*5.2. Application of pCDs in Drug Delivery*

The bioavailability of drugs is often limited by poor water solubility [115–118]. pCDs have been used for drug encapsulation, which improves the stability of drugs and effectively regulates their release. pCDs can greatly improve the solubility of poorly watersoluble drugs; additionally, they can also be used to prepare carrier systems that control drug release over a long time. CD has a special structure, which can enhance the biocompatibility and degradability of the drug by forming an inclusion compound, as well as a high loading rate of drug molecules and improvement of the controlled release performance. CDs can control the release of drugs and reduce their toxicity [119,120].

Oliveria et al. [47] used a high-yield reaction route based on polyglutamic acid, and used β-CD or γ-CD for the synthesis. The novel polymer had an average of ~17 CD cavities and was characterized using nuclear magnetic resonance, MALDI-MS, and DLS. It was determined to be a carrier of doxorubicin in human tumor cells, and this inclusion compound has antiproliferative activity in the tumor cells. Bisphosphonate is a mature drug with a wide range of applications in medicine. However, the side chain and nature of the phosphorus group may cause poor water solubility, thereby affecting its bioavailability. Mallard et al. [121] proved that CDs can be used as a bisphosphonate carrier. Through bisphosphonate functionalized CD, a cyclodextrin/bisphosphonate polymer (CD/BP) was synthesized and characterized. The formation of CD/BP was characterized by onedimensional and two-dimensional nuclear magnetic resonance spectroscopy, isothermal titration, calorimetry, and ultraviolet-visible spectrophotometry, which showed that cyclodextrin is an effective carrier for bisphosphonates. CD/BP can be used to treat parasitic diseases, in particular, to prevent Chagas disease [122,123]. This provides a better treatment plan for the treatment of sleeping sickness caused by parasites. Ho et al. [124] proposed a submicrocarrier with an average hydrodynamic size of 400 to 900 nm through electrostatic gelation of anionic β-CD and chitosan (SMCs). This could address the issues of poor solubility of drugs and the limited bioavailability and pharmacological effects. It was used to improve the solubility and clinically relevant anti-infective controlled release properties of ciprofloxacin. In the study, it was found that when the encapsulation efficiency (~90%) and load capacity (~9%) of sMC were maximized, the molar ratio of ciprofloxacin to β-CD was 1:1. The results showed that regardless of their size, after 24 h of incubation, the cells absorbed sMC well without pathological changes. The sMC was non-toxic and had very good biocompatibility, and it is a suitable system with promising prospects for the treatment of extracellular lung infections. Khelghati et al. [125] focused on reducing the side

