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Review

Cyclodextrins as Anti-inflammatory Agents: Basis, Drugs and Perspectives

by
Silvia Lucia Appleton
1,†,
Silvia Navarro-Orcajada
2,†,
Francisco Juan Martínez-Navarro
3,4,*,
Fabrizio Caldera
1,
José Manuel López-Nicolás
2,
Francesco Trotta
1 and
Adrián Matencio
1,*
1
Dip. Di Chimica, Università di Torino, via P. Giuria 7, 10125 Torino, Italy
2
Departamento de Bioquímica y Biología Molecular A, Unidad Docente de Biología, Facultad de Veterinaria, Regional Campus of International Excellence “Campus Mare Nostrum”, Universidad de Murcia, 30100 Murcia, Spain
3
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
4
Department of Medicine (Hepatology), Albert Einstein College of Medicine, Bronx, NY 10461, USA
*
Authors to whom correspondence should be addressed.
†
Both authors contributed equally to the manuscript.
Biomolecules 2021, 11(9), 1384; https://doi.org/10.3390/biom11091384
Submission received: 30 July 2021 / Revised: 9 September 2021 / Accepted: 17 September 2021 / Published: 19 September 2021
Browse Figure
Versions Notes

Abstract

:
Inflammation is a biological response of the immune system to harmful stimuli. Importantly, inflammation is also a hallmark of several human diseases such as cancer or diabetes. Novel drugs to treat this response are constantly researched, but the formulation is usually forgotten. Cyclodextrins (CDs) are a well-known excipient for complexing and drug delivery. Anti-inflammatory drugs and bioactive compounds with similar activities have been favored from these CD processes. CDs also illustrate anti-inflammatory activity per se. This review tried to describe the capacities of CDs in this field, and is divided into two parts: Firstly, a short description of the inflammation disease (causes, symptoms, treatment) is explained; secondly, the effects of different CDs alone or forming inclusion complexes with drugs or bioactive compounds are discussed.

1. Introduction

Inflammation is a biological process of the immune system in response to harmful stimuli, such as pathogens, damaged cells, or toxic compounds. Inflammation is a hallmark of many diseases including cancer and auto-immune diseases such as psoriasis and rheumatoid arthritis [1]. Immune cells, blood vessels and different immune-mediators are timely orchestrated with the ultimate goal of restore homeostasis by eliminating the initial cause of the damage, achieve resolution, and promote regeneration [2]. Genetic and environmental factors can easily disrupt such precise process interfering with the resolution of inflammation and uncontrolled acute inflammatory response gives place to chronic inflammation, which contributes to a variety of chronic inflammatory conditions [3]. The field has vastly focused on pharmacological ways, not only drugs but also bioactive compounds, to help control and resolve inflammatory responses in multiple scenarios. However, some of them could present low stability or bioavailability needing a formulation improvement. An increase in the drug quantity is sometimes a good solution, but it can cause an increase in adverse side effects. For that reason, the desired solution starts with the increase of stability or bioavailability of the molecule changing the formulation, by for example using cyclodextrins (CDs) [4].
CDs are well-known members of the science community for their uses to solubilize poor-soluble drugs [4,5,6]. Chemically, CDs are truncated cone-shaped oligosaccharides made up of α-(1,4) linked glucose units, obtained by the degradation of starch by the enzyme cyclodextrin glucosyltransferase. The most common CDs are the natural α, β and γ-CD, which contain six, seven and eight glucose units, respectively. The CD ring is a conical cylinder of an amphiphilic nature, with a hydrophilic outer layer (formed by the hydroxyl groups) and a lipophilic cavity [7,8]. When poorly-soluble drugs are complexed with CD, it is created the so-called “inclusion complex” [9,10,11]. To improve the properties of CD monomers, different chemically obtained derivates (e.g., Hydroxylpropyl-β-CD or Methyl-β-CD among others) and polymers have been shown to possess better capacities, such as complexation efficiency or release than natural CDs [12,13,14]. The administration of the drug as complex could increase the efficacy and capacities of the formulation, being an interesting point to improve current treatments. The present review aims to provide a general overview of the use of CDs and their derivatives in the control of inflammation and related processes.

2. Inflammation

2.1. Basic Principles

The inflammatory response is developed upon activation of Toll-like receptors (TLRs) and other Pattern Recognition Receptors (PRRs) [15,16,17,18,19]. When an insult is detected, epithelial cells and tissue-resident macrophages initiate the inflammatory response. The production of diverse proinflammatory chemokines and cytokines, like TNF-α, IL1B and CXCL8, induce the migration of neutrophils and monocytes, which will differentiate into macrophages, to the inflammation site [17,20]. The release of these mediators and others such as leukotriene B4 (LTB4) and histamine regulate the series of cascade events involved in the inflammatory response including vasodilatation, increased blood vessels permeability, increased expression of endothelial adhesion molecules, swelling and recruitment of immune cells [19,21,22,23]. Inflammation can be classified into acute and chronic phases, based on the severity and duration of the inflammatory response.
In the local acute inflammation, vascular changes and the infiltration of immune cells, mainly neutrophils and macrophages, into the tissues could cause swelling, pain, fever and erythema [24]. When the damage has been cleared, the acute inflammatory process is resolved through the release of pro-resolution and anti-inflammatory molecules, such as protectins, maresins, resolvins and lipoxins [18,25,26,27]. In the case that resolution is not achieved and acute inflammatory response is sustained, a chronic inflammatory response is established and could last several months to years. When inflammation becomes chronic, most characteristics of acute inflammation, such as immune cell accumulation and increased vascularity, continue. However, among the infiltrated cells, in chronic inflammation, there are also lymphocytes [24]. At this stage, neutrophil degranulation promotes lymphocyte activation, which triggers the release of mediators that attract more immune cells to the inflamed tissue. Chronic inflammation could occur when the response is not able to clear a pathogen, in hyper-sensitivity diseases, like autoimmune or allergic diseases, and during long-time exposure to a toxic agent exogenous or endogenous, such as silica or cholesterol, respectively [27].

2.2. Inflammatory Diseases

There is a rising incidence in modern societies of cases of systemic chronic inflammation and chronic inflammatory diseases, which are becoming one of the major causes of morbidity and mortality in developed countries [28,29,30]. Systemic chronic inflammation increased the risk of suffering different diseases, like some types of cancer [31], non-alcoholic fatty liver disease [32], metabolic syndrome [33] and type-2 diabetes [34]. C-reactive protein (CRP) is the main chronic inflammation biomarker, it has been associated with an increase in risk for coronary heart disease and cardiovascular disease mortality [35,36]. There is a large range of chronic inflammatory disease, rheumatoid arthritis, diabetes, inflammatory bowel disease, atherosclerosis, Crohn’s disease, allergies, asthma or psoriasis are some examples among them. Due to this situation, in recent years, several studies using different animal models and clinical trials have been focused on finding new molecular targets and compounds to treat these chronic conditions [37,38,39,40].

2.3. Anti-Inflammatory Drugs

Corticosteroids are one of the most effective therapy to treat chronic inflammatory diseases. They suppress the multiple inflammatory genes by reversing histone acetylation through binding to glucocorticoid receptors [41]. They are commonly used to treat autoimmune diseases, asthma, psoriasis and rheumatic arthritis. Long-term use of corticosteroids could lead to developing adverse effects, like hypertension, metabolic issues and peptic ulcer [42].
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used by the population; they inhibit cyclooxygenase (COX) enzyme activity [43,44,45]. These enzymes are responsible for the productions of different inflammatory mediators as prostaglandins, thromboxanes and prostacyclines [46]. The NSAIDs are highly effective during acute inflammation to reduce the symptoms but they are not curative, and their chronic use could be harmful [47].
Usually, chronic inflammation disease treatments are limited, and their efficacy diminishes along the application time. One of the most powerful is the biologic therapy, which consists of the use of antibodies (suffix -mab) or fusion proteins (suffix -cept) that target specifically the main pro-inflammatory cytokines like TNF-α and IL1-β and block them [48,49]. This approximation usually is used when other treatments are not effective, due to possible side effects [50].

3. Cyclodextrins as Agents for Treatment

In this section, the effect of CDs alone and complexed with drugs and bioactive compounds against inflammation is discussed (Figure 1).

