## 3 In Vivo Applications of MIP-Based DDS
### Drug Reservoirs
RTILs and deep eutectic solvents (DESs) can be associated as dispersing media, aiming to stabilize and prevent CNTs reaggregation and increasing template's solubility. Replacing conventional porogens with \"green solvents\" reduces the dangers they exhibit on humans and environment [12]. This approach has been selected for the fabrication of a controlled-release powder with fenbufen (FB) imprints made of single-walled carbon nanotubes (SWCNTs)-doping MIP nanocomposite-based binary green porogen system. The binary system consisted of RTIL 1-butyl-3-methylimidazolium tetrafluoroborate ([BMIJBF4), which acts as a dispersing media for CNTs, and DES choline chloride/ethylene glycol (ChCl/EG). Choosing FB as the template was based on the premise that its inclusion in a DDS could reduce its harmful gastro-intestinal side effects. The complex drug reservoir proved to be highly effective in vivo, offering a relative bioavailability of 143.3% [33]. Another approach for the design of MIPs is to use pH and temperature changes as external stimuli for improved drug delivery. Hydrogel-based MIPs (hydroMIPs) are materials that integrate MIPs and a stimuli-responsive hydrogel, resulting in polymers that can reversibly shrink or swell in response to environmental changes (pH, temperature, enzymes). For example, [PERSON] et al. developed an original thermoresponsive hydroMIP-DDS for the delivery of gatifloxacin (GTX). Herein, frontal polymerization (FP) technique was tested for MIP synthesis, an alternative that allows the conversion of monomer into polymer by using the heat released from the polymerization reaction to create a self-sustaining front that propagates throughout an unstirred monomeric mixture. FP has many advantages compared to other techniques: shorter reaction time, low-energy consumption, homogeneity enhancement of polymer chains. Moreover, hydrogels prepared by FP exhibit higher swelling rates and ratios compared to those prepared by bulk polymerization. The most common thermo-responsive polymer is poly(N-isopropylacrylamide) (pNIPAm) because its low cloud point temperature (CPT) of 32 \({}^{\circ}\)C. PNIPAm undergoes a reversible phase transition in water, changing from soluble chains below CPT to hydrophobic aggregates above it. Hydrogel imprinting brings significant improvements over conventional hydrogels, in terms of binding affinity, loading capacity, and selectivity towards various templates. The pH-responsiveness of the gel was shown by a significantly lower drug release in acidic medium, and faster release at higher temperatures (43 \({}^{\circ}\)C), suggesting that the imprinting effect may also be temperature dependent [35]. Solvent-responsiveness is another technique used for obtaining controlled-release drug reservoirs. For instance, LC is capable of solvent-responsive deformation, controlled entirely by the nature of the solvent environment (miscibility, polarity, and hydrogen bonding). A solvent-responsive floating LC-MIP was developed recently, aiming at the gastrocnemius controlled release of S-amlodipine (S-AML). As expected, in vivo studies showed that floating LC-MIPs exhibit a prolonged gastric residence time, over 60 min, and high bioavailability. The floating behavior of LC-MIPs in aqueous medium was attributed of their solvent-responsive deformation [36].