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Chapter

Strategies to Develop
Cyclodextrin-Based Nanosponges
for Smart Drug Delivery
Gjylije Hoti, Silvia Lucia Appleton Alberto, Rubin Pedrazzo,
Claudio Cecone, Adrián Matencio, Francesco Trotta
and Fabrizio Caldera

Abstract

In recent years, the development of various cyclodextrin (CD)-based

nanosponges (NSs) has gained great importance in the controlled and-or targeted
release of drugs due to their versatility and simple preparation. In this chapter, an
introduction of different administration routes is explained. Further, different ways
to obtain CD-NSs and their classification are shown with a brief explanation of the
characterization of the inclusion complexes. Finally, illustrative examples in diverse
processes or diseases will be reviewed and explained to demonstrate the potential
of CD-NSs. Therefore, this division will serve to compile information on CD-NSs
in recent years and to illustrate to readers how to generate and apply different
derivatives of interest.

Keywords: Cyclodextrin nanosponges, drug delivery, synthesis, nanocarrier, release

1. Introduction

Society demands better treatments for each disease and therefore the industry
tries to obtain them. Novel drugs with better bioactivity are researched to achieve
the best result in our bodies. However, several novel drugs present problems related
to their chemical properties that prevent them from being used as a pharma or
nutraceutical product. The molecule can be unstable in water solution, and/or easily
oxidized, and presents poor bioavailability. Different strategies might improve the
current therapy. One possibility is to find a good formulation, which stabilizes the
drug or carries it to the desired tissue. Moreover, the adverse effect due to the dosage
can also be reduced. For this reason, a great number of carriers are been proposed to
challenge the previous problems.
One of them is called cyclodextrin (CD), truncated cone-shaped oligosac-
charides made up of α-(1→4) linked glucopyranoside units with six, seven
and eight glucose units, α, β and γ-CD, respectively [1, 2]. A derivative called
2-Hydroxypropyl-βCD (HPβ-CD) is used as an orphan drug for Niemann Pick
disease type C [3, 4]. Complexes formed of molecules and cyclodextrins (CDs)
are called “inclusion complexes”. Generally, CDs encapsulate poorly water-soluble
compounds and hydrophobic moieties of amphiphilic molecules. Nevertheless, the

1
Smart Drug Delivery

solubility of these complexes not only depends on the CD used but also on different
factors such as pH or guess molecule [5–8]. The capacity of CDs to increase solubil-
ity and protect several molecules has increased their use in the pharmaceutical and
food industries [1, 9, 10].
However, the improvement achieved by adding CDs is sometimes insufficient.
Then, researchers developed a novel material based on these excipients baptized
as Cyclodextrin-based Nanosponge (CD-NS), innovative cross-linked polymer
structures with a three-dimensional network, and with a crystalline and amorphous
structure, spherical and possessing good swelling properties [11]. Recent reviews
[12–14] point to their wide potential and minimal toxicity [15, 16]. Some applica-
tions of these polymers include i) increasing the apparent solubility of poorly
soluble drugs, ii) modulating drug release and activity, iii) protecting drugs against
several agents, iv) enhancing bioactivities, v) absorbing contaminants ability, vi)
delivering the drug, etc.
Cross-linking CDs brings significant benefits to CD-NSs compared with the
respective native CDs. In general, CD-NSs can form complexes with a series of dif-
ferent molecules due to their structure. They achieve a hindered diffusion of loaded
guest molecules, thus promoting slower release kinetics [17, 18]. Another important
property of CD-NSs is that they can be easily recovered from aqueous media and
recycled. Although they are insoluble, soluble hyperbranched NS can also be
synthesized [19]. Finally, one of their principal disadvantages has been recently
solved, they have been tested as a good carrier not only for small molecules but also
for higher ones like proteins [20, 21].
This chapter tends to be a first step for the researcher who starts with CD-NSs:
i) an introduction of the routes of administration, including advantages and
disadvantages is explained, ii) an explanation about the various types of CD-NSs,
including its synthesis and classification is written, iii) the different ways to charac-
terize the inclusion complexes are reported and iv) examples of smart delivery are
displayed as an encourage study to demonstrate their potential.

