Redox‐ and <scp>pH</scp> ‐Responsive Block Copolymer Nanocarriers With Dual Drug Conjugation Through Dynamic Covalent and Hydrogen Bonds

ABSTRACT Loading of multiple drugs in a nanocarrier with high entrapment efficiency is important for combination therapy in cancer treatment. Here, a block copolymer comprising hydrophobic poly(ε‐caprolactone) block with a defined number of pendent propargyl groups, polyethylene glycol monomethyl ether as a hydrophilic block, and a redox‐responsive disulfide group at the block junction is synthesized using click chemistry and ring‐opening polymerization (ROP). Benzaldehyde and thymine groups are introduced in the side chains for selective attachment of anti‐cancer drugs, doxorubicin (DOX) and methotrexate (MTX), via the formation of pH‐responsive imine linkage and hydrogen bonds, respectively. The drug‐conjugated block copolymers are assembled into spherical micelles of &lt; 200 nm, and the preferential release of DOX and MTX in response to acidic pH and redox conditions is shown. At pH 5, DOX release was 59.5%, and MTX release was 40% compared to 13% and 12% at pH 7.4, whereas at pH 5 with 10 mM GSH, a DOX release of 81.5% was observed after 48 h. Cellular uptake of drug‐conjugated micelles and their apoptosis compared to free DOX in the MDA‐MB‐231 breast cancer cells is demonstrated. Caveolae‐mediated endocytosis was found to be the major pathway used by drug‐loaded nanocarriers.