effects of adriamycin by designing a pH-sensitive magnetic hyperbranched β-CD as a nanolevel drug carrier. Nanoparticles were released more under acidic conditions and were released less under neutral alkaline conditions. The results of hemolysis analysis showed that the synthesized nanocarriers were completely biocompatible. In vitro studies have shown that free doxorubicin has a higher cytotoxicity than doxorubicin-loaded nanocarriers, demonstrating its high potential to deliver doxorubicin to tumor tissues. Li et al. [126] reported the design and synthesis of a new multifunctional nuclear initiator based on octanorbornene functionalized γ-CD, which is an eight-arm star polymer [127,128] prepared by a nuclear-preferred ring-opening metathesis polymerization reaction. Hexaethylene glycol functionalized with norbornene was used to graft from the initiator. Using norbornenefunctionalized polyethylene glycol (PEG) to extend the chain of the omega functional group to produce water-soluble diblock brush arm star copolymer (DBASC), the size of DBASC was between 10–11 nm, with very good thermal stability, long-range order, and crystallinity. Because of the introduction of γ-CD, DBASC has excellent solubility, enhanced drug binding ability, shows low toxicity, and has a strong inhibitory effect on MCF-7 breast cancer cells. Star polymers represent a new type of modular polymer platform with potential applications in nanostructure self-assembly and drug delivery. Das et al. [129] used β-CD as a drug delivery vehicle for drug cells with amino acid-based ionic liquid (AAIL) substitutes, which could improve the bioavailability of the therapeutic agent. Therefore, the use of β-CD is preferred to stabilize AAIL in our work, and AAIL can be further separated in a controlled manner. Because of its importance in the field of biotechnology, electrodialysis separation, and drug delivery, AAILs, i.e., proline nitrate PN and β-CD are proposed as a model system. In this work, the experimental measurements were theoretically related to quantum chemistry methods. Two-dimensional correlation experiments show the characteristics of PN and β-CD binding. These fascinating results were clarified with the help of molecular docking simulation studies. The confirmation with antibacterial research was consistent with the experimental results. The new AILs-based inclusion compounds have little toxicity and can be used as potential carriers. The results reported were encouraging for the practical application of AAIL and β-CD. Viale et al. [130] synthesized fibrin gel (FBG) and an amino-pCDs inclusion complex (oCD-NH2/Dox) in 2019, demonstrating that the FBG can be used in clinical or experimental applications to release different doxorubicin (Dox) nanoparticles. The fibrinogen (FG) and Ca2+ concentrations may change this activity. In vivo data support that the overall and local toxicity of FBG loaded with oCD-NH2/Dox is lower than that of FBG loaded with Dox. The results indicate that when administered locally via FBG loaded with oCD-NH2/Dox, the therapeutic index of Dox may increase, providing the possibility for using these delivery systems to treat neuroblastoma. Haley et al. [131] reported that a drug delivery system made of pCDs allowed for local administration of amphotericin B (AmB) (the leading drug for the treatment of clinical fungal infections), which can reduce toxicity to the host cells while maintaining the ability to eliminate fungal activity. By exploiting the molecular interaction between the CD cavity and the drug, a slow and sustained delivery rate of AmB was achieved. Lin [132] reported that β-cyclodextrin-{poly(lactide)-poly(2-(dimethylamino)ethylmethacrylate)-poly[oligo(2 ethyl-2-oxazoline)methacrylate]}<sup>21</sup> [β-CD-(PLA-PDMAEMA-PEtOxMA)21] monomolecular micelles act as gold nanoparticles (GNP); the in situ formation and subsequent Dox encapsulated template were applied for the development of anti-cancer drug delivery and computer tomography (CT) imaging to form a pH-responsive therapeutically reactive nanocomposites in situ. Through a combination of experiments and dissipative particle dynamics (DPD) simulations, the formation, microstructure, and distribution of GNP and Dox were studied. Under acidic tumor conditions, Dox-loaded micelles had an encapsulation efficiency of 41–61%, showing rapid release (88% after 102 h). Both in vitro and in vivo experiments have shown excellent anti-cancer efficacy and effective CT imaging performance for β-CD-(PLA-PDMAEMA-PEtOxMA)21/Au/DOX. Single-molecule micelles represent a class of multifunctional nanocarriers for therapeutic diagnostics. Nanoparticle carriers are now a hot frontier field, and the intelligentization of drug loading can greatly

increase chances of curing diseases such as cancer and NPC. In recent years, research on biodegradable nanocarriers has gradually increased, and pCDs have been used in new forms of drug delivery. Liu et al. [133] synthesized a new type of star-shaped nanocarrier (C12H25)14-β-CD-(SS-mPEG)<sup>7</sup> (CCSP) for anti-tumor activity in 2019. The DOX-loaded nanocarrier CCSP has good biocompatibility, high drug loading, good stimulus response release performance, and low leakage, which have potential in anti-cancer intelligence. It is worth noting that Ran Namgung et al. [134] designed a new type of nano-assembled drug delivery system formed by the interaction between polymer-cyclodextrin conjugate and polymer-paclitaxel conjugate, which is the most popular CD polymer. This is one of the successful drug delivery systems. Nano-components have high stability, which can effectively deliver paclitaxel to targeted cancer cells through passive and active targeting mechanisms and effectively release them. Ying et al. [135] introduced the cationic CD loop into the multi-arm PEG backbone in a sterically selective manner, and developed a multiarm pCD polyrotaxane nanocarrier platform that protectively encapsulates the interleukin 12 (IL-12) encoding plasmid for immune gene therapy of colon cancer. Compared with the linear pCD polyrotaxane, the multi-arm polymer design significantly improves the circulating half-life, and the reported tumor suppressor effect is excellent and non-toxic. Nowadays, pCD as an API is a hot topic in the field of biomedicine. For example, Atsushi Tamura et al. [136] have developed an acid-labile β-CD/Pluronic P123-based polyrotaxane for the treatment of a fatal metabolic disease, Niemann-Pick Type C (NPC), compared to the general 2-hydroxypropyl β-cyclodextrin (HP-β-CD) drug treatment, it can not only promote cholesterol excretion and prolong the life of the animal in animal models, and the required dose is greatly reduced, which has huge advantages compared with traditional medicine. In addition, in order to enhance the pharmacokinetics and biodistribution characteristics, and thereby improve the efficacy at lower doses, Aditya Kulkarn et al. [137] designed a β-CD-based polymer prodrug ORX-301, which is composed of β-CD two. It is formed by the polymerization of azide monomer and bifunctional ketal. It overcomes the main limitations of current β-CD-based NPC therapy, and is a potential alternative to existing treatment methods (Table 1).


**Table 1.** Abstracts of papers for pCDs used as drug delivery vehicles.
