Design of molecularly imprinted hydrogels with thermoresponsive drug binding sites

Drug delivery systems (DDS) regulate the spatiotemporal distribution of drugs in vivo to maximize efficacy and minimize side effects. Stimuli-responsive hydrogels, which exhibit a drastic change in volume in response to external stimuli such as temperature and pH, have attracted considerable interest as drug reservoirs for self-regulating DDS, as stimuli-responsive changes in the network size can regulate drug diffusion. However, such hydrogels have the disadvantage of leaking drugs even in the absence of stimulation. Proteins such as hemoglobin have dynamic molecular binding sites that modify their binding capacities by their conformational changes induced when an effector molecule binds to allosteric sites. Such dynamic binding sites are useful for loading drugs into reservoirs because their conformational changes can be used to control drug loading and release. In this study, we prepared thermoresponsive hydrogels with a controlled drug binding capacity to design drug reservoirs capable of both suppressing drug leakage below the transition temperature and accelerating drug release above it. Dynamic molecular binding sites were created by molecular imprinting that used 4,4'-diaminodiphenyl sulfone (dapsone) as the model drug, β-cyclodextrin (CD) as the ligand, and N-isopropylacrylamide as the primary monomer. The molecularly imprinted (MIP) and nonimprinted (NIP) hydrogels with CD ligands, as well as the poly(N-isopropylacrylamide) (PNIPAAm) hydrogels without CD ligands, drastically shrunk above their transition temperature because of the PNIPAAm major chains changing conformation from a hydrophilic random coil to a hydrophobic globule as temperature increased. Because the MIP hydrogel has dynamic molecular binding sites, it absorbs a larger amount of dapsone than the NIP hydrogels in an aqueous solution below the transition temperature. The amount of dapsone adsorbed into the MIP hydrogel significantly decreased with increasing temperatures above 37 °C, despite the fact that the hydrophobic interaction between the polymer chains and dapsone became strong. The decrease in dapsone adsorption capability of the MIP hydrogel is due to a conformational change from a swollen to a shrunken state as temperature increases. The MIP hydrogel suppressed drug leakage below its transition temperature due to the high binding capacity of dynamic binding sites, but accelerated the drug release above its transition temperature due to the collapse of dynamic molecular binding sites, in contrast to the drug release behavior of general PNIPAAm-based hydrogels. Thus, the thermoresponsive MIP hydrogels with dynamic molecular binding sites regulated drug release in response to a change in temperature.