3.1. Drugs

Among the significant number of CD-based formulations that have reached the market [51], the CD-anti-inflammatory drug complexes [52] seem to hold a prominent position.
As far as NSAIDs are concerned, CDs overcame the formulation issues caused by their poor water solubility [53]. The great achievements reached triggered intense research over the years [54,55]. A recent systematic review [55] collects the studies conducted in this last decade (2010-2020) and shows how cyclodextrins have had a huge impact on the formulation of NSAIDs with over 600 articles found in the literature, with 24 different NSAIDs investigated and 60 formulations obtained through combinations of CDs and NSAIDs. It emerges that meloxicam, followed by diclofenac, flurbiprofen, ibuprofen, piroxicam, aceclofenac and oxaprozin is the most studied anti-inflammatory drugs and some of the most recent studies are listed in Table 1 as examples. Among CD types, β-CD and HPβ-CD are frequently used, often combined with meloxicam, piroxicam, ibuprofen and piroxicam, flurbiprofen, respectively.
Successful NSAID-CD complexes have also been patented [63] and commercialized [5]. The first one was introduced in Europe in the 1980s with Brexin, a formulation made up of piroxicam and β-CD [52]. Others are Mobitil (meloxicam/β-CD) produced in Egypt and Flogene (piroxicam/β-CD) in Brazil [5].
Alongside solid dosage forms (suppositories and tablets), there are also liquid CD-based formulations. Indocid Eye drop solution is an HPβ-CD-indomethacin combination and Voltaren Ophtha Eye Drops, an HPγ-CD-diclofenac combination for treating eye inflammation, in which the cyclodextrin is not only a drug solubility enhancer but also a penetration promoter without being harmful to the cornea.
CDs were successful also in the delivery of another class of drugs used for the treatment of inflammation, that is, glucocorticoids [64]. Glucocorticoids are used to restrain inflammation, allergy and immune response and make organ transplants possible [64]. Natural and synthetic steroids are currently used, and dexamethasone is an example of synthetic steroid, which is often used but has low solubility in water. Indeed, the hydrophobicity of glucocorticoids has made their formulation challenging.
At the moment, transdermal is the most common route of administration with glucocorticoid-based formulations in the form of hydrogels. Unfortunately, they can be harmful after continuous exposure to organic co-solvents (e.g., ethanol or DMSO) used for the solubilization of glucocorticoids. CDs have therefore been investigated as a possible alternative to prevent the use of co-solvents.
The attempts made in the delivery of steroids in vitro, preclinical, and clinical studies are collected in the systematic review conducted by Santos et al. [54], which shows the effectiveness of CDs in the delivery of steroids when compared with the free drug in terms of inhibition of inflammatory mediators and edema reduction. For example, a hydrocortisone acetate-βCD complex was studied in vitro and good results were achieved as far as solubility, stability and drug release are concerned [65]. Dexamethasone combined with HPβ-CD was tested in vivo on rabbits affected by uveitis and improved the inflammation condition [66]. Alpha-methyl prednisolone complexed with a CD polymer drastically reduced the arthritis scores and paw edema compared with pure drug [67].
Prednisolone 21-hemisuccinate in α-CD was tested on rats with inflammatory bowel disease and colon damage score and myeloperoxidase activity were reduced [68,69]. Dexamethasone has been investigated in clinical studies for the treatment of diabetic macular edema and cataract with successful results. The CDs selected were γ-CD and HPβ-CD, administered topically (ophthalmic route) [70,71].
The aforementioned studies are grouped in the following Table 2.
In-depth knowledge of CDs, as well as the efforts for the optimization of CD formulations, has led to the development of supramolecular structures (e.g., self-assembled systems, cross-linked polymers, drug-conjugates), which improved the limits of single CDs and transformed them into advanced drug delivery systems [51,72].
Indeed, the use of CDs is limited as guest molecules need to interact and fit inside the CD cavity, as a consequence hydrophilic or high molecular weight drugs are not suitable for complexation with CDs. One of the strategies proposed is reacting native cyclodextrins with a cross-linking agent to form insoluble polymers, called nanosponges (NSs) [13]. They have a peculiar cage-like structure formed by cyclodextrins connected by nanochannels, which can be modulated and consequently affect the inclusion capacity. There is a broad number of molecules that can be incorporated inside NSs as there are many interaction sites available for the formation of inclusion and non-inclusion complexes [73]. In particular, the hydrophobic CD cavities with hydrophilic nanochannels of the polymeric network around them permit interaction with drugs having different degrees of lipophilicity and structures [74], including NSAIDs and steroids.
Cavalli et al. tested the capacity of cyclodextrin based nanosponges (CD-NSs) to load lipophilic drugs, i.e., dexamethasone and flurbiprofen. The NS not only loaded the drugs but also released them in a sustained manner [75]. Shende et al. [53] compared CD with CD-NSs for the delivery of meloxicam to understand the improvements that a NS could provide. The low aqueous solubility of meloxicam was enhanced when encapsulated inside NSs and improved compared to CDs. Additionally, the zeta potential was highly negative in the NS formulation, thus suggesting that it was stable. It was then tested in vitro and in vivo and an improvement in rat paw edemas was achieved. The authors thus concluded that NS could be promising drug delivery systems in which the release of meloxicam is controlled to obtain the maximum anti-inflammatory effect.
In another study, β-cyclodextrin nanosponges were used to deliver naproxen. Not only the NS was able to carry the drug but also to prolong and modulate its release being pH-sensitive [76]. Additionally, ibuprofen has been the focus of a few studies [77,78], in which the objective was to understand the diffusion properties of the drug across the NS matrix to optimize polymer synthesis, thus opening the way to the design of drug delivery systems with the desired drug release properties.

