REVIEW ARTICLE
https://doi.org/10.37819/nanofab.009.1823 Nanofabrication (2024) 9 | 1
Unleashing the potential of cyclodextrin-based
nanosponges in management of colon cancer: A review
Popat Mohitea, Shubham Mundeb,
Anil Pawarc, Sudarshan Singhd
Abstract: Colon cancer ranked second in terms of incidence in
the world, yearly it shows an increase in the tendency of mor-
tality. It is estimated that by the year 2035 total number of
deaths will increase by 75 %. The treatment of cancer includes
surgery, radiation therapy, and chemotherapy, however, they
are limited due to their targeted therapeutic potential and side
effects. In the case of a conventional drug delivery system, it is
desired that the drug delivery system should be able to protect
the therapeutic from degradation and safety target to the de-
sired site. Cyclodextrin-based nanosponges (NS) are a versatile
platform for colon cancer treatment, surpassing the limitations
of conventional drug delivery systems. Nanosponge offers sev-
eral advantages such as improved drug solubility, enhanced sta-
bility, targeted delivery, and potential for combination therapy
due to its highly cross-linked structure. The fabrication of NS
includes the use of biopolymers for the controlled release of
drugs from pores through diffusion. These pores can efciently
encapsulate a wide range of therapeutic agents, enabling regu-
lated release, and addressing challenges associated with poor
solubility and limited stability of drugs used in the management
of colon cancer. Additionally, their functionalization enables tar-
geted drug delivery to colon cancer cells, minimizing off-target
effects. Though several benets are associated with NS, fur-
ther research is needed to address regulatory considerations
and scale up NS for translation into clinical practice. Overall,
cyclodextrin-based NS holds promise in revolutionizing colon
cancer treatment and improving patient outcomes.
Keywords: Cyclodextrin; Colon cancer; Drug delivery; Improved
Solubility; Nanosponges.
1. INTRODUCTION
Nanotechnology (NT) has tremendously enabled the exploration in
development of nanomedicine, a subeld that is highly benecial to
healthcare. It discovers unique physical, chemical, and biological prop-
erties of drug material at the nanometre scale to diagnose, treat, or pre-
vent diseases (Anjum et al., 2021). In the last thirty years, the discipline
of NT has been a crucial area of research, due to the unique chemical,
electrical, optical, biological, and magnetic properties of nanomaterials
(Sindhwani & Chan, 2021). NT has managed to attract signicant at-
tention because when NT joins hands with biotechnology, it gives birth
to a platform that holds immense potential and importance for diversity
in applications (Laouini et al., 2021). Highly cross-linked structures,
nanosponges, have been widely used in the last decade for various
Article history:
Received: 18-11-2023
Revised: 13-02-2024
Accepted: 04-04-2024
Published: 27-05-2024
a AETs St. John Institute of
Pharmacy and Research,
Palghar, Maharashtra, India.
Corresponding Author:
mohitepb@gmail.com
b AETs St. John Institute of
Pharmacy and Research,
Palghar, Maharashtra, India.
c MESs College of Pharmacy,
Sonai, Tal-Newasa, Ahmednagar,
Maharashtra, India.
d Faculty of Pharmacy, Chiang Mai
University, Chiang Mai 50200,
Thailand.
Ofce of Research Administration,
Chiang Mai University, Chiang
Mai 50200, Thailand.
Corresponding Author:
sudarshansingh83@hotmail.com
© The Author(s), 2024
REVIEW ARTICLE Popat Mohite et al.
2 | Nanofabrication (2024) 9 https://doi.org/10.37819/nanofab.009.1823
therapeutic applications (Kumar & Rao, 2021). NS
is dened as hydrophilic, water-insoluble, and su-
pramolecular 3D-hyper-reticulated nanoporous
structures with high stability over a wide range
of temperatures and pH (Kumar et al., 2020). Cy-
clodextrins (CDs) have been used in the synthesis
of NS providing cooperative properties between
the amphiphilicity and high surface area (Kumar
& Rao, 2021). However, it should be stressed that
the application of cyclodextrin in the fabrication of
nanosponges (CDNSs) is still at an early stage.