2. Routes of administration, advantages, and disadvantages

The choice of the route of administration is crucial as it dramatically affects

drug bioavailability and thus requires specific delivery strategies. Parenteral
routes include intravenous, intramuscular, and subcutaneous routes, whereas the
enteral routes are the oral, sublingual, and rectal routes [22]. Others are inhalation,
intranasal, etc. [23]. In this section, each route will be described briefly and special
attention will be paid to the oral route, which is the most desired but, at the same
time, the most challenging.
When administered via intravenous injection (IV), the drug reaches the sys-
temic circulation directly bypassing absorption and carrying out its effect rapidly.
This route is ideal for unstable or scarcely absorbed drugs (e.g. blood products),
and irritating drug formulations, the administration of which via subcutaneous and
intramuscular routes will be painful. It is also intended for patients who are not able
to take the formulations orally, due to mental disorders, nausea, or vomiting.
Intramuscular injection (IM) can involve various muscles, including the gluteal
muscle to which up to 5 ml of the formulation can be administered. Via this route,
aqueous or oil-based solutions, suspensions, and emulsions are accepted. Aqueous
solutions are generally absorbed in 10–30 minutes, whereas drugs insoluble at
interstitial pH or suspended in oil-based solutions present a long time of absorp-
tion. Vascularisation of the muscle, the volume, and the osmolarity of the injected
formulations also affect the absorption time. A depot preparation of the drug can

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Strategies to Develop Cyclodextrin-Based Nanosponges for Smart Drug Delivery
DOI: [Link]

be given via this route with a sustained release of the drug into the bloodstream. IM
injection is selected when the drug has a low oral bioavailability or when the patient
is not compliant. Vaccines are also administered via this route.
Subcutaneous injections can be given in the forearm or abdomen. Up to 2 ml of
the formulation can be administered. Together with aqueous solutions and suspen-
sions, adrenalin can be added to induce vasoconstriction and therefore increase
the residence time of drugs (e.g. local anesthetics) or hyaluronidase to make the
extracellular matrix more fluid, thus improving the absorption rate.
The absorption rate is extremely variable as it is influenced by the blood flow.
Subcutaneous injections are also used for depot formulations. It is easy to admin-
ister and requires minimal skills, thus allowing self-administration. Insulin and
heparin are given via this route.
Among all, oral delivery has been recognized as the most attractive route, as it is
cheap, simple, accepted by patients, requires fewer sterility restrictions, and offers
more possibilities in the design of the formulation (including sustained and con-
trolled delivery) [24]. It is used for drugs with topical action in the gut and systemic
effects when they reach the bloodstream. However, it is not suitable for emergencies
in which an immediate effect is fundamental.
Over the past few years, many efforts have been made to develop oral delivery
systems able to overcome the obstacles in the gastrointestinal tract (GI) in which the
mechanism of absorption is complex with multiple levels of barriers [24].
There is a long list of variables that influence the GI absorption of drugs, which
are grouped in technical challenges, physicochemical properties of the drug, and
environmental factors [25].
The technical challenges concern the pharmaceutical form, i.e. liquid or solid.
In solid forms, the rate and extent of disintegration, and dissolution of the formula-
tion are important to a drug, and to carry out its effect, needs to be in a solution for
developing the absorption.
Most drugs are absorbed in the small intestine, characterized by a large surface
area of absorption and having a crucial influence on bioavailability.
The walls of the GI tract are characterized by the presence of mucus, which
has been a target for drug delivery systems (DDS) capable of mucopenetration or
mucoadhesion [24]. Mucopenetration consists in regulating the hydrophobicity/
hydrophilicity of the carrier’s matrix or combining mucolytic enzymes to promote
drug penetration. On the contrary, mucoadhesive carriers, which have attracted sig-
nificant attention [26–28], can adhere to mucus, thus increasing the residence time.
CD NSs have proven to possess this property, making them particularly promising
for oral delivery [20].
Last but not least, the first-pass effect should be borne in mind when dealing
with the oral route as it is certainly a limiting factor. It refers to the metabolism
(mainly in the liver) of the drug before it reaches the systemic circulation, which
may lead to a drop in bioavailability [29]. For this reason, several drugs are adminis-
tered via other enteral routes (e.g. rectal and sublingual).
The sublingual route offers the benefit of bypassing the first-pass effect due to
the passive diffusion through the highly permeable mucosa underneath the tongue.
It is simple with a low risk of infection and the effect is rapid. Nitroglycerin is
administered via this route.
The rectal route exploits the highly vascularized rectal mucosa for drug absorp-
tion. The first-pass effect is partially avoided. It is indicated for patients with
gastrointestinal motility problems, nausea, vomiting, and children.
Inhalation is used to obtain a rapid effect as the drug crosses the large surface
area of the respiratory tract epithelium and reaches the systemic circulation.
It avoids the first-pass metabolism. The particle size and morphology of the

3
Smart Drug Delivery

Route of Advantages Disadvantages

administration
Oral • easy • not Emergency therapy
• safe • not for GI-sensitive drugs (unless they
are encapsulated
• cheap
• first pass effect
• risk of interaction with food and drugs
Sublingual • rapid effect • uncertain dosage
• suitable for emergency therapy

