## 3 In Vivo Applications of MIP-Based DDS
### Targeted DDS
Preliminary results confirmed this hypothesis by demonstrating a high imprinting factor of the imprinted polymer, which consequently suggests superior binding and recognition properties towards the template. Moreover, the improved bioavailability was attributed to the boronic acid fraction [39]. One of the most frequently adopted methods for the external steering of MIP-DDSs is through magnetic field guiding [40]. A magnetic MIP-DDS is most commonly made of an iron oxide nanoparticle core and a drug-loaded MIP shell, delivered to the tumor site with the aid of an external magnetic field. They can be also coated with different polymeric materials to improve their biocompatibility. For instance, DOX loaded magnetic MIPs coated with polydopamine were very effective in a mouse breast adenocarcinoma model. Polydopamine was selected because of its high biocompatibility, with the purpose of increasing the NPs stability against oxidation. In vivo studies proved their superior therapeutic effect, high survival rates in mice, and good biocompatibility [40]. Stimuli-responsive MIPs are a new generation of intelligent therapeutic systems that can adjust their properties in response to various external or internal stimuli [41]. Although such DDSs have been successfully validated under in vitro conditions [42,43], unfortunately this level of valued potential has not yet been demonstrated in vivo. The surface functionalization of imprinted nanoparticles with neutral hydrophilic polymers, such as poly (ethylene glycol) (PEG), would assist such nanomaterials in evading the immune system by modifying the nature and number of proteins that are adsorbed on their surface, giving rise to the so-called PC. PC refers to a layer of proteins that covers the administered nanocarrier, formed through the interaction between circulating proteins and the delivery system. Similar strategies to manipulate PC formation and to endow an immune stealth feature to non-imprinted nanosized DDSs imply the controlled exposure to endogenous de-opsonin proteins (human serum albumin, transferrin, apolipoprotein E) prior to intravenous administration [44]. Additionally, such pretreatments would allow the extension of blood circulation time of DDSs leading to enhanced bioavailability of the API. Biodegradable building blocks could further contribute to the much-desired biocompatibility, ensuring the lack of acute and long-term toxicity of such imprinted nanocarriers. For example, fructose was used as a biodegradable monomer/cross-linker for the controlleddelivery of olanzapine to the brain, by means of magnetic iron oxide-coated silica NPs. In addition to its high biocompatibility, fructose was selected because it can be used as an energy source by the healthy braincells after degradation. The targeted DDS showed high selectivity and biocompatibility, controllable performance, and low toxicity [45]. Similarly, tannic acid was used as a monomer/cross-linker for the fabrication of a magnetic fluorescent multi core-shell structure MIPs-based NPs, aiming to offer a sustained and targeted delivery of 5-fluorouracil (5-FU) in cancer treatment. Tannic acid is a biodegradable polyphenolic compound with potential anticancer effects. Some of its many benefits include high biodegradability, low cost, high antioxidant capacity, antimutagenic and antimicrobial properties. Surprisingly, tannic acid is also a natural cross-linker due to the hydroxyl and carboxyl groups that can efficiently interact with the polymeric backbone. In vivo studies showed that both 5-FU magnetic MIPs and tannic acid determine tumor morphology change and cell death, suggesting their anticancer efficacy as targeted DDS [46].