CDs have been studied for over a century and
widely used as a pharmaceutical excipient or being
capable of incorporating therapeutic molecules into
their central cavity (Hoti et al., 2021; Kawano et
al., 2015). Currently, CDs are widely used in food
products, textiles, toiletry, and various cosmetics as
well as in certain medical products (Liu et al., 2022;
Sharma & Baldi, 2016). CDs complexation tech-
nique is mostly used to alter the solubility of drugs
(Semalty, 2014). The solubility of drug drastically
changes when it complexed with cyclodextrins due
to the ability to encapsulate hydrophilic as well as
lipophilic drugs
Colon cancer (CC) is the third most common
cause of death in the world with a survival rate of
only 10 % and majorly affects old ages (Basu et al.,
2024; Bhattacharya et al., 2023; Bhattacharya et al.,
2024; Mohite et al.; Parihar et al., 2024; Sahu et al.,
2024). It starts in the epithelial region and advanc-
es to polyp adenoma and then to carcinoma. The
conditions correlated with chronic inammation,
mutagen exposure, and abdominal obesity (Pothu-
raju et al., 2020). The survival rate of CC improves
by employing adjuvant and non-adjuvant therapies,
surgery, radiotherapy and chemotherapy alone.
However, their efciency is limited due to inherent
susceptibility (Zeng et al., 2018).
CC faces challenges in terms of effective man-
agement, particularly due to limitations encountered
with conventional drug delivery systems (Kalaydina
et al., 2018). Issues such as poor solubility, limited
stability, and inadequate targeting abilities hinder
the therapeutic outcomes of conventional approach-
es. However, advancements in NT have opened up
new possibilities for enhancing drug delivery in CC
treatment. One such innovation is the utilization of
CDNSs that offer unique advantages in improving
the efcacy and safety of therapeutic agents. The
use of CDNSs in the treatment of CC enhances drug
solubility and bioavailability, targeted delivery to
CC cells, prolonged, and controlled drug release,
and protection of drugs from degradation with po-
tential for combination therapy. By functionalizing
the NS, they can be specically targeted to CC cells,
minimizing off-target effects, and reducing sys-
temic toxicity. The NS are a novel class of colloi-
dal systems having a unique appearance and highly
cross-linked structure which enables the entrapment
of drugs in the cavity. Moreover, the porous struc-
ture of NS enables sustained and controlled release
of drugs, ensuring a continuous therapeutic effect.
Additionally, the encapsulation of drugs within NS
protects against degradation, improving their stabil-
ity and shelf life. Furthermore, the ability of NS to
encapsulate multiple drugs allows for combination
therapy, targeting multiple pathways involved in CC
progression simultaneously.
The present review aims to provide insight into
the limitations encountered with conventional drug
delivery systems in the management of CC that
necessitate alternative approaches. CDNSs offer
advantageous features such as enhanced solubil-
ity, targeted delivery, sustained release, and drug
protection, making them a promising solution for
improving CC treatment. Therefore, utilization of
such NS as the carrier has the potential to overcome
the challenges associated with conventional drug
delivery systems with enhanced efcacy and safety
of therapeutic agents in colon cancer management.
Cyclodextrin
Cyclodextrins are a family of cyclic oligosaccharides
composed of glucose units that possess a unique mo-
lecular structure with a hydrophobic cavity and a
hydrophilic outer surface (Fig. 1). This structural ar-
rangement provides CDs several advantages, making
them valuable in various applications, including drug
delivery (Mura, 2020; Tiwari et al., 2010).
Figure 1. The torus-like shape of cyclodextrin.
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One of the primary advantages of CD is its abil-
ity to improve the solubility of poorly soluble drugs
(Archontaki et al., 2002). CD can form inclusion
complexes with hydrophobic drugs by encapsulat-
ing them within their hydrophobic cavities. This in-
clusion complex formation enhances the solubility
of the drugs, allowing for their effective formula-
tion into various dosage forms (Ahsan et al., 2001).
By improving the solubility, CD attenuates the bio-
availability of drugs, ensuring that enough amount
of the drug is available for absorption, which in turn
enhances the therapeutic efcacy of the pharma-
ceutical formulation. CDs also offer the advantage
of enhancing the stability of drugs (Arima et al.,
1998). By encapsulating drugs within their cavities,
CD protects the drug molecules from degradation
under environmental factors such as light, moisture,
and oxygen. Moreover, this encapsulation improves
the stability of the drugs, extending their shelf-life
and maintaining their efcacy over a longer peri-
od. Furthermore, CDs mask the unpleasant tastes
and odors of drugs, making them more palatable
for patients. This property is particularly benecial
in the development of oral dosage forms, especially
for pediatric and geriatric populations where patient
compliance can be a challenge (Arias et al., 2000).