3.2. Anti-Inflammatory Bioactive Compounds

Bioactive compounds from natural sources could be an appealing alternative to synthetic drugs when designing a CD-formulation with anti-inflammatory activity (Table 3). Some example of these compounds can include stilbenes (resveratrol), flavanones (hesperidin and alpinetin), flavanolols (ampelopsin and dihydromyricetin), flavones (baicalein, apigenin, chrysin, luteolinnaringenin and naringin), flavonols (galangin), flavonoid glycosides (diosmin and rutin) and terpenes (betulin and zerumbone) [79].
Resveratrol is the most-studied stilbene found in wine and grapes and possesses a limited solubility in water. Lin et al. (2020) [80] have successfully integrated it in HPβ-CD/PVP electrospun nanofibers to overcome that problem and tested them in HaCAT keratinocytes. Treated cells suppressed Particle Matter (PM)-induced expression of inflammatory proteins, COX-2 and matrix metalloproteinase-9 (MMP-9) at a dose of 20 µM, indicating that nanofibers retained the anti-inflammatory activity of the compound. Lim et al. 2020 [81] evaluated the anti-inflammatory effect of pterostilbene, an analogue of resveratrol, complexed with HPβ-CD in RAW 264.7 macrophage cells treated with Fusobacterium nucleatum. The results showed that the inclusion complexes inhibit NF-κB activity and decrease the expression of TNF-α, IL-1β and IL-6, while cytokine IL-10 was not affected.
The isoflavone genistein was encapsulated in HPβ-CD in order to improve its solubility and bioavailability for atopic dermatitis applications. These complexes were found to down-regulate mRNA expression of anti-inflammatory cytokines (IL-1α, IL-1β, IL-6 and TNF-α) below the concentration that caused cytotoxicity (10 µg/mL) [82]. Another flavonoid, baicalein, enhanced its solubility and stability after encapsulation in HPβ-CD, and the inclusion complexes were used to design a thermosensitive hydrogel formulation that alleviated inflammation in animals with cervicitis [83].
Table
Table 3. Summary of the most relevant bioactive compounds and their effects.
Table 3. Summary of the most relevant bioactive compounds and their effects.
Type of CDBioactive CompoundNatural SourceEffectReference
HPβ-CD/PVPResveratrolWine, grapes and blackberriesInduced expression of inflammatory proteins, COX-2 and MMP-9[80]
HPβ-CDGenisteinSoybeansDown-regulate mRNA expression of anti-inflammatory cytokines[82]
HPβ-, Mβ- and HPγ-CDCurcuminTumericTreating inflammatory disorders[84,85]
HPβ- and β-CDCitralLemons and orangesReduced total leukocyte migration into the pleural cavity and TNF-α levels[86]
HPβ-CDNaringeninGrapefruits and orangesReduced TNF- α levels[87]
β-CDCarvacrolOregano essential oilDecrease level of IL-1β, IL-6, MIP-2 and TNF-α and higher of IL-10[88]
α-CDMoringinMoringaDown-regulated pro-inflammatory cytokines TNF-α and IL-1β[89]
Curcumin, a natural coloring from turmeric, decreased the extent and severity of the injury of the large intestine in synthetic dextran sulfate solution (DSS)-induced experimental colitis model in Sprague Dawley rats when complexed with HPβ-CD and Mβ-CD at 1:1 and 1:2 stoichiometries [84]. Additionally, the use of water-soluble curcumin with HPβ-CD or HPγ-CD to manufacture a medicament for treating inflammatory disorders such as rheumatoid arthritis, psoriasis, ulcerative colitis and Crohn’s disease, has been patented [85]. Along with cyclodextrins, Sawant et al. (2014) developed PEG-coated zinc ferrite nanoparticles with curcumin/β-CD complexes that protect erythrocyte membrane against lysis induced hypotonic solution. As human red blood cells membranes are similar to lysosomal membranes, they considered the prevention of hypotonicity-induced erythrocyte membrane lysis as a measure of anti-inflammatory activity.
Ellagic acid complexed with β-CD was also able to protect erythrocyte membrane from lysis induced by heat and hypotonicity, as well as protect albumin from denaturation, demonstrating that the encapsulation improves the anti-inflammatory effects of the bioactive compound [90]. Although the authors prepared 1:2 complexes with CDs, it has been described that ellagic acid can form 1:1 complexes with CDs in the presence of borax [91].
The inhibition of COX or LOX by different betalains, a family of bioactive compounds with interesting bioactivities was recently published [92]. The problems of stability of these compounds can be solved with CDs when the inclusion complex is formed [93].
Some natural compounds from citric fruits have also been encapsulated in cyclodextrins and their anti-inflammatory activity evaluated in animal models. This is the case of citral/β-CD and citral/HPβ-CD complexes which reduced total leukocyte migration into the pleural cavity and TNF-α levels in Swiss mice fed with 100 mg/kg [86]; naringenin/HPβ-CD complexes which also decreased TNF-α levels and showed similar activity to that achieved with naringenin as supplied but administering only one-fifth of its dose [87]; and limonin/β-CD and limonin/γ-CD complexes which reduced the volume of paw edema in Wistar rats fed with 0.12 mg/kg, as well as, improved articular function by the decrease in the degree of bone resorption, soft tissue swelling and osteophyte formation [94].
Neochlorogenic acid, a phenolic compound, has been demonstrated to inhibit microglia activation and pro-inflammatory responses in the brain (inhibition of TNF-α and IL-1β and block of phosphorylated NFκB p65 and p38) [95] and recently, its complexation in natural and modified cyclodextrins have been evaluated at different pH [96].
Terpenoids complexes like carvacrol with β-CD have been tested in animal models for anti-inflammatory effects revealing a reduction in hyperalgesia and in spontaneous and palpation-induced nociception in mice with a tumor on the hind paw [97], and a decrease in muscle tissue myeloperoxidase activity (MPO) and edema after carrageenan treatment in rats [88]. In the last study, the authors also observed a lower level of IL-1β, IL-6, MIP-2 and TNF-α and higher of IL-10 as compared to the vehicle group. A greater reduction of paw edema formation induced by carrageenan was observed in mice treated with the monoterpene p-cymene complexed with β-CD in comparison with p-cymene alone [98]. Furthermore, pedunculoside was embedded into a β-CD polymer with the cross-linking agent epichlorohydrin. The resulting complex exhibited low toxicity and acted more effectively on mice ear edema than the free triterpene, possibly because the improvement of aqueous solubility after encapsulation contributes to the absorption [99]. Moreover, complexation with β-CD improved the solubility and stability of linalool, leading to an enhancement in its antinociceptive and analgesic effects by the reduction of total leukocyte migration and TNF-α levels in peritoneal fluid [100], and a significant reduction of hyperalgesia on chronic non-inflammatory muscle pain model [101].
Moringin, the main isothiocyanate from Moringa oleifera seeds, was complexed in α-CD to increase solubility and stability. The complexes down-regulated pro-inflammatory cytokines TNF-α and IL-1β in LPS activated macrophages cells by preventing IκB-α phosphorylation, suppression of Akt and p38 phosphorylation and translocation of NF-κB [89]. Additionally, modulation of oxidative stress was observed.
The alkaloid berberine was also described to have an anti-inflammatory effect and its complexation in natural β-CD and α-CD was achieved, revealing that the latter provided a better yield [102]. Coumestrol, a plant estrogen, was found to induce cell proliferation and migration in the inflicted wound in Wistar rats after being supplied in HPβ-CD complexes [103].
Centella asiatica extract is rich in asiaticoside, a bioactive compound that is described to promote the synthesis of collagen and acidic mycopolysaccharides and inhibit the inflammatory phase in wound healing that causes hypertrophic scars and keloids. Srichana et al. (2016) [104] developed a topical spray formulation with this extract and HPβ-CD that was non-irritating in the rat model and was able to completely heal an excision wound after 14 days, faster than the control. Moreover, Terminalia sericea extract with 86 % of sericoside was encapsulated in γ-CD, HPγ-CD, HPβ-CD and Mβ-CD to improve its solubility, and the oil/water formulation containing the complexes results in a 2.6-fold higher percutaneous penetration of sericoside in excised pig skin compared with pure extract [105].
Brazilian green propolis extract rich in artepillin C and also p-coumaric acid, baccharin, drupanin and cinnamic acid, was complexed with γ-CD and orally administered to mice [106]. A down-regulation of mRNA levels of TNF-α, decrease in gene expression of serum amyloid P and induction of hepatic ferritin gene expression were observed, while endogenous antioxidant activity was not affected.
Complexes of basil essential oil/β-CD aimed to enhance bioavailability, also inhibit granuloma formation and leukocyte recruitment to the peritoneal cavity, and prevent paw edema formation by the decrease in vascular permeability [107]. Pinheiro et al. (2017) [108] develop β-CD and HPβ-CD complexes with Copaiferamultijuga oleoresin that retained anti-inflammatory activity measured by carrageenan-induced paw edema test. Moreover, electrospun nanofibers of HPβ-CD and plai oil from Zingiber cassumunar Roxb. have been proposed as an alternative topical application due to the anti-inflammatory activity of this essential oil [109].

3.3. CD as Active Agents in Inflammatory Diseases

The capacity of CDs to complex different agents can be used to manage inflammation directly, as occurs with other diseases such as Niemann Pick or neurological diseases [110,111,112]. A case is the atherosclerosis, where the cholesterol accumulation in veins starts the recruitment of macrophages and the inflammation response [113]. HPβ-CD was able to treat atherosclerosis not only by increasing the efflux of cholesterol [114] but also through macrophage reprogramming [115] by the LXR-mediated signaling pathway; cholesterol efflux was increased as a result of ABCA1 and ABCG1 upregulation, which was corroborated in another recent study where this CD reduced the levels of plasma triglycerides and inflammatory cytokines, and also increased the level of plasma HDL-cholesterol. HPβ-CD demonstrated to interact with cholesterol crystal reducing the IGs deposition and the activation of complement activation as measured by terminal complement activation and lowered specific receptor expression on monocytes [116]. Even, the administration of HPβ-CD reduced the level of pro-inflammatory cytokines (IL-1α, TNF or IL-6 among others). This effect was tested with another deposition such as monosodium urate crystal without effect, suggesting a specific effect against cholesterol crystals. Pilely et al., in 2019 discovered that α-CD inhibits cholesterol crystal-induced complement-mediated inflammation as HPβ-CD [117].

4. Discussion

In the light of the considerations made above, it is clear that CDs respond to the need to optimize treatments that already exist, making them more effective, stable and safe. Encapsulation of CDs has been demonstrated to be efficient in solving these kind of issues [8,118] while maintaining or even increasing the biological activity of these agents because they act as multifunctional excipients in that they are solubility enhancers, prevent drug–drug and drug–additive interactions within a formulation, eliminate unpleasant smells or tastes and reduce side effects [5,53,119,120]. Even their own activity as active drugs could promote possible synergetic capacities [116]. In fact, they can be found in numerous pharmaceutical forms, e.g., tablets, suppositories, droplets and spray.
Last but not least, they can be used to develop advanced drug delivery systems that go beyond the limits of single cyclodextrins. As a perspective, all these properties have been found to be ideal for the formulation of anti-inflammatory drugs and bioactive compounds. In addition, novel CDs are created to improve the possible limitations, being able to complex not only drugs but also heavier molecules such as proteins. Bearing the above features in mind and judging by the number of studies conducted, they are certainly in the limelight, so research on this topic is far from over.
In conclusion, this review emphasizes the role of CDs for inflammation treatment. They have been used to improve the release and bioavailability of different approved drugs. Similar studies have been carried out with bioactive compounds where the managing of inflammation responses such as oxidation and the expression of pro-inflammatory cytokines were reduced. On the other hand, CDs have demonstrated their own capacities with cholesterol mediated inflammation processes, managing the complement activation. In summary, this review indicates a possible combinatorial effect where the drug is complexed with CDs against inflammation. In simple terms, the application of CD lays the groundwork for future progress opening up a new realm of other advanced applications expected to arise soon.

Author Contributions

Conceptualization, A.M. and F.J.M.-N.; methodology, A.M.; investigation, S.L.A., S.N.-O. and F.J.M.-N.; data curation, S.L.A. and S.N.-O.; writing—original draft preparation, S.L.A., S.N.-O., F.J.M.-N. and A.M.; writing—review and editing, F.C., J.M.L.-N., F.T. and A.M.; visualization, F.J.M.-N.; supervision, A.M.; project administration, A.M.; funding acquisition, J.M.L.-N., F.T and A.M. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Spanish Ministry of Science and Innovation, project AGL2017-86526-P (MCI/AEI/FEDER, UE) and by the “Programa de Ayudas a Grupos de Excelencia de la Región de Murcia, Fundación Séneca, Agencia de Ciencia y Tecnología de la Región de Murcia (Spain)” (Project 19893/GERM/15).

Acknowledgments

This work is the result of a predoctoral contract for the training of research staff (for Silvia Navarro-Orcajada, number 21269/FPI/19) and also an aid to postdoctoral training and improvement abroad (for Adrián Matencio, number 21229/PD/19) both financed by the Fundación Séneca (Región de Murcia, Spain).

