ABSTRACT
Molecular recognition, the preferential attraction and specific binding between ligand and receptor molecules, is a fundamental concept in nature. It occurs when two molecules are geometrically and chemically complementary. Example interactions include enzyme/ substrate, antigen/antibody, RNA/protein, as well as a host of small molecule/protein interactions. Molecular recognition has traditionally been viewed as a lock-and-key mechanism, but many examples of induced fit are now recognized. Building upon these highly specific interactions, many approaches have been explored to synthesize materials that mimic natural molecular recognition. Among the various existing approaches, molecular imprinting has received considerable attention, offering several distinct advantages suitable for a broad range of applications. Molecular imprinting is the synthesis of a highly cross-linked polymer network containing template molecule-induced binding cavities that are complementary to both the spatial configuration and the functionality of the target template molecules. The earliest attempts to synthesize polymers for molecular recognition were inspired by the theory of Pauling, formulated in the 1940s, on the complex question of antibody formation in the immune system (Ansell, Ramstrom et al. 1996; Mosbach and Ramstrom 1996). Pauling proposed that antibodies behaved like denatured proteins in the presence of chemical functionalities on the antigen, where their amino acid chains would be free to move to form
an antigen-guided shape via a mechanism he termed “molecular complementariness.” Thus the antibody would then memorize a specific moiety of the antigen (Pauling 1940). While incorrect, this idea that a freely moving polymer chain could form a complementary mold around a structure inspired the field of molecularly imprinted polymers (MIPs). Since MIP technology was first developed, the majority of molecules imprinted have been targets of low molecular weights (MWs), with many successful examples exhibiting high selectivity for the template over similar molecules. In contrast, macromoleculebased MIPs have seen much less success. The first report on protein imprinting was published in 1985 (Glad, Norrlow et al. 1985), and since this seminal work, many intrinsic limitations of protein (macromolecule) imprinting have been identified, including permanent entrapment, chemical complexity, conformational flexibility, and solubility incompatibility with many polymer solutions (Turner, Jeans et al. 2006; Ge and Turner 2008). Macromolecule imprinting still draws considerable attention from both scientific and industrial communities, given the unique advantages of MIPs over natural receptors, such as the low cost and robustness of polymers lending MIP technology to a wide range of applications. In this review, we highlight advances in developing “plastic antibodies.” Applications of protein MIPs, which have been expanded to areas of analytical separation, biosensors, environmental monitoring, medical diagnostics, and targeted therapeutics, will also be discussed. We present our recent MIP work aiming to detect misfolded/ pathogenic proteins using novel functional monomers that may also serve as catalysts exhibiting artificial chaperone activity. We conclude with a preview of our applications of MIP-coated nanoparticle therapeutics that can be activated through electromagnetic (EM) excitation. 2.1.1 Strategies for Synthesis of Molecularly Imprinted Polymers
The basic principle for MIP synthesis is relatively straightforward, and most published protocols follow the same general procedure. The functional monomers are mixed with the complementary template to form a prepolymerization complex, which is subsequently polymerized with a cross-linker in the presence of a proper solvent, most often an aprotic and nonpolar solvent. The mixture is cured to give a porous, highly crosslinked, and rigid material. The template molecules are then removed by washing with a solvent or a combination of chemical or enzymatic treatments, resulting in an imprinted matrix with molecular-scale cavities complementary in shape and functionality to the template molecules. Molecularly imprinted polymers posses a “permanent memory” of the template, most often demonstrated by enhanced rebinding of template molecule to the MIP versus a nonimprinted polymer equivalent (NIP). The selectivity of the MIP for the original template over structural analogues is a more challenging test for MIPs that work best for low-MW templates. The basic principles of molecular imprinting are illustrated in the scheme shown in Fig. 2.1.
