Miktoarm Amphiphilic Block Copolymer with Singlet Oxygen-Labile Stereospecific β-Aminoacrylate Junction: Synthesis, Self-Assembly, and Photodynamically Triggered Drug Release.

Incorporation of a desired stimuli-responsive unit in a stereospecific manner at the specific location within a nonlinear block copolymer architecture is a challenging task in synthetic polymer chemistry. Herein, we report a facile and versatile method to synthesize AB2 miktoarm block copolymers bearing a singlet oxygen (1O2)-labile regio and stereospecific β-aminoacrylate linkage with 100% E-configuration at the junction via a combination of amino-yne click chemistry and ring opening polymerization. Using this strategy, a series of 1O2-responsive AB2 amphiphilic miktoarm (MA) copolymers composed of hydrophilic polyethylene glycol (PEG) as the A constituent and hydrophobic polycaprolactone (PCL) as the B constituent (MA-PEG- b-PCL2) was synthesized by varying the block length of PCL. The self-assembly characteristics of these well-defined MA-PEG- b-PCL2 copolymers in an aqueous condition were studied by solvent displacement and thin-film hydration method, and their morphologies were investigated using transmission electron microscopy. The copolymers formed spherical, cylindrical, or lamella morphologies, depending on the chain length and preparation conditions. A hydrophobic photosensitizer chlorin e6 (Ce6) and anticancer drug doxorubicin (DOX) were efficiently encapsulated into the hydrophobic core of MA-PEG- b-PCL2 copolymer micelles. These coloaded micelles were taken up by human breast cancer (MDA-MB-231) cells. Upon red laser light irradiation, the 1O2-generated by the Ce6 induced photocleavage of the β-aminoacrylate moiety, leading to the dissociation of the micellar structure and triggered intracellular drug release for effective therapy. Overall, rapid disassembly upon 1O2 generation and subsequent controlled intracellular drug release suggested that these micelles bearing β-aminoacrylate linkage have a huge potential for on-demand drug delivery.