Near-Infrared Light-Responsive Shell-Crosslinked Micelles of Poly(d,l-lactide)- b -poly((furfuryl methacrylate)- co -( N -acryloylmorpholine)) Prepared by Diels-Alder Reaction for the Triggered Release of Doxorubicin

In the present study, we developed near-infrared (NIR)-responsive shell-crosslinked (SCL) micelles using the Diels-Alder (DA) click reaction between an amphiphilic copolymer poly(d,l-lactide) - -poly((furfuryl methacrylate) - -( -acryloylmorpholine) ) (PLA - -P(FMA - -NAM )) and a diselenide-containing crosslinker, bis(maleimidoethyl) 3,3'-diselanediyldipropionoate (BMEDSeDP). The PLA - -P(FMA - -NAM ) copolymer was synthesized by RAFT polymerization of FMA and NAM using a PLA -macro-chain transfer agent (PLA -CTA). The DA reaction between BMEDSeDP and the furfuryl moieties in the copolymeric micelles in water resulted in the formation of SCL micelles. The SCL micelles were analyzed by H-NMR, FE-SEM, and DLS. An anticancer drug, doxorubicin (DOX), and an NIR sensitizer, indocyanine green (ICG), were effectively incorporated into the SCL micelles during the crosslinking reaction. The DOX/ICG-loaded SCL micelles showed pH- and NIR-responsive drug release, where burst release was observed under NIR laser irradiation. The in vitro cytotoxicity analysis demonstrated that the SCL was not cytotoxic against normal HFF-1 cells, while DOX/ICG-loaded SCL micelles exhibited significant antitumor activity toward HeLa cells. Thus, the SCL micelles of PLA - -P(FMA - -NAM ) can be used as a potential delivery vehicle for the controlled drug release in cancer therapy.