Dual pH and Temperature Stimuli-Responsive Magnetic Nanohydrogels for Thermo-Chemotherapy

Dual stimuli pH and temperature-responsive nanohydrogels based on poly(N-isopropylacrylamide)-chitosan have been synthesized. Fe3O4 magnetic nanoparticles (NPs) (similar to 12 nm) have been incorporated into hydrogels to achieve temperature optimized magnetic nanohydrogel (MNHG) for magnetic hyperthermia with lower critical solution temperature, LCST > 42 degrees C. The composite was further investigated for its potential application in drug delivery and in vitro cancer cell cytotoxicity. Waterbath assisted drug release studies were carried out using anti-cancer drug doxorubicin (DOX) in acetate buffer medium (pH similar to 4.6) to mimic tumor cell environment which is slightly acidic in nature. The pH and temperature responsiveness of the system was demonstrated by DOX release under different conditions. The released amount of DOX was found to be nearly 4 mu g/mg above hyperthermia temperature (similar to 42 degrees C) as opposed to only 1.9 mu g/mg of MNHG at physiological temperature (37 degrees C) under acidic environment (pH similar to 4.6). Further, AC magnetic field (AMF) induced heating of NPs entrapped inside hydrogels showed appreciable reduction of cell population in human breast (MCF-7) and cervical carcinoma (HeLa) cell lines for given duration of field exposures. Quantitatively, death percentages of HeLa cells were nearly 35 and 45% while for MCF-7, these were 20 and 70% when exposed to AMF for 10 and 30 min, respectively. Further the cell killing efficacy of MNHG loaded with DOX was assessed under AMF using HeLa cell lines. The AMF induced heat triggered DOX release from the MNHG which enhances the cell death up to 85% due to combined effect of thermo-chemotherapeutics. The present system with both pH and temperature responsivity serves as a promising candidate for a combination therapy.