Rectal • for pediatric use • risk of irritation

• for patients with impaired GI • unpredictable absorption
function

Inhalation • rapid absorption • risk of irritation

• suitable for general anesthesia and • specific equipment is needed
emergency therapy

Intravenous • suitable for emergency therapy • complications due to rapid onset

• adjustable • allergic reactions
• accurate dosage

Intramuscular • rapid absorption • small volumes

• systemic administration of hydro- • painful
philic drugs
• care must be taken to avoid veins and
• administration of sustained-release arteries
formulations
• risk of infections and abscesses

Subcutaneous • rapid absorption • administration of very small volumes

• administration of sustained-release
formulations

Table 1.
Advantages and disadvantages of the main routes of administration.

formulation inhaled are crucial. It is mainly used for the treatment of respiratory
diseases. The intranasal route enables the drug to be absorbed via passive diffusion
across the highly-vascularised respiratory epithelium directly into the systemic
circulation. Nasal decongestants and anti-allergic drugs are administered via this
route (Table 1).

3. Synthesis and classification of CD-NSs

The choice of appropriate synthetic conditions, allowed to obtain both water-

soluble and water-insoluble polymer products, known also as CD-NSs or insoluble,
and branched or soluble polymer [30–32]. The latter case allowed to overcome the
limits of pristine CDs in terms of solubility in water and specific organic solvent,
while the resulting formation of a three-dimensional cross-linked network was
related to the presence of interstitial spaces among the monomers [33]. In this
regard, the nature of the cross-linker and its amount in respect to the CD, ratio
which defines the so-called cross-linking density, are presented to have a great
impact on the properties and structure of the final material [34]. Also, being said
interstices wider and more hydrophilic in respect to the cavities of CDs, a wider
hosting capability was observed as a result.

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Strategies to Develop Cyclodextrin-Based Nanosponges for Smart Drug Delivery
DOI: [Link]

3.1 General synthesis protocol

The most common method announced for the synthesis of CD based polymers,
is characterized by employing a suitable solvent which could be either organic
solvent or, in specific cases water, for the dissolution of the CDs. Afterwards, under
continuous stirring, the chosen linking agent is added to the solution. Nevertheless,
when required, the introduction of a catalyst occurs before the linking agent, and
in specific cases, an increase in temperature is necessary to start the cross-linking
reactions. The use of an ultrasound bath instead of stirring was also considered
[35]. Eventually, either a sol–gel process or a precipitation polymerization can be
observed, leading to the formation of a monolithic block or a precipitate, respec-
tively. Also, in those cases in which the cross-linker is in the liquid form, and able to
solubilize the CD, a melt polymerization can be performed [36, 37].
Once the synthesis is completed, the solvent, the catalyst, eventual unreacted
monomers, and by-products are removed from the synthesized product by purifica-
tion with water or other volatile solvents. In the end, a dry solid powder is collected
[37–39]. Another well-known approach to synthesize CD-NSs is achieved through
simple dehydration reactions. In this case, the CDs and the cross-linker, which is
usually an acid bearing two or more carboxylic groups, are solubilized in water.
After the addition of a suitable catalyst, the solution is heated to remove the water
introduced as solvent as well as the water released as a by-product of the cross-
linking condensation reaction. Moreover, the use of vacuum together with the
temperature allows to shift the equilibrium of the reaction toward the products [40,
41]. Besides, less used synthetic routes report the use of interfacial or radical polym-
erization. In the first case, two immiscible phases such as a water solution of CD and
a chlorinated solvent solution containing the chosen cross-linker, are mixed and
stirred vigorously. The cross-linking occurs rapidly at the interface of the immiscible
phases, and a precipitate is obtained [39]. While in the second case, a multistep
procedure involving also preliminary derivatization of CD was displayed [42].

3.2 General classification

In general, based on the technological evolution of these materials, CD-NSs can

be classified into four generations, considering their chemical composition and
properties [19]. The first generation comprises all those NSs synthesized by a simple
one-step reaction of CDs with a cross-linker. This generation was further divided into
sub-categories according to the chemical nature of the linking molecules adopted for
the synthesis. In this frame, carbonate, ester, ether, and urethane types are the most
reported. These specific types of NSs will be described in more detail in the following
paragraphs. Subsequently, the introduction of specific functions such as charge or
luminescence to the final polymer structure defined the second generation of NSs.
These materials displayed more complex polymer architectures achieved either via
pre- or post-synthesis functionalization. In the first case, the introduced functions
were limited to the surface of the polymer, whereas in the second case a more homo-
geneous distribution was observed. Referring to the division into generations, the 3rd
generation deals with stimuli-responsive NSs, able to modulate their behavior (for
example increasing/decreasing a drug release) according to the external environment.

