| Chitosan-based tri-component copolymers, chitosan-g-poly(e-caprolactone)-(g-poly(oligo(ethylene glycol) methacrylate)) (CS-PCL-POEGMA, CPP), are developed as multifunctional micelles for anti-tumor therapy.2-Bromoisobutyric acid and poly(e-caprolactone) are first site-specifically conjugated onto the hydroxy groups of chitosan backbone through conventional coupling chemistry to give CS-PCL-Br, using sodium dodecyl sulphate-chitosan complex as an organo-soluble intermediate. CPP-PCL-Br is further used for initiating the single electron transfer living radical polymerization of OEGMA in the mixed solvent of dimethyl sulfoxide and lactic acid, yielding CPP. One-pot reaction of CPP with a small amount of NaN3 under the catalysis of Cu(I)Br/tris-(2-dimethylaminoethyl)amine converts the bromo ends of POEGMA grafts to azide functionality, which is used for conjugation of folic acid targeting moiety via azide-alkyne click reactions.The resultant tri-component copolymers can assemble into spherical micelles with three layers which contain PCL as inner core, chitosan as shell and POEGMA as corona. With electrostatic interaction, ICG can be easily loaded on the shell layer of micelle, the light and thermal stability and photothermal behavior of it can increase dramatically. On the same time, doxorubicine (Dox), a model hydrophobic chemotherapeutic agent, was used to study the load and release behavior of this micelle. It shows that it can load Dox very well and inhibit its’burst release in neutral media. The load and release behavior of micelle will not be affected by the loading of ICG.The blank CPP micelles showed low cytotoxicity due to the presence of POEGMA brush as the corona layer. Upon NIR laser irradiation, the ICG-micelles induced apparent cycotoxicity towards HepG2 cells due to the photothermal effect of ICG. The anti-tumor effect of the dual-agent-loaded micelles was significantly enhanced when irradiated with NIR laser. |
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