polymers Review Cyclodextrin Monomers and Polymers for Drug Activity Enhancement Adrián Matencio 1,* , Gjylije Hoti 1 , Yousef Khazaei Monfared 1 , Azam Rezayat 1,2, Alberto Rubin Pedrazzo 1 , Fabrizio Caldera 1 and Francesco Trotta 1,* 1 Dip. Di Chimica, Università di Torino, Via P. Giuria 7, 10125 Torino, Italy; [email protected] (G.H.); [email protected] (Y.K.M.); [email protected] (A.R.); [email protected] (A.R.P.); [email protected] (F.C.) 2 Department of Chemistry, Faculty of Science, Lorestan University, Khorramabad, Iran * Correspondence: [email protected] or [email protected] (A.M.); [email protected] (F.T.) Abstract: Cyclodextrins (CDs) and cyclodextrin (CD)-based polymers are well-known complexing agents. One of their distinctive features is to increase the quantity of a drug in a solution or improve its delivery. However, in certain instances, the activity of the solutions is increased not only due to the increase of the drug dose but also due to the drug complexation. Based on numerous studies reviewed, the drug appeared more active in a complex form. This review aims to summarize the performance of CDs and CD-based polymers as activity enhancers. Accordingly, the review is divided into two parts, i.e., the effect of CDs as active drugs and as enhancers in antimicrobials, antivirals, cardiovascular diseases, cancer, neuroprotective agents, and antioxidants. Keywords: cyclodextrins; polymers; enhancers; stability; drug; bioactivity; review Citation: Matencio, A.; Hoti, G.; Monfared, Y.K.; Rezayat, A.; Pedrazzo, A.R.; Caldera, F.; Trotta, F. Cyclodextrin Monomers and Polymers for Drug Activity 1. Introduction Enhancement. Polymers 2021, 13, 1684. Cyclodextrins (CDs) are well-known in the scientific community for their use to solu- https://doi.org/10.3390/ bilize poorly soluble drugs [1]. Moreover, cyclodextrin (CD) presents intrinsic bioactivity polym13111684 to manage some diseases such as atherosclerosis or Niemann Pick type C [2,3]. Chemically, CDs are truncated, cone-shaped oligosaccharides made up of α-(1,4)-linked glucose units, Academic Editor: Dong Jin Yoo obtained by the degradation of starch by the enzyme cyclodextrin glucosyltransferase (CGTAse). The most common CDs are the natural α, β, and γ-CD, which contain six, seven, Received: 14 April 2021 and eight glucose units, respectively. The CD ring is a conical cylinder of an amphiphilic Accepted: 19 May 2021 nature, with a hydrophilic outer layer (formed by the hydroxyl groups) and a lipophilic Published: 21 May 2021 cavity [4,5]. When poorly soluble drugs are complexed with CD, it creates the so-called “inclusion complex” [6–13]. To improve the properties of CD monomers, different chemi- Publisher’s Note: MDPI stays neutral cally obtained derivates (e.g., hydroxypropyl-β-CD or methyl-β-CD among others) and with regard to jurisdictional claims in polymers have been shown to possess better capacities, such as complexation efficiency or published maps and institutional affil- release, than natural CDs [14–16]. iations. After the first applications of CDs in the pharmaceutical industry in the 1980s [17], a growing interest was observed for inclusion complexes with several applications. This was an introduction of a safe way to deliver drugs overcoming the downsides of traditional anticancer treatments as an example [18]. A recent search on PubMed, performed by Copyright: © 2021 by the authors. us in May 2021, pointed to more than five thousand publications available since 1974 Licensee MDPI, Basel, Switzerland. containing the keyword “cyclodextrin inclusion complexes”. The pie chart in Figure1 This article is an open access article presents the entries found by combining “cyclodextrin inclusion complexes” with “type of distributed under the terms and biological applications” (such as antimicrobial, anticancer activity, etc.). In this figure, the conditions of the Creative Commons high percentages of all the publications dealing with antioxidant (21.62%), antimicrobial Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ (18.92%), and anticancer activity (16.22%) show that these biological applications, among 4.0/). others, are the most extensively explored. Polymers 2021, 13, 1684. https://doi.org/10.3390/polym13111684 https://www.mdpi.com/journal/polymers Polymers 2021, 13, x FOR PEER REVIEW 2 of 18 the high percentages of all the publications dealing with antioxidant (21.62%), antimicro- bial (18.92%), and anticancer activity (16.22%) show that these biological applications, Polymers 2021, 13, 1684 among others, are the most extensively explored. 