulative release rates of PTX in nanoreactor were 43.98 % at pH = 5.5 and 14.98 % at pH 7.4 after 96h respectively, exhibiting pH sensitive drug release behavior. Also 25.98 % and 17.52 % of PTX release were observed respectively in the medium with 10 mM DTT and without DTT after 96h, displaying redox responsive drug release behavior. The fluorescence intensity of tumor sites for the Dir loaded nanoreactor was higher than that of the free Dir group, displaying the targeting ability of HSA and SA. In tumor site, glucose oxidase can catalyze glucose to generate hydrogen peroxide, and hydroxyl radical is generated under an iron-based Fenton reaction between hydrogen peroxide and iron ion to kill tumor cells to realize chemodynamic therapy. After administration, the average tumor weight of the NS group was 2.516g, while nanoreactor group was 0.322g, displaying the synergistic therapy and excellent anticancer efficacy.