Dual pH- and Temperature-Responsive Performance and Cytotoxicity of N-Isopropylacrylamide and Acrylic Acid...

Background: Polymer-coated mesoporous silica nanoparticles have attracted immense research interest in stimuli-responsive drug delivery systems due to their drug-releasing ability on demand at specific sites in response to external or internal signals. However, the relationships between the coated-copolymer encapsulation and drug delivery performance in the hybrid nanocomposites was rarely reported. Therefore, the main objectives of the present work are to explore the cell uptake, cellular internalization, cytotoxicity, and hemolysis performance of the fluorescent hybrid materials with different polymer-encapsulated amounts. Methods: Using (2-(2-aminoethyl)-6-(dimethylamino)-1H-benzo[de]isoquinoline-1,3(2H)-dione)-doped poly[(N-isopropylacrylamide)-co-(acrylic acid)] (PAN) as a shell and bimodal mesoporous silicas (BMMs) as a core, the dual pH- and temperature-responsive mesoporous PAN@M-BMMs with the fluorescent performances were synthesized via a radical polymerization approach. The effects of the PAN-coated thicknesses on their physicochemical properties and structural features were demonstrated via XRD and SAXS patterns, SEM and TEM images, FT-IR spectra, and TG analysis. Their mass fractal (D) evolutions were elucidated on the basis of the SAXS patterns and fluorescence spectra. Results: The D values increased from 2.74 to 2.87 with an increase of the PAN-coated amount from 17 to 26.5% along with the particle size from 76.1 to 85.6 nm and blue-shifting of their fluorescent emission wavelength from 470 to 444 nm. Meanwhile, the PAN@M-BMMs exhibited a high ibuprofen (IBU) loading capacity (13.8%) and strong dual pH-/temperature-responsive drug-releasing performances (83.1%) at pH 7.4 and 25 °C, as comparison with that (17.9%) at pH 2.0 and 37 °C. The simulated results confirmed that the adsorption energy decreased from -67.18 kJ/mol for pure BMMs to -116.76 kJ/mol for PAN@M-BMMs, indicating the PAN-grafting on the surfaces of the BMMs core was beneficial to improve its IBU-adsorption capacity. Its uptake in the HeLa cell line was performed via microplate readers, confocal microscopy, flow cytometry, and ICP measurement, showing a low cytotoxicity at a concentration up to 100 µg/mL. Specially, P_0.2AN@M-BMMs had a superior cellular uptake and fluorescence properties via the time-dependent uptake experiments, and exhibited the highest silicon content via the cellular internalization analysis, as compared to other carriers. Hemolysis tests confirmed the hemolysis rates below 5%. Conclusions: These demonstrations verified that PAN@M-BMMs should be a promising biomedical application prospect.