2 of 18 Figure 1. Distribution of biological applications of CD inclusion complexes reported in the literature (using keywords: “cyclodextrin inclusion complexes” in combination with “antimicrobial activity”, “cholesterol-related diseases”, “diet agent”, “antiviral activity”, “cardiovascular”, “neurological Figure 1. diseases”,Distribution “anticancer”, of biological “antioxidant”, applications and “diabetes”). of CD All inclusion publication complexes data were obtained reported from in the litera- ture (usingPubMed, keywords: covering “cyclodextrin the period from 1978inclusion until April complexes” 2021. in combination with “antimicrobial activity”, “cholesterol-relatedMoreover, an increase diseases”, in the concentration “diet agent”, of “antiviral poorly soluble activity”, drugs increases “cardiovascular”, their “neu- rological diseases”,solubility and “anticancer”, bioactivity [5 ,“antioxidant”,19]. Furthermore, and the correct“diabetes”). formulation All publication might increase data the were ob- tained fromeffectiveness PubMed, of covering therapies th ate the period same concentrationfrom 1978 until of the April drug. 2021. In contrast to the effects of increasing the quantity of drug to achieve the dosage, some effects of complexation such as a higher bioaccessibility, drug stabilization, or target delivery may affect the whole Moreover,effectivity an of the increase therapy; CDin monomersthe concentration and polymers of have poorly demonstrated soluble real capacitiesdrugs increases in their solubilitythis and area bioactivity [20,21]. Different [5,19]. reviews Furthermore, have been recently the published correct about formulation the capacities might of CDs increase the effectivenessas drugs, of therapies in drug delivery, at the and same their effects concentr in membranesation of [ 1the,2,22 drug.,23], the In present contrast review, to the effects therefore, presents a different point of view. It aims to provide deeply, a general overview of of increasingthe use the of CD quantity monomers of and drug polymers to achi as enhancerseve the for dosage, improving some the bioactivities effects of thecomplexation such as amolecules higher bioaccessibility, at a fixed concentration, drug without stabilization, undervaluing or thetarget effects delivery of the concentration. may affect the whole effectivity of the therapy; CD monomers and polymers have demonstrated real capacities 2. Cyclodextrin Monomers and Polymers as Drugs Themselves in this area [20,21].In general, Different it is easy to reviews find CD monomers have been as excipients recently in published drug formulation. about In somethe capacities of CDs as drugs,cases, CD in itself drug is effective delivery, against and the their disease effects [2]. This in section membranes will try to describe[1,2,22,23], some the present review, therefore,examples (Table presents1) of this a capacity. different point of view. It aims to provide deeply, a general overview2.1. of Anticholesterol the use of EffectCD monomers and polymers as enhancers for improving the bio- activities of thePerhaps molecules the complexation at a fixed of cholesterol concentr is theation, principal without application undervaluing of CDs in pharma the [24 ];effects of the concentration.in this section, we take a look at different targets associated with this target and others: For cholesterol-related diseases such as Niemann–Pick disease Type C (NPC, a rare disease resulting in the accumulation of lipids (generally cholesterol) in the cells [25]) 2. Cyclodextrinor atherosclerosis Monomers (cholesterol and Polymers accumulation as in Drugs the wall Themselves of arteries), CDs are the most In general,promising it treatment is easy forto find their capacityCD monomers to complex as the excipients lipids and mobilize in drug them formulation. [3]. It has In some been demonstrated that Mβ-CD and HPβ-CD reduce cholesterol accumulation [26–29]. cases, CDPilely itself et al.,is ineffective 2019 discovered against that theα-CD disease and HP [2].β-CD This can section solubilize will cholesterol try to crys- describe some examplestals, (Table reducing 1) of the this complement-mediated capacity. inflammation by binding of C1q (via IgM) and ficolin-2 to cholesterol crystals, which resulted in reduced phagocytosis and reduced ROS production [30]. Moreover, different derivatives such as HPγ-CD (which cannot complex 2.1. Anticholesterolcholesterol) mobilize Effect cholesterol; the treatment with HPγ-CD and HPβ-CD [31] induced Perhaps the complexation of cholesterol is the principal application of CDs in pharma [24]; in this section, we take a look at different targets associated with this target and oth- ers: For cholesterol-related diseases such as Niemann–Pick disease Type C (NPC, a rare disease resulting in the accumulation of lipids (generally cholesterol) in the cells [25]) or atherosclerosis