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

CDcyclodextrin
HPβ-CD2-hydroxypropyl β-cyclodextrin
HPγ-CD2-hydroxypropyl γ-cyclodextrin
Mβ-CDmethyl β-cyclodextrin
PVPpolyvinylpyrrolidone
PEGpolyethylene glycol
TNF-αtumoral necrosis factor α
ILinterleukin
MPOmyeloperoxidase
MIP-2macrophage inflammatory protein
NF-κBnuclear factor κB
LPSLipopolysaccharide
TLRToll-like receptor
PRRsPattern Recognition Receptor
CRPC-reactive protein
NSAIDNonsteroidal anti-inflammatory drug
LOXLipoxygenase
COXCyclooxygenase

References

  1. Gregersen, P.K.; Behrens, T.W. Genetics of Autoimmune Diseases—Disorders of Immune Homeostasis. Nat. Rev. Genet. 2006, 7, 917–928. [Google Scholar] [CrossRef]
  2. Abdulkhaleq, L.A.; Assi, M.A.; Abdullah, R.; Zamri-Saad, M.; Taufiq-Yap, Y.H.; Hezmee, M.N.M. The Crucial Roles of Inflammatory Mediators in Inflammation: A Review. Vet. World 2018, 11, 627–635. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Zhou, Y.; Hong, Y.; Huang, H. Triptolide Attenuates Inflammatory Response in Membranous Glomerulo-Nephritis Rat via Downregulation of NF-ΚB Signaling Pathway. Kidney Blood Press. Res. 2016, 41, 901–910. [Google Scholar] [CrossRef] [PubMed]
  4. Jansook, P.; Ogawa, N.; Loftsson, T. Cyclodextrins: Structure, Physicochemical Properties and Pharmaceutical Applications. Int. J. Pharm. 2018, 535, 272–284. [Google Scholar] [CrossRef] [PubMed]
  5. Brewster, M.E.; Loftsson, T. Cyclodextrins as Pharmaceutical Solubilizers. Adv. Drug Deliv. Rev. 2007, 59, 645–666. [Google Scholar] [CrossRef] [PubMed]
  6. Santos, C.I.A.V.; Ribeiro, A.C.F.; Esteso, M.A. Drug Delivery Systems: Study of Inclusion Complex Formation between Methylxanthines and Cyclodextrins and Their Thermodynamic and Transport Properties. Biomolecules 2019, 9, 196. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  7. Kurkov, S.V.; Loftsson, T. Cyclodextrins. Int. J. Pharm. 2013, 453, 167–180. [Google Scholar] [CrossRef] [PubMed]
  8. Matencio, A.; Navarro-Orcajada, S.; García-Carmona, F.; López-Nicolás, J.M. Applications of Cyclodextrins in Food Science. A Review. Trends Food Sci. Technol. 2020, 104, 132–143. [Google Scholar] [CrossRef]
  9. Matencio, A.; Bermejo-Gimeno, M.J.; García-Carmona, F.; López-Nicolás, J.M. Separating and Identifying the Four Stereoisomers of Methyl Jasmonate by RP-HPLC and Using Cyclodextrins in a Novel Way. Phytochem. Anal. 2017, 28, 151–158. [Google Scholar] [CrossRef]
  10. Matencio, A.; Caldera, F.; Pedrazzo, A.R.; Monfared, Y.K.; Dhakar, N.K.; Trotta, F. A Physicochemical, Thermodynamical, Structural and Computational Evaluation of Kynurenic Acid/Cyclodextrin Complexes. Food Chem. 2021, 356, 129639. [Google Scholar] [CrossRef]
  11. López-Nicolás, J.M.; García-Carmona, F. Effect of Hydroxypropyl-β-Cyclodextrin on the Aggregation of (E)-Resveratrol in Different Protonation States of the Guest Molecule. Food Chem. 2010, 118, 648–655. [Google Scholar] [CrossRef]
  12. Salazar, S.; Guerra, D.; Yutronic, N.; Jara, P. Removal of Aromatic Chlorinated Pesticides from Aqueous Solution Using β-Cyclodextrin Polymers Decorated with Fe3O4 Nanoparticles. Polymers 2018, 10, 1038. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Krabicová, I.; Appleton, S.L.; Tannous, M.; Hoti, G.; Caldera, F.; Pedrazzo, A.R.; Cecone, C.; Cavalli, R.; Trotta, F. History of Cyclodextrin Nanosponges. Polymers 2020, 12, 1122. [Google Scholar] [CrossRef] [PubMed]
  14. Matencio, A.; Dhakar, N.K.; Bessone, F.; Musso, G.; Cavalli, R.; Dianzani, C.; García-Carmona, F.; López-Nicolás, J.M.; Trotta, F. Study of Oxyresveratrol Complexes with Insoluble Cyclodextrin Based Nanosponges: Developing a Novel Way to Obtain Their Complexation Constants and Application in an Anticancer Study. Carbohydr. Polym. 2020, 231, 115763. [Google Scholar] [CrossRef]
  15. Chovatiya, R.; Medzhitov, R. Stress, Inflammation, and Defense of Homeostasis. Mol. Cell 2014, 54, 281–288. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  16. Medzhitov, R. Origin and Physiological Roles of Inflammation. Nature 2008, 454, 428–435. [Google Scholar] [CrossRef] [PubMed]
  17. Schmid-Schonbein, G.W. Analysis of Inflammation. Annu. Rev. Biomed. Eng. 2006, 8, 93–131. [Google Scholar] [CrossRef] [Green Version]
  18. Ortega-Gomez, A.; Perretti, M.; Soehnlein, O. Resolution of Inflammation: An Integrated View. EMBO Mol. Med. 2013, 5, 661–674. [Google Scholar] [CrossRef] [PubMed]
  19. Dempsey, P.W.; Vaidya, S.A.; Cheng, G. The Art of War: Innate and Adaptive Immune Responses. Cell. Mol. Life Sci. 2003, 60, 2604–2621. [Google Scholar] [CrossRef]
  20. Silva, M.T. When Two Is Better than One: Macrophages and Neutrophils Work in Concert in Innate Immunity as Complementary and Cooperative Partners of a Myeloid Phagocyte System. J. Leukoc. Biol. 2010, 87, 93–106. [Google Scholar] [CrossRef]
  21. Kumar, V.; Sharma, A. Neutrophils: Cinderella of Innate Immune System. Int. Immunopharmacol. 2010, 10, 1325–1334. [Google Scholar] [CrossRef]
  22. Beutler, B. Innate Immunity: An Overview. Mol. Immunol. 2004, 40, 845–859. [Google Scholar] [CrossRef] [PubMed]
  23. Mayadas, T.N.; Cullere, X.; Lowell, C.A. The Multifaceted Functions of Neutrophils. Annu. Rev. Pathol. 2014, 9, 181–218. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. Huether, S.E.; McCance, K.L. Understanding Pathophysiology, 6th ed.; Elsevier: St. Louis, MO, USA, 2017; ISBN 9780323354097. [Google Scholar]
  25. Serhan, C.N.; Levy, B.D. Resolvins in Inflammation: Emergence of the pro-Resolving Superfamily of Mediators. J. Clin. Investig. 2018, 128, 2657–2669. [Google Scholar] [CrossRef]
  26. Serhan, C.N. Pro-Resolving Lipid Mediators Are Leads for Resolution Physiology. Nature 2014, 510, 92–101. [Google Scholar] [CrossRef] [Green Version]
  27. Kumar, V.; Abbas, A.K.; Aster, J.C.; Perkins, J.A. Robbins Basic Pathology, 10th ed.; Elsevier: Philadelphia, PA, USA, 2018; ISBN 9780323353175. [Google Scholar]
  28. Furman, D.; Campisi, J.; Verdin, E.; Carrera-Bastos, P.; Targ, S.; Franceschi, C.; Ferrucci, L.; Gilroy, D.W.; Fasano, A.; Miller, G.W.; et al. Chronic Inflammation in the Etiology of Disease across the Life Span. Nat. Med. 2019, 25, 1822–1832. [Google Scholar] [CrossRef]
  29. Bennett, J.M.; Reeves, G.; Billman, G.E.; Sturmberg, J.P. Inflammation—Nature’s Way to Efficiently Respond to All Types of Challenges: Implications for Understanding and Managing “the Epidemic” of Chronic Diseases. Front. Med. 2018, 5, 316. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  30. GBD 2017 Causes of Death Collaborators. Global, Regional, and National Age-Sex-Specific Mortality for 282 Causes of Death in 195 Countries and Territories, 1980–2017: A Systematic Analysis for the Global Burden of Disease Study 2017. Lancet 2018, 392, 1736–1788. [Google Scholar] [CrossRef] [Green Version]
