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

Graphical A novel containing cinnamaldehyde pH-sensitive biodegradable linear copolymer carrier mPEG- b -poly(Schiff base-acetal) was designed and synthesized, which could co-delivery of cinnamaldehyde and gemcitabine to same tumor cells and pH-responsive release cinnamaldehyde and gemcitabine for double drug synergistic antitumor therapy. 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.