3.2.1 CD-based polyurethane NSs

Urethane, or carbamate, CD-NSs are synthesized by reacting CDs (or a different

dextrin) with a suitable diisocyanate as, for example, hexamethylene diisocyanate
(HDI), toluene–2,4-diisocyanate (TDI). The reaction scheme is reported below

5
Smart Drug Delivery

(Figure 1, inset a). The resulting NSs are usually characterized by a rigid structure and
a negligible swelling in water (in comparison with other CD-NSs), and organic solvent
and high resistance to chemical degradation. Carbamate CD-NSs, were originally
developed by Li and Ma for the treatment of wastewaters, as an alternative for acti-
vated carbon. They demonstrated with NSs remarkable performances in the removal
of organic molecules such as p-nitrophenol reducing concentration of waste from
10−7–10−9 M to ppt level. The surface area was usually lower than activated carbon,
(1–2 m2/g, two orders of magnitude) but it is supposed that organic molecules can be
adsorbed, diffuse through the surface, and be absorbed inside the bulk of NSs [43].
The good affinity of organic molecules showed for pollutants [44], is also dem-
onstrated by the application of urethane NSs in the complexation with biologically
relevant compounds, such as bilirubin or amino acids. In 2006, Tang et al. evaluated
the difference in absorption of aromatic amino acids and branched-chain amino
acids: the absorption of branched-chain amino acids was negligible whereas NSs
absorbed 24% of the aromatic amino acids.
In previous works the same polymer was tested for the absorption of bilirubin,
reducing the initial concentration of bilirubin (40 mg/l) up to 92.6% after the addi-
tion of the NS [45].

3.2.2 CD-based polycarbonate NSs

Polycarbonate CD-NSs are usually synthesized using active difunctional carbonyl

compounds such as 1,1′-carbonyldiimidazole, triphosgene, and diphenylcarbonate
(Figure 1, inset b). Since the resulting CD NSs present carbonate bonds between
CD monomers, these NSs present short cross-linking bridges and, consequentially,
a reduced swelling ability (if compared to CD- based polyesters NSs, for example)
and good stability to acidic solutions. The affinity to organic molecules and the
surface area are comparable to carbamate NS [46]. The ability of β-CD carbonate NS
to remove from wastewater chlorinated persistent organic pollutants (also known as
POP) was investigated by Trotta and Cavalli in 2009 [47]: the absorption efficiency
was higher than the average of activated carbon. For the specific case of hexachloro-
benzene the NS was capable of removing around 99.5% of the pollutant.

Figure 1.
Schematic synthesis of a) CD-based polyurethane NSs and b) CD-based polycarbonate NSs.

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Strategies to Develop Cyclodextrin-Based Nanosponges for Smart Drug Delivery
DOI: [Link]

An interesting method to evaluate the degree of cross-linking of carbonate β-CD

NSs, employing infrared and Raman spectroscopy, was described by Castiglione et
al. [48]. Data from spectroscopic analysis and chemical computation demonstrated
a correlation between the intensity of carbonyl absorption peak and the degree of
cross-linking: the degree of cross-linking increased with the amount of cross-linker,
in total agreement with the stoichiometry. Dealing with sugar-based predominantly
amorphous materials, the reported method represents a valid and advantageous
alternative to x-ray. The crosslinking density or the amount of crosslinker, strongly
influences the stiffness and elastic properties of the NSs. Rossi et al. demonstrated
in their study that the mechanical features of the NSs can be easily tuned by chang-
ing the molar ratio CD/cross-linker, on the other hand, the CD used for the synthe-
sis does not affect the mechanical properties of the final NS [34, 49].