  31. Taniguchi, K.; Karin, M. NF-κB, Inflammation, Immunity and Cancer: Coming of Age. Nat. Rev. Immunol. 2018, 18, 309–324. [Google Scholar] [CrossRef]
  32. Kazankov, K.; Jorgensen, S.M.D.; Thomsen, K.L.; Moller, H.J.; Vilstrup, H.; George, J.; Schuppan, D.; Gronbaek, H. The Role of Macrophages in Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis. Nat. Rev. Gastroenterol. Hepatol. 2019, 16, 145–159. [Google Scholar] [CrossRef]
  33. Hotamisligil, G.S. Inflammation, Metaflammation and Immunometabolic Disorders. Nature 2017, 542, 177–185. [Google Scholar] [CrossRef]
  34. Jin, C.; Henao-Mejia, J.; Flavell, R.A. Innate Immune Receptors: Key Regulators of Metabolic Disease Progression. Cell Metab. 2013, 17, 873–882. [Google Scholar] [CrossRef] [Green Version]
  35. Ridker, P.M. A Test in Context: High-Sensitivity C-Reactive Protein. J. Am. Coll. Cardiol. 2016, 67, 712–723. [Google Scholar] [CrossRef]
  36. Emerging Risk Factors Collaboration. C-Reactive Protein Concentration and Risk of Coronary Heart Disease, Stroke, and Mortality: An Individual Participant Meta-Analysis. Lancet 2010, 375, 132–140. [Google Scholar] [CrossRef] [Green Version]
  37. Martinez-Navarro, F.J.; Martinez-Menchon, T.; Mulero, V.; Galindo-Villegas, J. Models of Human Psoriasis: Zebrafish the Newly Appointed Player. Dev. Comp. Immunol. 2019, 97, 76–87. [Google Scholar] [CrossRef] [PubMed]
  38. Martinez-Navarro, F.J.; Martinez-Morcillo, F.J.; Lopez-Munoz, A.; Pardo-Sanchez, I.; Martinez-Menchon, T.; Corbalan-Velez, R.; Cayuela, M.L.; Perez-Oliva, A.B.; Garcia-Moreno, D.; Mulero, V. The Vitamin B6-Regulated Enzymes PYGL and G6PD Fuel NADPH Oxidases to Promote Skin Inflammation. Dev. Comp. Immunol. 2020, 108, 103666. [Google Scholar] [CrossRef] [PubMed]
  39. Patil, K.R.; Mahajan, U.B.; Unger, B.S.; Goyal, S.N.; Belemkar, S.; Surana, S.J.; Ojha, S.; Patil, C.R. Animal Models of Inflammation for Screening of Anti-Inflammatory Drugs: Implications for the Discovery and Development of Phytopharmaceuticals. Int. J. Mol. Sci. 2019, 20, 4367. [Google Scholar] [CrossRef] [Green Version]
  40. Kianmeher, M.; Ghorani, V.; Boskabady, M.H. Animal Model of Asthma, Various Methods and Measured Parameters: A Methodological Review. Iran. J. Allergy Asthma Immunol. 2016, 15, 445–465. [Google Scholar]
  41. Barnes, P.J. How Corticosteroids Control Inflammation: Quintiles Prize Lecture 2005. Br. J. Pharmacol. 2006, 148, 245–254. [Google Scholar] [CrossRef]
  42. Rice, J.B.; White, A.G.; Scarpati, L.M.; Wan, G.; Nelson, W.W. Long-Term Systemic Corticosteroid Exposure: A Systematic Literature Review. Clin. Ther. 2017, 39, 2216–2229. [Google Scholar] [CrossRef] [Green Version]
  43. Oyler, D.R.; Parli, S.E.; Bernard, A.C.; Chang, P.K.; Procter, L.D.; Harned, M.E. Nonopioid Management of Acute Pain Associated with Trauma: Focus on Pharmacologic Options. J. Trauma Acute Care Surg. 2015, 79, 475–483. [Google Scholar] [CrossRef]
  44. Shekelle, P.G.; Newberry, S.J.; FitzGerald, J.D.; Motala, A.; O’Hanlon, C.E.; Tariq, A.; Okunogbe, A.; Han, D.; Shanman, R. Management of Gout: A Systematic Review in Support of an American College of Physicians Clinical Practice Guideline. Ann. Intern. Med. 2017, 166, 37–51. [Google Scholar] [CrossRef] [Green Version]
  45. Dawood, M.Y. Primary Dysmenorrhea: Advances in Pathogenesis and Management. Obstet. Gynecol. 2006, 108, 428–441. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  46. Vane, J.R. Inhibition of Prostaglandin Synthesis as a Mechanism of Action for Aspirin-like Drugs. Nat. New Biol. 1971, 231, 232–235. [Google Scholar] [CrossRef] [PubMed]
  47. Marcum, Z.A.; Hanlon, J.T. Recognizing the Risks of Chronic Nonsteroidal Anti-Inflammatory Drug Use in Older Adults. Ann. Longterm Care 2010, 18, 24–27. [Google Scholar]
  48. Campanati, A.; Giuliodori, K.; Ganzetti, G.; Liberati, G.; Offidani, A.M. A Patient with Psoriasis and Vitiligo Treated with Etanercept. Am. J. Clin. Dermatol. 2010, 11 (Suppl. 1), 46–48. [Google Scholar] [CrossRef]
  49. Ryan, C.; Korman, N.J.; Gelfand, J.M.; Lim, H.W.; Elmets, C.A.; Feldman, S.R.; Gottlieb, A.B.; Koo, J.Y.; Lebwohl, M.; Leonardi, C.L.; et al. Research Gaps in Psoriasis: Opportunities for Future Studies. J. Am. Acad. Dermatol. 2014, 70, 146–167. [Google Scholar] [CrossRef] [PubMed]
  50. Molinelli, E.; Campanati, A.; Ganzetti, G.; Offidani, A. Biologic Therapy in Immune Mediated Inflammatory Disease: Basic Science and Clinical Concepts. Curr. Drug Saf. 2016, 11, 35–43. [Google Scholar] [CrossRef]
  51. Otero-Espinar, F.J.; Torres-Labandeira, J.J.; Alvarez-Lorenzo, C.; Blanco-Méndez, J. Cyclodextrins in Drug Delivery Systems. J. Drug Deliv. Sci. Technol. 2010, 20, 289–301. [Google Scholar] [CrossRef]
  52. Crini, G. Review: A History of Cyclodextrins. Chem. Rev. 2014, 114, 10940–10975. [Google Scholar] [CrossRef] [PubMed]
  53. Shende, P.K.; Gaud, R.S.; Bakal, R.; Patil, D. Effect of Inclusion Complexation of Meloxicam with β-Cyclodextrin- and β-Cyclodextrin-Based Nanosponges on Solubility, in Vitro Release and Stability Studies. Colloids Surf. B Biointerfaces 2015, 136, 105–110. [Google Scholar] [CrossRef]
  54. Santos, P.L.; Brito, R.G.; Quintans, J.S.S.; Araujo, A.A.S.; Menezes, I.R.A.; Brogden, N.K.; Quintans-Junior, L.J. Cyclodextrins as Complexation Agents to Improve the Anti-Inflammatory Drugs Profile: A Systematic Review and Meta-Analysis. Curr. Pharm. Des. 2017, 23, 2096–2107. [Google Scholar] [CrossRef] [PubMed]
  55. Miranda, G.M.; Bessa, J.R.; Teles, Y.C.F.; Cocou, S.; Alexandre, M.; Goncalves, M.S.; Ribeiro-filho, J. Inclusion Complexes of Non-Steroidal Anti-Inflammatory Drugs with Cyclodextrins: A Systematic Review. Biomolecules 2021, 11, 361. [Google Scholar] [CrossRef]
  56. Rein, S.M.T.; Lwin, W.W.; Tuntarawongsa, S.; Phaechamud, T. Meloxicam-Loaded Solvent Exchange-Induced in Situ Forming Beta-Cyclodextrin Gel and Microparticle for Periodontal Pocket Delivery. Mater. Sci. Eng. C 2020, 117, 111275. [Google Scholar] [CrossRef] [PubMed]
  57. Hamilton, D.A.; Ernst, C.C.; Kramer, W.G.; Madden, D.; Lang, E.; Liao, E.; Lacouture, P.G.; Ramaiya, A.; Carr, D.B. Pharmacokinetics of Diclofenac and Hydroxypropyl-β-Cyclodextrin (HPβCD) Following Administration of Injectable HPβCD-Diclofenac in Subjects With Mild to Moderate Renal Insufficiency or Mild Hepatic Impairment. Clin. Pharmacol. Drug Dev. 2018, 7, 110–122. [Google Scholar] [CrossRef] [Green Version]
  58. Shinde, U.A.; Joshi, P.N.; Jain, D.D.; Singh, K. Preparation and Evaluation of N-Trimethyl Chitosan Nanoparticles of Flurbiprofen for Ocular Delivery. Curr. Eye Res. 2019, 44, 575–582. [Google Scholar] [CrossRef]
