Phospholipid End-Capped Bioreducible Polyurea Micelles as a Potential Platform for Intracellular Drug Delivery of Doxorubicin in Tumor Cells

Bioreducible polymeric nanocarriers bearing disulfide bonds have been widely used for intracellular therapeutic delivery, since they are quickly sliced or reduced in the reductive milieu of cytosol. Incorporation of hydrophobic phospholipid analogues to polymers improves the biocompatibility by reducing the protein adsorption and platelet adhesion on the cell membranes. In this study, we have developed a series of bioreducible polyureas (PUs) bearing disulfide linkages in their backbone and phospholipid moieties in their chain ends. The reducible PUs exhibit interesting self-assembly behavior and controlled release profiles at intracellular mimic conditions. The self-assembled hybrid nanocarriers with an average diameter of about 110 nm efficiently encapsulated the model anticancer drug doxorubicin (Dox). The in vitro Dox release profile demonstrated a good glutathione (GSH)-responsive release of Dox at 10 mM GSH. An in vitro cell viability assay was also performed with various cell lines. The antitumor activity tests using HCT15 and HCT116 cancer cells showed that Dox-loaded nanocarriers bearing disulfide linkages induced significantly higher cytotoxicity in cancer cells than those without disulfide linkages. Hence, the PU nanocarriers bearing disulfide linkers and α,ω-phospholipid moieties have a promising potential to trigger the drug into the intracellular compartment of cancer cells.