3.2.3 CD-based polyester NSs

Ester CD-based NSs are synthesized using dianhydrides or di/polycarboxylic

acids, such as pyromellitic dianhydride (PMDA), ethylenediamine- tetraacetic
dianhydride (EDTA dianhydride), butanetetracarboxylic dianhydride, citric acid
[46, 50].
Dissimilarly from polycarbonate and polyurethane NSs, polyester NSs are gener-
ally able to absorb remarkable amounts of water (up to 25 times/g dry sample),
and form stable hydrogels. Similarly as seen before with mechanical properties, the
swelling capability of the CD-NSs is generally dependent on the degree of cross-
linking. The swelling capability is usually inversely proportional to the density of
cross-linking: the lower the degree of cross-linking, the higher the water uptake.
The structure of the material dramatically influences chemical stability. Ester NSs
are subjected to hydrolysis in aqueous media more easily than polycarbonate and
polyurethane NSs. The structure is remarkably interesting because of the presence
of free carboxyl groups in their chemical structure, moieties that can be exploited
for the absorption of cations, using the material as an ionic exchange resin.
There are in literature many examples of the formation of complexes with a
metal cation. The metal ions complexation ability of pyromellitic NSs is studied by
Berto et al. in for different metal cations, such as Al3+, Mn2+, Co2+, Ni2+, Cu2+, Zn2+,
Cd2+ and Pd2+.
In most cases, pyromellitic NSs were found to be capable of absorbing more than
70% of the tested cation [51].
A similar test of removing heavy metals from wastewaters, crosslinking also
CDs with citric acid, is performed by Rubin Pedrazzo et al. in 2019 [52]. At a metal
concentration of 500 ppm, the pyromellitic NSs (substituted before absorption
with Na+) exhibited a higher retention capacity than the citrate NSs. At lower metal
concentrations (≤ 50 ppm) both the citrate and the pyromellitic NSs showed high
retention capacities (up to 94% of the total amount of metal). While in the pres-
ence of interfering sea water salts, the citrate NSs were able to selectively adsorb a
significantly higher amount of heavy metals than the pyromellitic NSs.
For ester NSs, similar studies of the correlation of cross-linking degree with
properties are performed. Surprisingly, the highest cross-linking degree was
observed in the sample prepared using the molar ratio 1: 6, CD: PMDA [53].
Higher contents of cross-linker, molar ratios like 1:8 and 1:10, led to a
decrease of the degree of cross-linking; this is possibly related to the steric
hindrance generated by the pyromellitic units linked to CDs. Interestingly, by
working under limited dilution conditions during the reaction and with an even
lower CD/cross-linker ratio (e.g., 1:2 molar ratio), it is possible to obtain a hyper-
branched water-soluble polymer [54]. As already described for carbonate NSs,

7
Smart Drug Delivery

Raman and Brillouin scattering experiments permitted Rossi et al. to evaluate a

relationship between the mechanical characteristics of the polyester pyromellitic
β-CD NS and the molar ratios CD/cross-linker: as seen before, stiffness and
elasticity of the polymeric structure can be tuned by varying the amount of
cross-linker [49].

4. Inclusion complex preparation and analysis

4.1 Preparation of inclusion complexes

Once the CD-NS is ready, the inclusion complex can be obtained by several
procedures [55] as its summarized in Figure 2. Firstly, it is performed the classical
mixing of drug and CD-NS in a solvent, commonly water for 24 h to form the com-
plexes. In this procedure, we should consider the insoluble or soluble nature of our
complexes. Depending on this, the desire fraction is purified. Using kneading, the
drug and the CD-NS are mixed in a mortar with an appropriate quantity of water
or another solvent to form the complexes. At this point, other additional techniques
are used to form the powder: The solvent can be removed using lyophilization, co-
evaporation, or spray-drying procedures.

4.2 Analysis of inclusion complexes

Different techniques can be employed to characterize not only inclusion com-

plexes but also CD-NS. For information purposes, we will name some of them and
briefly explain their possibilities [56, 57]:

4.2.1 Ultraviolet/visible spectroscopy

UV–vis is a simple, easy, and fast method for studying the host-guest com-
plexation when its formation changes any particularity of the spectrum of a guest
molecule or to check the solubilization efficacy [14, 16, 58, 59].

Figure 2.
Different methods to prepare inclusion complexes.

8
Strategies to Develop Cyclodextrin-Based Nanosponges for Smart Drug Delivery
DOI: [Link]

4.2.2 Fourier-transform infra-red (FTIR)

This technique is usually used in solid complexes, generally in the range of

400–4000 cm−1, although it depends on the studied drug [58, 60]. Changes in the
characteristics bands of the guest molecule or shifts in the wavenumber can indicate
the formation of the complex. In addition, the same principle can be used to follow
the CD-NS synthesis.

4.2.3 Nuclear magnetic resonance (NMR) spectroscopy

NMR is one of the most useful procedures to obtain complete analytical infor-
mation of the CD-NS and the complex formed. An alteration in the chemical shift
of the protons occurs when the drug enters the CD-NS providing specific informa-
tion about the orientation of the guest molecule inside the cavity.

4.2.4 Thermogravimetric analysis (TGA)

TGA determines the changes of weight to temperature increases. The com-

parison of the weight loss profile of pure components, physical mixture, and the
complex shows differences correlatives to the complex formation. A stage on TGA
around 300°C is found in CD-NS due to CD decomposition [59].

