A New Biodegradable Linear mPEG‐b‐poly(Schiff Base‐Acetal) Copolymer Carrier Co‐Delivery Cinnamaldehyde and Gemcitabine for Combined Anticancer Therapy

Abstract Due to significant pH difference among the healthy tissue, tumor tissue as well as intracellular endo/lysosome, constructing pH‐responsive biodegradable nanodrug delivery systems has received more and more attention. Herein, double‐end alkenylated acetal monomer (based on cinnamaldehyde (CA)) and double‐end sulfhydrylation Schiff base monomer were designed and synthesized, and three pH‐responsive biodegradable block copolymer mPEG‐ b ‐poly(Schiff base‐acetal) (P1), mPEG‐ b ‐poly(acetal) (P2), and mPEG‐ b ‐poly(Schiff base) (P3) were obtained by Michael addition reaction. All these polymers could be self‐assembled with gemcitabine (GEM) to form GEM‐loaded micelles. Proton nuclear magnetic resonance ( 1 H NMR) and dynamic light scattering (DLS) experiments proved that these polymer micelles have good pH responsiveness. The size and morphology of both blank and GEM‐loaded micelles were characterized by DLS and scanning electron microscope (SEM). The GEM/P1, GEM/P2, and GEM/P3 micelles exhibited pH‐sensitive drug release properties and the GEM/P1 micelles has the relatively fastest drug release rate. Containing multiple acetal and Schiff base moieties GEM/P1 micelles showed fastest cellular internalized rate and best in vitro antitumor activity among all GEM‐loaded micelles.