## 3 In Vivo Applications of MIP-Based DDS
### Drug Reservoirs  
When addressing the design of drug reservoirs, the range of templates of interest to be imprinted is very broad. Some of the typical templates include small organic molecules such as pesticides, active pharmaceutical ingredients (APIs), aminoacids, peptides, and glucides. However, novel strategies recently emerged for imprinting larger compounds, such as proteins, cells, bacteria, and viruses [12]. Insulin has been successfully included in a biomimetic MIP-DDS for oral administration, as an alternative to the traditional subcutaneous formulation for diabetes [27]. Due to its peptide structure, insulin can easily benefit from being embedded in a MIP, as it is readily degradable in the gastro-intestinal tract. N-hydroxymethyl acrylamide (HEAA)-based MIPs exhibited an enhanced hypoglycemic effect in vivo, quantified by 60% reduction in blood glucose levels in the first 2-3 h. Surprisingly, no secondary hypoglycemic adverse effects were noticed, subsequently suggesting the favorable safety profile of this biomimetic platform [27]. Enantioselective MIPs are also potential strategies for designing systems with a controlled delivery. More than a decade ago, [PERSON] et al. developed and evaluated the performance of a transdermal system for the enantioselective-controlled delivery of S-propranolol, which consisted of four components: the backing layer, a chitosan gel as the reservoir, a MIP-based membrane, and the release liner. Chitosan was selected as the gel vehicle due to its favorable characteristics, such as high selectivity for the S-enantiomer release, low toxicity, and reduced immunogenicity. An intriguing aspect regarding this study was the preparation of MIP-based membrane by reactive pore filling of a bacterial cellulose membrane. The enantioselective-controlled delivery of S-propranolol from the racemic propranolol-loaded gel formulation was based on the membrane's high selectivity towards the eutomer. In vitro release tests revealed that an increase in the pH of the receiving solution enhances the enantioselective release of S-propranolol. Explanation lies in the fact that increasing the pH leads to a higher degree of ionization of the monomer, causing the stronger affinity towards the S-enantiomer at the recognition sites, promoting its transfer through the stereoselective membrane. The following skin permeation studies surprisingly revealed that cellulose alone provides a low to moderate natural-occurring selectivity for the enantioselective release of propranolol. Finally, the transdermal patch has proven its in vivo effectiveness as a drug reservoir due to the ability to selectively regulate the release of S-propranolol, with a limited transport of the distomer [28]. Oral DDS formulations can be improved by designing systems with superior floating properties for the improved bioavailability (BA) of a desired drug. The floatation approach implies that the drug reservoir must exhibit a lower density compared to gastric fluids, which leads to its increased gastric residence time following oral administration. This can be achieved by using a liquid crystal (LC), 4-methylphenyl dicyclohexyl ethylene (MPDE) as functional monomer [29]. LC-MIPs can imprint and recognize templates at a very low level of crosslinking. Compared to conventional MIPs, they have a higher number of available binding sites, which can overcome the challenge of the low employment of imprinting sites. Due to a decrease in the cross-linking level, the mass transfer of templates can be significantly improved, while superior release profiles are achieved. However, the imprinting effect of LC-MIPs is usually weaker due to the low degree of cross-linking [30]. In one study, MPDE and polyhedral oligomeric silsesquioxanes (POSS) were used to fabricate a floating MIP-DDS for the oral administration of capecitabine (CAP). Throughout in vitro and in vivo studies, the therapeutic system exhibited a sustained release and superior BA of CAP, consequences to its increased gastric floatation effect in aqueous media [29].