4.2.5 Differential scanning calorimetry (DSC)

It can provide detailed information about their physical and energetic proper-
ties. The comparison of the thermal curves of single components, their physical
mixture, and the presumed inclusion compound ought to provide insight into
modifications and interactions due to the formation of the inclusion complex. The
change that occurs in the fusion point of the guest molecule is usually hiding by
the complex formation, while it remains in the physical mixture. This, and several
modifications in the shape and temperature peak of the CD dehydration and/or
with the disappearance of the drug melting peak among others, are proves of the
complexation.

5. Applications in smart drug delivery

5.1 Improving solubility and controlled release of drugs

5.1.1 CD-based polyurethane NSs

Another study showed the capability of CD polyurethane to reduce the levels

of natural product contaminants, particularly, Ochratoxin A (OTA) from spiked
solutions between 1 and 10 μgL-1 [61]. Following the attracted considerable interest
that these polymers have shown in their use for water purification systems [62] and
drug delivery [63], there were further done several chemical modifications on the
CD NSs. Even though the modified CD NSs were used to enhance the properties
and usefulness of CD NSs, their characterization at the molecular level remained
a challenge. Therefore, a study described the structural characterization at the
molecular level of both, native CD nanosponge polyurethanes and bionanosponge
polyurethane cyclodextrin nanocomposite (pMWCNT-CD/Ag-TiO2) showing a
great antibacterial and antifungal activity. The greatest antimicrobial activities
were in the case of the developed polyurethane nanocomposite (pMWCNT-CD/

9
Smart Drug Delivery

Ag-TiO2). Consequently, it was concluded that this developed synthesis can be

considered an active antimicrobial compound [64]. Another potential application
of CD polyurethane polymer is as immobilization supports in enzyme catalysis. The
lipase was immobilized into the aforementioned polymers via physisorption. It is
observed an improvement in the stability and catalytic activity of lipase, knowing
that the enzymes are generally unstable, insoluble in organic solvents, and sensitive.
Accordingly, this study presented the chance to prepare immobilized biocatalysts
with tunable catalytic activities attributed to the alteration of reaction conditions
[65]. Further research was focused on the novel polyurethanes containing simulta-
neously β-cyclodextrin (β-CD), β-glycerophosphate groups, and hexamethylene-
diisocyanate (HDI). This polymer developed was used to complex the delivering
therapeutic agents such as antibiotic ciprofloxacin. It was observed an improvement
of the drug release in the case of the drug-polymers complexation than that of the
free drug [63].

5.1.2 CD-based polycarbonate NSs

CD-based polycarbonate NSs synthesized using carbonyldiimidazole (CDI)

showed antimicrobial activity against various microorganisms such as E. coli, S.
aureus, P. aeruginosa, S. typhi, C. albicans, and Clostridia, when compared with
Ciprofloxacin that was used as a standard drug. The formulations were prepared
by polymer condensation, and interfacial phenomenon, and were effective for
6 months at a condition of 40°C and 75% of relative humidity [66]. This type of
CD NSs was further used to deliver and increase the activity of several anticancer
drugs such as paclitaxel [67], bortezomib [68], flutamide [69], tamoxifen [70], etc.
Following their high potential to entrap a variety of molecules, the β-CD/CDI NSs
were also used to deliver and improve the solubility and dissolution of paliperidone,
an antipsychotic drug for the treatment of schizophrenia [71]. Further, rilpivirine is
used for the treatment of HIV infection but has low aqueous solubility. Therefore,
the β-CD/CDI NSs presented a strategy to improve this drawback and also the
bioavailability and dissolution rate [72]. The antioxidant activity of kynurenic acid,
an endogenous substance, was improved by loading it in β-CD/CDI NSs. The higher
antioxidant activity was observed because of the increment in solubilization of
kynurenic acid [60]. CD-based polycarbonate NSs synthesized using diphenyl car-
bonate (DPC) were used to overcome the poor solubility and stability of Babchi oil
that is known for possessing numerous activities such as antifungal, antibacterial,
antiviral, antitumor, antioxidant, etc. [73]. Further, the bioactive properties of the
piperine, an alkaloid with anti-microbial, anti-inflammatory, anti-cancer proper-
ties, etc., were protected by the β-CD/DPC NSs [74]. This type of NSs exhibited
complexing ability toward nifedipine, as an oral calcium channel blocking agent
that is used to treat angina pectoris and hypertension. It was observed an improve-
ment in the oral solubility of nifedipine after its incorporation into NSs [75].

