Facile construction of noncovalent graft copolymers with triple stimuli-responsiveness for triggered drug delivery

A triple stimuli-responsive nanoparticle derived from a noncovalently grafted amphiphilic copolymer was reported. The noncovalent graft copolymer, abbreviated as Dex-β-CD/Fc-PLA, was constructed by the host–guest interactions between β-cyclodextrin (β-CD) grafted dextran (Dex-β-CD) and ferrocene (Fc) terminated poly(lactide) (Fc-PLA). The synthetic Dex-β-CD/Fc-PLA copolymers and precursors were characterized by 1H NMR, FT-IR, UV-Vis, GPC, 2D NOESY 1H NMR and cyclic voltammetry (CV) analyses. The noncovalent amphiphilic copolymers could self-assemble into spherical nanoparticles (NPs) with dextran as the hydrophilic shell and PLA as the hydrophobic core in aqueous solution. The average particle size of Dex-β-CD/Fc-PLA NPs decreased from 118 nm to 79 nm with the increasing amount of hydrophobic PLA segments. Ascribed to the integration of many benzoic imine bonds and Fc groups, the NPs could remain stable at pH 7.4 but decomposed in the acidic and oxidizing (NaClO and positive voltage) media, as indicated by DLS and TEM measurements. The copolymer was used to encapsulate the hydrophobic anticancer drug doxorubicin (DOX) to achieve DOX-loaded NPs, which showed rather low drug release under simulated physiological conditions but significantly enhanced release in the simulated oxidizing and acidic media. MTT assays revealed that the pristine copolymer possessed low toxicity against both normal and cancer cells, but the DOX/Dex-β-CD/Fc-PLA NPs showed much higher selective toxicity on A549 cancer cells than normal HUVEC cells. Furthermore, the results from fluorescence microscopy demonstrated that these NPs could efficiently deliver and release DOX into the nuclei of A549 cells. The present biocompatible copolymers with triple stimuli-sensitivities are promising for the efficient intracellular delivery of hydrophobic anticancer drugs.