  59. Volkova, T.; Surov, A.; Terekhova, I. Metal–Organic Frameworks Based on β-Cyclodextrin: Design and Selective Entrapment of Non-Steroidal Anti-Inflammatory Drugs. J. Mater. Sci. 2020, 55, 13193–13205. [Google Scholar] [CrossRef]
  60. Mishra, M.; Chawla, V.; Chawla, P. Pectin, Beta-Cyclodextrin, Chitosan and Albumin Based Gastroprotective Systems for Piroxicam Maleate: Synthesis, Characterization and Biological Evaluation. Int. J. Biol. Macromol. 2019, 122, 127–136. [Google Scholar] [CrossRef] [PubMed]
  61. Sharma, G.; Kaur, M.; Raza, K.; Thakur, K.; Katare, O.P. Aceclofenac-β-Cyclodextrin-Vesicles: A Dual Carrier Approach for Skin with Enhanced Stability, Efficacy and Dermatokinetic Profile. RSC Adv. 2016, 6, 20713–20727. [Google Scholar] [CrossRef]
  62. Maestrelli, F.; Mura, P.; Cirri, M.; Mennini, N.; Ghelardini, C.; Mannelli, L.D.C. Development and Characterization of Fast Dissolving Tablets of Oxaprozin Based on Hybrid Systems of the Drug with Cyclodextrins and Nanoclays. Int. J. Pharm. 2017, 531, 640–649. [Google Scholar] [CrossRef]
  63. Beech, E.; Rodwell, A.; Squires, M. Pharmaceutical Formulation Comprising NSAID and Cyclodextrin. U.S. Patent 9,138,482, 22 September 2015. [Google Scholar]
  64. Schwarz, D.H.; Engelke, A.; Wenz, G. Solubilizing Steroidal Drugs by β-Cyclodextrin Derivatives. Int. J. Pharm. 2017, 531, 559–567. [Google Scholar] [CrossRef]
  65. Tan, L.; Li, J.; Liu, Y.; Zhou, H.; Zhang, Z.; Deng, L. Synthesis and Characterization of β-Cyclodextrin-Conjugated Alginate Hydrogel for Controlled Release of Hydrocortisone Acetate in Response to Mechanical Stimulation. J. Bioact. Compat. Polym. 2015, 30, 584–599. [Google Scholar] [CrossRef]
  66. Kesavan, K.; Kant, S.; Singh, P.; Pandit, J.K. Effect of Hydroxypropyl-β-Cyclodextrin on the Ocular Bioavailability of Dexamethasone from a PH-Induced Mucoadhesive Hydrogel. Curr. Eye Res. 2011, 36, 918–929. [Google Scholar] [CrossRef]
  67. Hwang, J.; Rodgers, K.; Oliver, J.; Schluep, T. Alphamethylprednisolone Conjugated Cyclodextrin Polymer-Based Nanoparticles for Rheumatoid Arthritis Therapy. Int. J. Nanomed. 2008, 3, 359–371. [Google Scholar]
  68. Yano, H.; Hirayama, F.; Arima, H.; Uekama, K. Prednisolone-Appended Alpha-Cyclodextrin: Alleviation of Systemic Adverse Effect of Prednisolone after Intracolonic Administration in 2,4,6-Trinitrobenzenesulfonic Acid-Induced Colitis Rats. J. Pharm. Sci. 2001, 90, 2103–2112. [Google Scholar] [CrossRef]
  69. Yano, H.; Hirayama, F.; Kamada, M.; Arima, H.; Uekama, K. Colonspecific Delivery of Prednisolone-Appended Alpha-Cyclodextrin Conjugate: Alleviation of Systemic Side Effect after Oral Administration. J. Control. Release 2002, 79, 103–112. [Google Scholar] [CrossRef]
  70. Tanito, M.; Hara, K.; Takai, Y.; Matsuoka, Y.; Nishimura, N.; Jansook, P. Topical Dexamethasone-Cyclodextrin Microparticle Eye Drops for Diabetic Macular Edema. Investig. Ophthalmol. Vis. Sci. 2011, 52, 7944–7948. [Google Scholar] [CrossRef]
  71. Saari, K.; Nelimarkka, L.; Ahola, V.; Loftsson, T.; Stefánsson, E. Comparison of Topical 0.7% Dexamethasone-Cyclodextrin with 0.1% Dexamethasone Sodium Phosphate for Postcataract Inflammation. Graefe’s Arch. Clin. Exp. Ophthalmol. 2006, 244, 620–626. [Google Scholar] [CrossRef] [PubMed]
  72. Mura, P. Advantages of the Combined Use of Cyclodextrins and Nanocarriers in Drug Delivery: A Review. Int. J. Pharm. 2020, 579, 119181. [Google Scholar] [CrossRef] [PubMed]
  73. Appleton, S.L.; Tannous, M.; Rosa, A.C.; Argenziano, M.; Muntoni, E.; Rossi, D.; Caldera, F.; Scomparin, A.; Trotta, F.; Cavalli, R. Nanosponges as Protein Delivery Systems: Insulin, a Case Study. Int. J. Pharm. 2020, 590, 119888. [Google Scholar] [CrossRef] [PubMed]
  74. Trotta, F.; Zanetti, M.; Cavalli, R. Cyclodextrin-Based Nanosponges as Drug Carriers. Beilstein J. Org. Chem. 2012, 8, 2091–2099. [Google Scholar] [CrossRef]
  75. Cavalli, R.; Trotta, F.; Tumiatti, W. Cyclodextrin-Based Nanosponges for Drug Delivery. J. Incl. Phenom. Macrocycl. Chem. 2006, 56, 209–213. [Google Scholar] [CrossRef]
  76. Deshmukh, K.; Shende, P. Toluene Diisocyanate Cross-Linked β-Cyclodextrin Nanosponges as a PH-Sensitive Carrier for Naproxen. Mater. Res. Express 2018, 5, 075008. [Google Scholar] [CrossRef]
  77. Ferro, M.; Castiglione, F.; Pastori, N.; Punta, C.; Melone, L.; Panzeri, W.; Rossi, B.; Trotta, F.; Mele, A. Dynamics and Interactions of Ibuprofen in Cyclodextrin Nanosponges by Solid-State NMR Spectroscopy. Beilstein J. Org. Chem. 2017, 13, 182–194. [Google Scholar] [CrossRef]
  78. Ferro, M.; Castiglione, F.; Punta, C.; Melone, L.; Panzeri, W.; Rossi, B.; Trotta, F.; Mele, A. Anomalous Diffusion of Ibuprofen in Cyclodextrin Nanosponge Hydrogels: An HRMAS NMR Study. Beilstein J. Org. Chem. 2014, 10, 2715–2723. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  79. Suvarna, V.; Gujar, P.; Murahari, M. Complexation of Phytochemicals with Cyclodextrin Derivatives—An Insight. Biomed. Pharmacother. 2017, 88, 1122–1144. [Google Scholar] [CrossRef]
  80. Lin, Y.-C.; Hu, S.C.-S.; Huang, P.-H.; Lin, T.-C.; Yen, F.-L. Electrospun Resveratrol-Loaded Polyvinylpyrrolidone/Cyclodextrin Nanofibers and Their Biomedical Applications. Pharmaceutics 2020, 12, 552. [Google Scholar] [CrossRef] [PubMed]
  81. Lim, Y.R.I.; Preshaw, P.M.; Lim, L.P.; Ong, M.M.A.; Lin, H.-S.; Tan, K.S. Pterostilbene Complexed with Cyclodextrin Exerts Antimicrobial and Anti-Inflammatory Effects. Sci. Rep. 2020, 10, 9072. [Google Scholar] [CrossRef]
  82. Choi, D.J.; Cho, U.M.; Choi, D.H.; Hwang, H.S. Effects of Anti-inflammation and Skin Barrier by Genistein Cyclodextrin Complex. J. Soc. Cosmet. Sci. Korea 2018, 44, 171–181. [Google Scholar] [CrossRef]
  83. Zhou, Q.; Zhong, L.; Wei, X.; Dou, W.; Chou, G.; Wang, Z. Baicalein and Hydroxypropyl-γ-Cyclodextrin Complex in Poloxamer Thermal Sensitive Hydrogel for Vaginal Administration. Int. J. Pharm. 2013, 454, 125–134. [Google Scholar] [CrossRef]
  84. Yadav, V.R.; Suresh, S.; Devi, K.; Yadav, S. Effect of Cyclodextrin Complexation of Curcumin on Its Solubility and Antiangiogenic and Anti-Inflammatory Activity in Rat Colitis Model. AAPS PharmSciTech 2009, 10, 752–762. [Google Scholar] [CrossRef] [Green Version]
  85. Neven, P.; Serteyn, D.; Delarge, J.; Scheer, E.; Kiss, R.; Mathieu, V.; Cataldo, D.; Rocks, N. Water Soluble Curcumin Compositions for Use in Anti-Cancer and Anti-Inflammatory Therapy. U.S. Patent No. 8,772,265, 8 July 2014. [Google Scholar]
  86. Campos, C.A.; Lima, B.S.; Trindade, G.G.G.; Souza, E.P.B.S.S.; Mota, D.S.A.; Heimfarth, L.; Quintans, J.S.S.; Quintans-Júnior, L.J.; Sussuchi, E.M.; Sarmento, V.H.V.; et al. Anti-Hyperalgesic and Anti-Inflammatory Effects of Citral with β-Cyclodextrin and Hydroxypropyl-β-Cyclodextrin Inclusion Complexes in Animal Models. Life Sci. 2019, 229, 139–148. [Google Scholar] [CrossRef]