5.1.3 CD-based polyester NSs

CD-based Ester NSs synthesized with pyromellitic dianhydride (PMDA) are

well known for delivering, enhancing solubility, and preventing the degradation
of various drugs such as Curcumin [76], Insulin [20], Resveratrol [77], Erlotinib
hydrochloride [78], among others. Ethylenediaminetetraacetic dianhydride
(EDTA) is another cross-linker to synthesize ester CD NSs. Based on HRMAS
probe-heads in a high-resolution NMR spectrometer on the transport properties
of Ibuprofen sodium salt (IP), it was found that these NSs can be utilized for the
rational design of smart systems for drug delivery and controlled release [79]. The

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Strategies to Develop Cyclodextrin-Based Nanosponges for Smart Drug Delivery
DOI: [Link]

various applications of CD-based polyester NSs ranging from the environment to

pharmacy, chemistry, agriculture, gene delivery, cosmetics, biocatalysis, brought
to a detailed study on their cross-linking density. Being a very challenging task, it
presented the effect of cross-linking density on β-CD NSs physicochemical proper-
ties. Flory-Rehner theory and rheology enabled the authors to understand the corre-
lation between the structural features of NSs and their physicochemical properties,
which is a key requirement for future applications [34].

5.2 Last generations of NSs for selected target drug delivery

Stimuli-responsive NSs represent the third generation, polymers that have been
designed to modulate their behavior according to the surrounding environment. In
this case, changes in the chemical structure of the material were reported to be trig-
gered by pH, temperature gradients, or oxidative/reducing conditions. This feature
was exploited for studying the targeted release of drugs, changes in color, and
permeability. The use of glutathione (GSH) bioresponsive CD-NS was proposed as
the system to deliver anticancer drugs or bioactive compounds [114–117]. This is
because GSH is 100 to 1000 times higher inside cells than that in the extracellular
fluids and circulation. Indeed, in cancer cells, this concentration is almost higher
being a good system for target drug delivery [118]. Different drugs such as doxoru-
bicin [115] or bioactive compounds such as resveratrol [116] were tested showing
a well-targeted drug delivery, and therefore is considered a promising therapy. In
addition, the linkage of cholesterol was proposed as a good procedure for increase
the targeted drug delivery of doxorubicin-loaded CD-NS [119].
Lastly, molecularly imprinted cyclodextrin-based polymers (Figure 3) define
the fourth generation of NSs. Molecular imprinting represents a specific approach
of inducing molecular recognition features to a three-dimensional polymer.
This property can be achieved as a result of the presence of a template molecule
introduced during synthesis. The template molecule after being removed from
the polymer matrix leaves size-complementary vacancies, enabling the network
to display high selectivity and affinity toward the chosen template. Eventually,

Figure 3.
Schematic synthesis of molecularly imprinted NSs.

11
Smart Drug Delivery

Drug Nanocarrier Outcome References

prepared
Controlled Drug Delivery

CD-based Polyurethane NSs

Erythromycin, vancomycin, βCD/HDI Long-term sustained release of [80]

and rifampicin antibiotics.

Mitomycin C ϒCD/HDI Prolonged anti-proliferative drug [81]

release.

CD-based Polycarbonate NSs

Curcumin βCD/DMC Increased anti-cancer drug solubility, [82]

and prolonged release.

Norfloxacin βCD/DPC Enhanced anti-bacterial drug [83]

permeability.

Tamoxifen βCD/CDI Increased anti-cancer drug solubility, [84]

and bioavailability.

Resveratrol βCD/CDI Increased the permeation, stability, [85]

and cytotoxicity against cancer

Camptothecin βCD/DPC Increased anti-cancer drug stability, [86]

and prolonged release.

Acyclovir βCD/CDI Enhanced anti-viral drug loading, [87]

and prolonged release.

Telmisartan βCD/DPC Enhanced anti-hypertensive drug [88]

solubility, improved bioavailability,
and prolonged release.

Babchi Oil βCD/DPC Enhanced anti-bacterial essential oil [89]

solubility, photo-stability, and safety.

Rilpivirine βCD/CDI; Enhanced anti-viral drug solubility, [90, 91]

PMDA; DPC and bioavailability.

Paclitaxel βCD/CDI Enhanced anti-cancer drug solubility, [92]

and pharmacological effect.

Sulfamethoxazole βCD/CDI Enhanced anti-bacterial drug [93]

solubility.

Quercetin βCD/DPC Enhanced anti-oxidative drug [94]

dissolution, and prolonged release.

Melatonin βCD/CDI Controlled drug release through skin. [95]

Kynurenic acid βCD/CDI Enhanced anti-oxidant potential of [96]

kynurenic acid.

D-Limonene βCD/DPC Enhanced anti-bacterial potential [97]

of the drug.

