## 3 pH-Responsive Molecularly Imprinted Polymers
[PERSON] _et al._ prepared a smart MIH by using 2-hydroxyethylmethacrylate (HEMA) and MBA as backbone and cross-linker respectively in the presence of Dox-Cu\({}^{2+}\)-4-VP complex [25]. The MIH showed a pH-responsive release property, not more than 10% of loaded drug was released from Dox-MIH at pH 7.2 in seven days. In contrast, near to 60% of loaded drug was released at pH 5.0 during the same period. These results indicated that Dox-MIH with pH-responsive behavior possessed great promise as a sustained-release delivery system of anticancer drugs. Another approach to realizing pH-responsive binding or releasing property is to exploit the swelling/shrinking behavior of the imprinted hydrogels upon variation of pH values. For instance, [PERSON] _et al._ designed a novel pH-responsive MIPs by using acrylic acid (AA) as an ionizable comonomer and acryloylamylase as a functional monomer [61], respectively, and the latter can form a helical inclusion-complex with template molecule (BPA) through hydrophobic interaction in aqueous solution [103] (Figure 5). The ionizable unites (carboxyl group) of the amylase-based MIPs displayed a reversible structural change of the imprinted binding sites upon varying the pH of the solution, ultimately leading to pH dependent binding of the template. Similarly, [PERSON] _et al._ reported pH-responsive and recognitive polymeric networks based on PEG star polymers to distinguish d-glucose from similar sugars by using methylacryl acid (MAA) as the ionizable comonomer [104]. In addition, equilibrium swelling and rebinding properties of BSA imprinted hybrid hydrogel microspheres based on calcium alginate and phosphate were also evaluated in different pH values and even ionic concentrations [105]. Recently, this type of pH-responsive imprinted hydrogels was applied as horseradish peroxidase mimetic enzymes. The novel enzyme-like catalytic system was based on an imprinted tetrapymer of 4-vinylpyridine (4-VP), chloro (3,7,12,17-tetramethyl-8,13-divinylporphyrin-2,18-dipropanoate(2-))iron(III) (hemin, used as the  
Figure 5: Outline of molecular imprinting using amylose. Reprinted with permission from Reference 103. Copyright 2002, Royal Society of Chemistry. catalytic center), AM, and NIPAm cross-linked by EGDMA with homovanillic acid as the template molecule. Under optimal pH conditions (close to the pI of the polymer), the imprinted gel shrunk to the smallest size with an excellent hydrophobic microenvironment in the imprinted nanostructures, which significantly increased the catalytic efficiency (Figure 6). This remarkably sensitive catalysis in response to pH conditions shows us an effective way to modulate the microenvironment around the catalytic centers for mimetic enzyme [64]. Post-modification of performed MIPs with pH-responsive polymers can also allow obtaining a pH-dependence binding capacity. [PERSON] _et al_. reported a pH-responsive MIP particles fabricated by pore-filling poly (acrylic acid) (PAA) gels into BPA-imprinted polyether sulfone particles [62]. The pH-dependence swelling and shrinking of the PAA gels in the MIPs particles gave rise to reversible control of the rebinding ability toward BPA due to the volume exclusion effect. Despite of a decrease in the adsorbed BPA amount (or rate) after filling the PAA gels, the methodology demonstrated a novel strategy to create pH-responsive MIPs as smart chemicals and as drug-delivery systems. Soon afterwards, [PERSON] _et al_. fabricated a pH-responsive controlled-release drug device based on a synthesized composite latex, which was consisted of a pH stimuli-responsive poly (hydroxyethyl methacrylate) (HEMA) and polycaprolactone-triol (PCL-T) blend, and a MIP with preloaded drug, (\(S\))-omeprazole. The pH-responsive releasing of (\(S\))-oeprazole was due to the PHEMA polymer in the composite latex, which was mainly functioned as a barrier to provide sustained release of the required pH-dependent drug.