  87. Gratieri, T.; Pinho, L.A.G.; Oliveira, M.A.; Sa-Barreto, L.L.; Marreto, R.N.; Silva, I.C.; Gelfuso, G.M.; Quintans, J.D.S.S.; Quintans-Junior, L.J.; Cunha-Filho, M. Hydroxypropyl-β-Cyclodextrin-Complexed Naringenin by Solvent Change Precipitation for Improving Anti-Inflammatory Effect in Vivo. Carbohydr. Polym. 2020, 231, 115769. [Google Scholar] [CrossRef]
  88. Souza, A.C.A.; Abreu, F.F.; Diniz, L.R.L.; Grespan, R.; DeSantana, J.M.; Quintans-Júnior, L.J.; Menezes, P.P.; Araújo, A.A.S.; Correa, C.B.; Teixeira, S.A.; et al. The Inclusion Complex of Carvacrol and β-Cyclodextrin Reduces Acute Skeletal Muscle Inflammation and Nociception in Rats. Pharmacol. Rep. 2018, 70, 1139–1145. [Google Scholar] [CrossRef]
  89. Giacoppo, S.; Rajan, T.S.; Iori, R.; Rollin, P.; Bramanti, P.; Mazzon, E. The α-Cyclodextrin Complex of the Moringa Isothiocyanate Suppresses Lipopolysaccharide-Induced Inflammation in RAW 264.7 Macrophage Cells through Akt and P38 Inhibition. Inflamm. Res. 2017, 66, 487–503. [Google Scholar] [CrossRef] [PubMed]
  90. Bulani, V.D.; Kothavade, P.S.; Kundaikar, H.S.; Gawali, N.B.; Chowdhury, A.A.; Degani, M.S.; Juvekar, A.R. Inclusion Complex of Ellagic Acid with β-Cyclodextrin: Characterization and In Vitro Anti-Inflammatory Evaluation. J. Mol. Struct. 2016, 1105, 308–315. [Google Scholar] [CrossRef]
  91. Matencio, A.; Navarro-Orcajada, S.; Garcia-Carmona, F.; López-Nicolás, J.M. Ellagic Acid-Borax Fluorescence Interaction. Application to a Novel Cyclodextrin-Borax Nanosensor for Analyzing Ellagic Acid in Food Samples. Food Funct. 2018, 9, 3683–3687. [Google Scholar] [CrossRef] [PubMed]
  92. Vidal, P.J.; López-Nicolás, J.M.; Gandía-Herrero, F.; García-Carmona, F. Inactivation of Lipoxygenase and Cyclooxygenase by Natural Betalains and Semi-Synthetic Analogues. Food Chem. 2014, 154, 246–254. [Google Scholar] [CrossRef]
  93. Matencio, A.; Guerrero-Rubio, M.A.; Gandía-Herrero, F.; García-Carmona, F.; López-Nicolás, J.M. Nanoparticles of Betalamic Acid Derivatives with Cyclodextrins. Physicochemistry, Production Characterization and Stability. Food Hydrocoll. 2020, 106176. [Google Scholar] [CrossRef]
  94. da Silva, S.A.V.; Clemente, A.; Rocha, J.; Direito, R.; Marques, H.C.; Sepodes, B.; Figueira, M.-E.; Ribeiro, M.H. Anti-Inflammatory Effect of Limonin from Cyclodextrin (Un)Processed Orange Juices in in Vivo Acute Inflammation and Chronic Rheumatoid Arthritis Models. J. Funct. Foods 2018, 49, 146–153. [Google Scholar] [CrossRef]
  95. Kim, M.; Choi, S.-Y.; Lee, P.; Hur, J. Neochlorogenic Acid Inhibits Lipopolysaccharide-Induced Activation and Pro-Inflammatory Responses in BV2 Microglial Cells. Neurochem. Res. 2015, 40, 1792–1798. [Google Scholar] [CrossRef]
  96. Navarro-Orcajada, S.; Matencio, A.; Vicente-Herrero, C.; García-Carmona, F.; López-Nicolás, J.M. Study of the Fluorescence and Interaction between Cyclodextrins and Neochlorogenic Acid, in Comparison with Chlorogenic Acid. Sci. Rep. 2021, 11, 3275. [Google Scholar] [CrossRef] [PubMed]
  97. Guimarães, A.G.; Oliveira, M.A.; Alves, R.D.S.; Menezes, P.D.P.; Serafini, M.R.; de Souza Araújo, A.A.; Bezerra, D.P.; Júnior, L.J.Q. Encapsulation of Carvacrol, a Monoterpene Present in the Essential Oil of Oregano, with β-Cyclodextrin, Improves the Pharmacological Response on Cancer Pain Experimental Protocols. Chem. Biol. Interact. 2015, 227, 69–76. [Google Scholar] [CrossRef]
  98. Quintans, J.D.S.S.; Menezes, P.P.; Santos, M.R.V.; Bonjardim, L.R.; Almeida, J.R.G.S.; Gelain, D.P.; Araújo, A.A.D.S.; Quintans-Júnior, L.J. Improvement of P-Cymene Antinociceptive and Anti-Inflammatory Effects by Inclusion in β-Cyclodextrin. Phytomedicine 2013, 20, 436–440. [Google Scholar] [CrossRef] [Green Version]
  99. Liu, C.; Zhang, W.; Yang, H.; Sun, W.; Gong, X.; Zhao, J.; Sun, Y.; Diao, G. A Water-Soluble Inclusion Complex of Pedunculoside with the Polymer β-Cyclodextrin: A Novel Anti-Inflammation Agent with Low Toxicity. PLoS ONE 2014, 9, e101761. [Google Scholar] [CrossRef] [PubMed]
  100. Quintans-Júnior, L.J.; Barreto, R.S.S.; Menezes, P.P.; Almeida, J.R.G.S.; Viana, A.F.S.C.; Oliveira, R.C.M.; Oliveira, A.P.; Gelain, D.P.; Júnior, W.D.L.; Araújo, A.A.S. β-Cyclodextrin-Complexed (−)-Linalool Produces Antinociceptive Effect Superior to That of (−)-Linalool in Experimental Pain Protocols. Basic Clin. Pharmacol. Toxicol. 2013, 113, 167–172. [Google Scholar] [CrossRef] [PubMed]
  101. Nascimento, S.S.; Camargo, E.A.; DeSantana, J.M.; Araújo, A.A.S.; Menezes, P.P.; Lucca-Júnior, W.; Albuquerque-Júnior, R.L.C.; Bonjardim, L.R.; Quintans-Júnior, L.J. Linalool and Linalool Complexed in β-Cyclodextrin Produce Anti-Hyperalgesic Activity and Increase Fos Protein Expression in Animal Model for Fibromyalgia. Naunyn-Schmiedebergs Arch. Pharmacol. 2014, 387, 935–942. [Google Scholar] [CrossRef] [PubMed]
  102. Hădărugăa, D.I.; Hădărugăa, N.G.; Miclea, L.M.; Vlaia, L.; Mircioiu, C. Bioactive Compounds (Hepatoprotective or Anti-Inflammatory Xenobiotics)/Cyclodextrin Nanoparticles: A Comparative Study. J. Agroaliment. Process. Technol. 2009, 15, 478–483. [Google Scholar]
  103. Bianchi, S.E.; Machado, B.E.K.; da Silva, M.G.C.; da Silva, M.M.A.; Bosco, L.D.; Marques, M.S.; Horn, A.P.; Persich, L.; Geller, F.C.; Argenta, D.; et al. Coumestrol/Hydroxypropyl-β-Cyclodextrin Association Incorporated in Hydroxypropyl Methylcellulose Hydrogel Exhibits Wound Healing Effect: In Vitro and in Vivo Study. Eur. J. Pharm. Sci. 2018, 119, 179–188. [Google Scholar] [CrossRef] [PubMed]
  104. Sawatdee, S.; Choochuay, K.; Chanthorn, W.; Srichana, T. Evaluation of the Topical Spray Containing Centella asiatica Extract and Its Efficacy on Excision Wounds in Rats. Acta Pharm. 2016, 66, 233–244. [Google Scholar] [CrossRef] [Green Version]
  105. Rode, T.; Frauen, M.; Müller, B.W.; Düsing, H.J.; Schönrock, U.; Mundt, C.; Wenck, H. Complex Formation of Sericoside with Hydrophilic Cyclodextrins: Improvement of Solubility and Skin Penetration in Topical Emulsion Based Formulations. Eur. J. Pharm. Biopharm. 2003, 55, 191–198. [Google Scholar] [CrossRef]
  106. Rimbach, G.; Fischer, A.; Schloesser, A.; Jerz, G.; Ikuta, N.; Ishida, Y.; Matsuzawa, R.; Matsugo, S.; Huebbe, P.; Terao, K. Anti-Inflammatory Properties of Brazilian Green Propolis Encapsulated in a γ-Cyclodextrin Complex in Mice Fed a Western-Type Diet. Int. J. Mol. Sci. 2017, 18, 1141. [Google Scholar] [CrossRef] [Green Version]
  107. Rodrigues, L.B.; Martins, A.O.B.P.B.; Ribeiro-Filho, J.; Cesário, F.R.A.S.; e Castro, F.F.; de Albuquerque, T.R.; Fernandes, M.N.M.; da Silva, B.A.F.; Júnior, L.J.Q.; Araújo, A.A.D.S.; et al. Anti-Inflammatory Activity of the Essential Oil Obtained from Ocimum Basilicum Complexed with β-Cyclodextrin (β-CD) in Mice. Food Chem. Toxicol. 2017, 109, 836–846. [Google Scholar] [CrossRef] [PubMed]