Azelaic acid βCD/DPC Enhanced drug solubility, and its [98]

depigmenting action on the skin
via antioxidant, and antityrosinase
effect.

Chrysin βCD/DPC Enhanced drug solubility, in-vitro [99]

antioxidant, and antitumoral
activity.

Paliperidone βCD/CDI Enhanced antipsychotic drug [100]

solubility.

12
Strategies to Develop Cyclodextrin-Based Nanosponges for Smart Drug Delivery
DOI: [Link]

Drug Nanocarrier Outcome References

prepared

Ferulic acid βCD/DPC Enhanced drug solubility, and [101]

bioavailability for the local therapy
of vessels wall.

Flutamide βCD/CDI Enhanced anti-cancer drug [102]

dissolution rate.

Griseofulvin βCD/DPC Enhanced antifungal oral drug [103]

bioavailability, and improved
dissolution rate.

CD-based Polyester NSs

Insulin βCD/PMDA Enhanced anti-diabetic drug [104]

stability, and prolonged release.

Imiquimod βCD/PMDA Enhanced drug aqueous solubility, [105]

and skin permeation capability.

Acetyl salicylic acid βCD/PMDA Enhanced anti-inflammatory drug [106]

stability, and prolonged release.

Doxorubicin βCD/PMDA Improved anti-cancer effectiveness. [107]

Meloxicam βCD/PMDA Increased anti-inflammatory drug [108]

solubility, and wettability.

Targeted Drug Delivery

DB103 - [2-(3, βCD/DPC Enhanced drug solubility, and [109]

4-dimethoxyphenyl)-3- bioavailability for the local therapy
phenyl-4H-pyrido] of vessels wall.

L-DOPA βCD/CDI; Enhanced drug solubility, and [110]

PMDA prolonged release.
(Molecularly
imprinted
cyclodextrin-
based polymers)

Doxorubicin Tripeptide Enhanced antioxidant potential, [111]

glutathione and it is useful in targeting chemo-
(GSH) resistant tumors.
nanosponge
(NS)

Strigolactones GSH/pH-NS Enhanced anticancer activity. [112]

Erlotinib hydrochloride GSH-NS Exhibited excellent drug [113]

(ETB) uptake, extended drug release,
in-vivo antitumor efficacy, and
biodistribution.
βCD, Beta Cyclodextrin; ϒCD, Gama Cyclodextrin; HDI, Hexamethylene diisocyanate; CDI, Carbonyldiimidazole;
DMC, Dimethyl Carbonate; DPC, Diphenyl carbonate; PMDA, Pyromellitic Dianhydride.

Table 2.
The use of cyclodextrin based nanosponges in drug delivery.

molecularly imprinted CD-NSs are studied as suitable material to develop biosen-

sors, drug delivery systems, catalysts, or synthetic antibody mimics [120–122].
A good example of this application is the L-Dopa as a novel possibility to treat
Parkinson’s Disease. The molecularly imprinted CD-NSs showed a slower and more
prolonged release profile than the non-imprinted NSs, indicating the good capacity
to better complex L-Dopa than non-imprinted NS. The use of CDs in controlled and
targeted drug delivery is shown in Table 2.

13
Smart Drug Delivery

6. Conclusions

CD-NSs are demonstrated to be safe, cheap, and biocompatible polymers.

Consequently, several authors are focused on this field recently achieving novel
applications. This chapter summarized the general information that will guide
the advanced research to investigate the CD-NSs. Information about the routes of
administration, synthesis protocols, recommendations, classifications, and applica-
tions of the novel synthesized materials, with special attention to targeted drug
delivery, are mostly collected. It is shown the ability of CD-NSs to entrap drugs
and to control their release from the matrix which can be modulated by different
physicochemical agents.
As a remark, CD-NS is a good promise to improve the current problems in drug
formulations and open novel strategies for drug delivery that identify the light in
the future.

Acknowledgements

This work is the result of aid to postdoctoral training and improvement abroad
(for Adrián Matencio, number 21229/PD/19) financed by the Fundación Séneca
(Región de Murcia, Spain).

Conflict of interest

The authors declare no conflict of interest.

Author details

Gjylije Hoti, Silvia Lucia Appleton Alberto, Rubin Pedrazzo, Claudio Cecone,
Adrián Matencio*, Francesco Trotta and Fabrizio Caldera
Department of Chemistry, University of Turin, Turin, Italy

*Address all correspondence to: [Link]@[Link];

[Link]@[Link]

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms
of the Creative Commons Attribution License ([Link]
by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,
provided the original work is properly cited.

14
Strategies to Develop Cyclodextrin-Based Nanosponges for Smart Drug Delivery
DOI: [Link]

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