## 4 Application of PCL-Based Materials in Nanoformulations
### Nanoparticles
The solvent emulsion-evaporation method was also used for intranasal brain delivery. PCL nanoparticles (about 300 nm) loaded with carboplatin (hydrophilic chemotherapy) were prepared for this purpose. In vitro cytotoxicity tests against human glioblastoma LN229 cells and in situ nasal perfusion tests conducted on rats showed better results compared to the use of a simple drug solution. The RPE effect has become the most important mechanism considered in the design of cancer therapy. Nanocarriers are designed to take advantage of this RPE effect and accumulate in the tumor environment for better targeting and therapeutic efficacy. Vascularized, mainly metastatic, tumors of the pancreas, prostate, and liver are less sensitive to the RPE effect than other tumor types [6]. PCL-based micelles have multiple advantages, including improved permeation and retention (EPR), increased blood circulation time, and increased endocytosis due to surface modification. For the treatment of hepatocellular carcinoma, [PERSON] and colleagues prepared lipidod-loaded micelles using polyethylene glycol-polycaprolactone (PEG-PCL) copolymers and amphiphilic hyaluronic acid-polycaprolactone (HA-g-PCL) copolymers [109]. The HA-g-PCL micelles showed high drug encapsulation efficiency (about 71%), stability in aqueous solutions, and high affinity and cytotoxicity towards HepG2 cells, despite their size of 274 nm. The combination of drugs of interest with PCL-based formulations allows for non-covalent encapsulation of these drugs (based on hydrogen bonding interactions, hydrophobic-hydrophobic interactions, or ionic interactions) [110]. In this case, several factors such as drug solubility, drug affinity for the polymer, nanoparticle core volume, and drug self-aggregation capacity can influence the drug loading capacity (DLC), which is the mass ratio of drug to polymer. The DLC of paclitaxel in PEG-b-PCL-based micelles, for example, increases with the length of the hydrophobic PCL block [111]. On the other hand, no significant increase was observed when a similar experiment was conducted with doxorubicin,a less hydrophobic compound [112]. Furthermore, studies on the effectiveness of administration using in vitro cytotoxicity studies have also indicated that longer hydrophilic arms compromise the therapeutic efficacy of star-shaped supramolecular micelles charged with DOX, resulting in significantly reduced cytotoxicity, as measured by a higher IC50 value [113]. In addition to several experimental approaches, physicochemical models have been used to predict the charge and stability of the drug based on compatibility parameters between the polymer and the drug [114]. Among these models is the Flory-Huggins interaction parameter (XFH), which has been successfully used to characterize polymer-drug compatibilities [115]. Studies on PCL-based models have shown that drug loading is strongly influenced by the polymer composition and the shape of the nanoparticles [116]. \"Worm-like\" structures exhibit a higher packing density of PEG halves on surfaces with reduced curvature, leading to higher packing constraints for the polymers. Under these conditions, PEG chains extend, thus increasing the thickness of the outer PEG layer. Consequently, \"worm-like\" structures exhibit a drug loading twice that of spherical NPs. This variety of methods in the field of nanoparticles can facilitate screening of formulations and be used for the rational design of new polymers and drug-specific nanocarriers. It should be noted that the combination of a drug with a specific nanocarrier can have a significant influence on the pharmacokinetic profile and pharmacological effect of the drug [117]. \"Intelligent\" stimulus-sensitive nanoparticles could improve therapeutic effectiveness by enabling controlled drug delivery to the site of action. These formulations can be activated by external or internal stimuli, such as pH changes, temperature, irradiation, magnetism, concentration gradients, or enzymatic activity.