Polymer Micelle with pH-Triggered Hydrophobic-Hydrophilic Transition and De-Cross-Linking Process in the Core and Its Application for Targeted Anticancer Drug Delivery

In this study, an novel amphiphilic block copolymer P[PEGMA-b-(DEMA-co-APMA)]-FA and its cross-linker uracil-(CH2)(6)-uracil (U-(CH2)(6)-U) were synthesized and used as the targeted and pH-responsive nanocarriers for anticancer drug delivery. The hydrophobic block of the copolymer contains adenine (A) and tertiary amine moieties and the hydrophilic block is terminated with a targeting ligand folic acid (FA). Under neutral pH, the hydrophobic chain segments of the copolymer are cross-linked by U-(CH2)(6)-U through the A-U nucleobase pairing based on complementary multiple hydrogen bonding, and the copolymer forms stable micelles with their mean diameter of around 170 urn in water. While under acidic pH, the micelles dissociate as a result of protonation of tertiary amines and disruption of the A-U nucleobase pairing. Flow cytometry and fluorescent microscope observation show that, when loaded with an anticancer drug DOX, the micelles can preferably enter folate receptor (FR)-positive cancer cells and kill the cells via intracellular release of the anticancer drug. Cytotoxicity tests (MTT tests) indicate that the micelles with FA on their surfaces exhibit higher cytotoxicity toward FR-positive cells than those without FA. This study provides useful insights on designing and improving the applicability of copolymer micelles for other targeted drug delivery systems.