Dual pH- and Temperature-Responsive Poly(dimethylaminoethyl methacrylate)-Coated Mesoporous Silica Nanoparticles as a Smart Drug Delivery System

Abstract Smart drug delivery systems (DDSs) are challenging topics these days. DDSs can increase the drug's half-life, protect drugs from filtration, and reduce the drug's side effects. Mesoporous silica is an inorganic material widely used as a drug carrier because of its high surface-to-volume ratio, surface modification ability, production of nanoparticles in different dimensions, shapes, and structures, biocompatibility, and non-toxicity. A robust smart drug delivery system was prepared by grafting poly(dimethylaminoethyl methacrylate) (PDMAEMA) onto mesoporous silica nanoparticles. The nanoparticles were modified with initiator moieties of atom transfer radical polymerization (ATRP). Then, PDMAEMA chains were grafted onto the nanoparticles as a pH- and temperature-sensitive shell with two different lengths using in situ ATRP. The high molecular weight PDMAEMA was highly efficient in controlled release of drug molecules, had lower leakage at pH 7.4, and avoided drug release in normal cells. The drug molecules were released by protonation of the polymer shell at acidic pH (pH 5). Upper critical solution temperature of 41 °C resulted in easily solvation of the shell polymers in an aqueous blood environment and prevented from their accumulation in body tissues. Consequently, this system has lower toxicity than the polymeric drug delivery systems with a lower critical solution temperature behaviour. X-ray diffraction analysis confirmed the successful synthesis of the mesoporous silica nanoparticles. Field-emission scanning electron microscopy analysis and nitrogen adsorption/desorption analysis showed that the nanoparticles have a fine network, mesoporous structure, and a mean size of around 17 nm that show their excellent capacity for loading drugs. Fourier-transform infrared spectroscopy showed that all the modification steps and polymerization were successfully implemented. Thermogravimetric analysis showed PDMAEMA chains with two different lengths grafted onto the nanoparticles. The hybrid nanoparticles with high and low molecular weight PDMAEMA shells showed weight loss of about 36 and 27%, respectively, till 800 °C. Transmission electron microscopy analysis also showed grafted polymer chains on the hybrid nanoparticles. Doxorubicin and methotrexate as the model cancer drugs were used to investigate their loading and release profile at different pH and temperatures. The release profile showed that the hybrid nanoparticles with a high molecular weight PDMAEMA shell prevented from the drug release at neutral pH and temperature successfully. A HeLa cell line was utilized for the in vitro analysis. According to MTT assay results these nanocarriers were killed less than 10% of cells in blank samples. IC50 was used for DOX and MTX that 50% cells were killed by treatment. MTT assay results proved that this carrier might afford great potential for the cancer drug delivery systems.