  108. Pinheiro, J.G.D.O.; Tavares, E.D.A.; da Silva, S.S.; Silva, J.F.; de Carvalho, Y.M.B.G.; Ferreira, M.R.A.; Araújo, A.A.D.S.; Barbosa, E.G.; Pedrosa, M.D.F.F.; Soares, L.A.L.; et al. Inclusion Complexes of Copaiba (Copaifera Multijuga Hayne) Oleoresin and Cyclodextrins: Physicochemical Characterization and Anti-Inflammatory Activity. Int. J. Mol. Sci. 2017, 18, 2388. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  109. Tonglairoum, P.; Chuchote, T.; Ngawhirunpat, T.; Rojanarata, T.; Opanasopit, P. Encapsulation of Plai Oil/2-Hydroxypropyl-β-Cyclodextrin Inclusion Complexes in Polyvinylpyrrolidone (PVP) Electrospun Nanofibers for Topical Application. Pharm. Dev. Technol. 2014, 19, 430–437. [Google Scholar] [CrossRef]
  110. Matencio, A.; Navarro-Orcajada, S.; González-Ramón, A.; García-Carmona, F.; López-Nicolás, J.M. Recent Advances in the Treatment of Niemann Pick Disease Type C: A Mini-Review. Int. J. Pharm. 2020, 584, 119440. [Google Scholar] [CrossRef]
  111. Matencio, A.; Caldera, F.; Cecone, C.; López-Nicolás, J.M.; Trotta, F. Cyclic Oligosaccharides as Active Drugs, an Updated Review. Pharmaceuticals 2020, 13, 281. [Google Scholar] [CrossRef]
  112. Barros, M.C.F.; Ribeiro, A.C.F.; Esteso, M.A. Cyclodextrins in Parkinson’s Disease. Biomolecules 2019, 9, 3. [Google Scholar] [CrossRef] [Green Version]
  113. Libby, P.; Ridker, P.M.; Maseri, A. Inflammation and Atherosclerosis. Circulation 2002, 105, 1135–1143. [Google Scholar] [CrossRef]
  114. Kritharides, L.; Kus, M.; Brown, A.J.; Jessup, W.; Dean, R.T. Hydroxypropyl-β-Cyclodextrin-Mediated Efflux of 7-Ketocholesterol from Macrophage Foam Cells. J. Biol. Chem. 1996, 271, 27450–27455. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  115. Zimmer, S.; Grebe, A.; Bakke, S.S.; Bode, N.; Halvorsen, B.; Ulas, T.; Skjelland, M.; De Nardo, D.; Labzin, L.I.; Kerksiek, A.; et al. Cyclodextrin Promotes Atherosclerosis Regression via Macrophage Reprogramming. Sci. Transl. Med. 2016, 8, 333ra50. [Google Scholar] [CrossRef] [Green Version]
  116. Bakke, S.S.; Aune, M.H.; Niyonzima, N.; Pilely, K.; Ryan, L.; Skjelland, M.; Garred, P.; Aukrust, P.; Halvorsen, B.; Latz, E.; et al. Cyclodextrin Reduces Cholesterol Crystal–Induced Inflammation by Modulating Complement Activation. J. Immunol. 2017, 199, 2910–2920. [Google Scholar] [CrossRef] [Green Version]
  117. Pilely, K.; Bakke, S.S.; Palarasah, Y.; Skjoedt, M.-O.; Bartels, E.D.; Espevik, T.; Garred, P. Alpha-Cyclodextrin Inhibits Cholesterol Crystal-Induced Complement-Mediated Inflammation: A Potential New Compound for Treatment of Atherosclerosis. Atherosclerosis 2019, 283, 35–42. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  118. Carneiro, S.B.; Costa Duarte, F.Í.; Heimfarth, L.; Siqueira Quintans, J.D.S.; Quintans-Júnior, L.J.; Veiga Júnior, V.F.D.; Neves de Lima, Á.A. Cyclodextrin–Drug Inclusion Complexes: In Vivo and In Vitro Approaches. Int. J. Mol. Sci. 2019, 20, 642. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  119. Lima, P.S.S.; Lucchese, A.M.; Araújo-Filho, H.G.; Menezes, P.P.; Araújo, A.A.S.; Quintans-Júnior, L.J.; Quintans, J.S.S. Inclusion of Terpenes in Cyclodextrins: Preparation, Characterization and Pharmacological Approaches. Carbohydr. Polym. 2016, 151, 965–987. [Google Scholar] [CrossRef]
  120. Matencio, A.; Hoti, G.; Monfared, Y.K.; Rezayat, A.; Pedrazzo, A.R.; Caldera, F.; Trotta, F. Cyclodextrin Monomers and Polymers for Drug Activity Enhancement. Polymers 2021, 13, 1684. [Google Scholar] [CrossRef] [PubMed]
Biomolecules 11 01384 g001 550
Figure 1. Schematic representation of CD/Corticosteroids and some CD/bioactive compounds complexes against inflammation (depending on the molecule, the pathway could change).
Figure 1. Schematic representation of CD/Corticosteroids and some CD/bioactive compounds complexes against inflammation (depending on the molecule, the pathway could change).
Biomolecules 11 01384 g001
Table
Table 1. Examples of recent studies conducted on CD-NSAID complexes.
Table 1. Examples of recent studies conducted on CD-NSAID complexes.
Type of CDNSAIDObjective of the studyReference
β-CDMeloxicamIn vitro evaluation for periodontitis treatment[56]
HP-β-CDDiclofenacClinical evaluation of the pharmacokinetics of
diclofenac in
patients with mild or
moderate renal insufficiency
or mild hepatic impairment		[57]
HP-β-CDFlurbiprofenIn vitro drug
release, mucoadhesion, and
irritation potential study for ocular delivery		[58]
β-CDIbuprofenIn vitro evaluation of
ibuprofen properties in metal organic frameworks		[59]
β-CDPiroxicamIn vivo evaluation of the analgesic activity and anti-ulcerogenic potential of piroxicam in rats[60]
β-CDAceclofenacEx vivo evaluation of
stability and transdermal
delivery to the inflammatory
sites in osteoarthritis		[61]
β-CDOxaprozinIn vivo evaluation of the anti-inflammatory activity on
adjuvant-induced arthritis in rats		[62]
Table
Table 2. Studies conducted on CD-steroid complexes.
Table 2. Studies conducted on CD-steroid complexes.
Type of CDSteroidObjective of the StudyReference
β-CDHydrocortisone acetateDetermination of the anti-inflammatory effect on LPS-stimulated RAW267[65]
HPβ-CDDexamethasoneDetermination of the anti-inflammatory effect on rabbits affected by uveitis[66]
γ-CDDexamethasoneClinical assessment of the anti-inflammatory effect on diabetic macular edema and cataract[70,71]
HPβ-CDDexamethasoneClinical assessment of the anti-inflammatory effect on diabetic macular edema and cataract[70,71]
α-CDPrednisolone 21-hemisuccinateDetermination of the anti-inflammatory effect on rats with inflammatory bowel disease[68,69]
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Lucia Appleton, S.; Navarro-Orcajada, S.; Martínez-Navarro, F.J.; Caldera, F.; López-Nicolás, J.M.; Trotta, F.; Matencio, A. Cyclodextrins as Anti-inflammatory Agents: Basis, Drugs and Perspectives. Biomolecules 2021, 11, 1384. https://doi.org/10.3390/biom11091384

AMA Style

Lucia Appleton S, Navarro-Orcajada S, Martínez-Navarro FJ, Caldera F, López-Nicolás JM, Trotta F, Matencio A. Cyclodextrins as Anti-inflammatory Agents: Basis, Drugs and Perspectives. Biomolecules. 2021; 11(9):1384. https://doi.org/10.3390/biom11091384

Chicago/Turabian Style

Lucia Appleton, Silvia, Silvia Navarro-Orcajada, Francisco Juan Martínez-Navarro, Fabrizio Caldera, José Manuel López-Nicolás, Francesco Trotta, and Adrián Matencio. 2021. "Cyclodextrins as Anti-inflammatory Agents: Basis, Drugs and Perspectives" Biomolecules 11, no. 9: 1384. https://doi.org/10.3390/biom11091384

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