Up-Conversion Cell Imaging and pH-Induced Thermally Controlled Drug Release from NaYF<sub>4</sub>:Yb<sup>3+</sup>/Er<sup>3+</sup>@Hydrogel Core–Shell Hybrid Microspheres

In this study, we report a new controlled release system based on up-conversion luminescent microspheres of NaYF<sub>4</sub>:Yb<sup>3+</sup>/Er<sup>3+</sup> coated with the smart hydrogel poly[(<i>N</i>-isopropylacrylamide)-<i>co</i>-(methacrylic acid)] (P(NIPAM-<i>co</i>-MAA)) (prepared using 5 mol % of MAA) shell. The hybrid microspheres show bright up-conversion fluorescence under 980 nm laser excitation, and turbidity measurements show that the low critical solution temperature of the polymer shell is thermo- and pH-dependent. We have exploited the hybrid microspheres as carriers for Doxorubicin hydrochloride (DOX) due to its stimuli-responsive property as well as good biocompatibility <i>via</i> MTT assay. It is found that the drug release behavior is pH-triggered thermally sensitive. Changing the pH to mildly acidic condition at physiological temperature deforms the structure of the shell, causing the release of a large number of DOX from the microspheres. The drug-loaded microspheres exhibit an obvious cytotoxic effect on SKOV3 ovarian cancer cells. The endocytosis process of drug-loaded microspheres is observed using confocal laser scanning microscopy and up-conversion luminescence microscopy. Meanwhile, the as-prepared NaYF<sub>4</sub>:Yb<sup>3+</sup>/Er<sup>3+</sup>@SiO<sub>2</sub>@P(NIPAM-<i>co</i>-MAA) microspheres can be used as a luminescent probe for cell imaging. In addition, the extent of drug release can be monitored by the change of up-conversion emission intensity. These pH-induced thermally controlled drug release systems have potential to be used for <i>in vivo</i> bioimaging and cancer therapy by the pH of the microenvironment changing from 7.4 (normal physiological environment) to acidic microenvironments (such as endosome and lysosome compartments) owing to endocytosis.