Temperature And Magnetic Dual Responsive Surface Molecularly Imprinted Polymers: The Recognition Mechanism And Sustainedly Release Towards 5-fluorouracil

With the increasingly severe environmental pollution, the incidence of human gastric cancer, colon cancer and some other cancers is rising. The traditional oral pharmaceutical intake and drug injection are hard for the drugs to effectively reach the lesion sites, leading to low effective drug concentration, small drug bioavailability and great side effects. In order to improve the effect of the treatment of diseases, many new sustained release systems have sprung up. At present, using biologically compatible polymer materials as drug carrier, selecting a particular drug molecule, and using molecular imprinting technology in sustained release system based on molecular simulation design idea to synthesize effective molecularly imprinted drug delivery system is one of the hot research topics in the field of medicine.Here, Fe₃O₄-encapsulating carbon microspheres were used as substrate materials. The generally used anti-cancer drug 5-fluorouracil（5-FU） was used as template molecule. Fe₃O₄@C microspheres were modified, and grafted with temperature-responsive monomer N-isopropyl acrylamide（NIPAM）. Based on the theory of molecular simulation design, temperature and magnetism dual responsive surface molecularly imprinted drug delivery material was prepared. This research can promote the development and application of molecular imprinting technology in the field of drug delivery system. The research contents are as follows:（1） The theoretical design of molecularly imprinted site and mechnism of recognization. Based on density functional theory, first, the different interaction site and energy between single 5-FU and NIPAM were simulated by DMol3 package, and the minimum interaction energy of 5-FU/NIPAM configuration was calculated as-46.49 k J/mol. Second, the interaction energy between 5-F U and different ratio of NIPAM molecule was also calculated. The calculation results demonstrate that the interaction energy in the composite structure gradually flattens out with the increase of NIPAM monomer proportion and tends to be stable. Combined with the experiment, the ratio of 5-FU to NIPAM is set up as 1:4 during the preparation of surface molecularly imprinted polymers. Finally, based on the above theoretical calculation, the model of 5-FU imprinted site（5-FU/PNIPAM） in the crosslinked network（PNIPAM） was constructed. The electrostatic potential and population analysis show that the formation of 5-FU molecularly imprinted site is theoretically feasible. The interactions include weak forces, such as hydrogen bonding, Van der Waal forces, and electrostatic interaction, which is produced by functional groups located on template molecule and PNIPAM. The interaction energy between molecularly imprinted site and the template molecule is-112.24 k J/mol.（2） Temperature and magnetism bi-responsive molecularly imprinted polymers（TMMIPs） based on Fe₃O₄@C microspheres were prepared by surface grafting polymerization. First, Fe₃O₄@C microspheres were prepared by solvothermal method. After that, the silanization of Fe₃O₄@C microspheres（Fe₃O₄@CSi） with activated surface was realized by introducing vinyl group under the optimized conditions. Finally, TMMIPs were prepared by using Fe₃O₄@CSi as matrix material, APS as initiator, NIPAM as temperature-responsive monomer, 5-FU as template, and N, N‘-methylene bisacrylamide（MBA） as cross linker. Characterization results show that the as-synthesized TMMIPs have an average diameter of about 150 nm with a typical core-shell structure, and the thickness of the coating layer is approximately 50 nm. The lower critical solution temperature of TMMIPs is 39.2℃, and the saturation magnetization of TMMIPs is 16.57 emu/g, which displays obvious superparamagnetism, thermo-sensitivity and favorable dispersibility.（3） The adsorption and controlled release performance of TMMIPs were tested by static adsorption and release experiment. The adsorption experiment shows that TMMIPs exhibit excellent adsorption capacity（up to 96. 53 mg/g at 25℃）, the adsorption equilibrium time is about 120 min, and the imprinting factor is 1.50. The adsorption kinetics can be well described by the pseudo-first-order and pseudo-second-order kinetic model. The isotherm adsorption data fit the Langmuir and Freundlich models. The selective recognition experiments verified that TMMIPs have affinity and selectivity towards 5-FU. The thermosensitive polymer in TMMIPs exhibits thermo-induced swelling/shrinking transition, and adsorption/release activities are accordingly modulated by temperature. 5-FU release rate increases with rising temperature, and is about 70% at 25℃ within 125 min.