Additionally, CDs effectively mask the undesirable
sensory attributes of drugs, increasing patient ac-
ceptance and adherence to the medication. In addi-
tion, CDs exhibit compatibility with various routes
of administration. They can be incorporated into
different pharmaceutical dosage forms, including
oral tablets, capsules, creams, gels, and even paren-
teral formulations. This versatility allows for their
use in diverse patient needs and preferences, ensur-
ing that CDs can be employed in a wide range of
pharmaceutical applications (Arias et al., 2000). Im-
portantly, CDs are considered safe and biocompat-
ible. Besides, CDs are readily eliminated from the
body without causing signicant adverse effects,
making them suitable for pharmaceutical applica-
tions and minimizing the potential for patient harm.
Limitation of native cyclodextrins
Cyclodextrins can include molecules of size and
polarity compatible with its lipophilic inner cavi-
ty. Native cyclodextrins are not able to incorporate
certain hydrophilic compounds or large molecules
(Sherje et al., 2017). One notable constraint is its
limited solubility in water, which can hinder its ef-
fectiveness in aqueous formulations. This solubility
issue may restrict its application in certain phar-
maceutical and food formulations, where water
solubility is a crucial factor. Additionally, plain cy-
clodextrin’s relatively low complexation efciency
with certain guest molecules may limit its ability
to encapsulate and stabilize specic compounds
effectively. The structural rigidity of cyclodextrins
can also pose challenges in accommodating larg-
er or more exible guest molecules, potentially re-
stricting their inclusion in the cyclodextrin cavity.
Moreover, the potential for retrogradation, wherein
the inclusion complexes may revert to their original
state over time, could impact the stability and shelf
life of products incorporating plain cyclodextrin.
Addressing these limitations has spurred research
efforts focused on modifying cyclodextrins, such
as derivatization or the development of novel deriv-
atives, to overcome these challenges and enhance
their overall utility in various applications (Puskás
& Malanga, 2017; Rapp et al., 2021).
2. FABRICATION TECHNIQUES
NANOSPONGES
Nanosponges are highly cross-linked porous struc-
tures that encapsulate the drugs in the cavity. The
maximum drug loading and porous nature are the
desired characteristics of NS. Therefore, the selec-
tion of a suitable and effective method is preferred.
NS can be synthesized by using different methods;
some of the methods are listed as follows
Solvent method
This method involves adding a solution of polymer
to an excess of the crosslinker, maintaining a tem-
perature of 10 °C for 48 h. Further, the mixture is
cooled, and excess water is added to it, which re-
sults in the formation of nanosponges. The prepared
nanosponges were ltered under a vacuum and col-
lected. Through a long-term Soxhlet extraction pro-
cess with ethanol, the mixture is puried (Farsana
et al., 2021).
Suitable solvents, such as dimethylformamide
and dimethyl sulfoxide which are polar aprotic sol-
vents, were used in the process (Kartik Tiwari &
Sankha Bhattacharya, 2022). To this, the polymer
was added and properly blended in different ratios
with crosslinker. Later crosslinked composition
is left to react for 48 h at a temperature range of
100 °C or up to the solvent’s reux temperature.
On completion of the reaction, the solution cooled
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down until it reached room temperature followed
by the addition of an excess quantity of double dis-
tilled water to obtain the product after vacuum l-
tration (Gadade & Pekamwar, 2020).
Naproxen sodium Nanosponges were developed
by Ilyas et al., utilizing the solvent diffusion meth-
od, and it was discovered that formulations had
a diffusion rate equal to 89 % and a drug loading
efciency near 98 %. Additionally, they investi-
gated stability studies, zeta potential, viscosity,
and particle size. The Fourier Transform Infrared
Spectroscopy results did not show any evidence
of a drug-excipient interaction. The ndings also
demonstrated outstanding drug release characteris-
tics and higher drug loading efcacy (Kartik Tiwari
& Sankha Bhattacharya, 2022).
Ultrasound-assisted method
The ultrasound-assisted method is another tech-
nique to synthesize NS using polymer under an
ultrasonic junction. The cross-linking process was
initiated in the presence of ultrasonic waves for
polymer and crosslinker at varied molar ratios, at
a temperature of 90 °C and for a specied period.
The temperature of the collected mixture reduced
slowly after sonication, and the product split harsh-
ly to separate unreacted polymer and reagents with
an excess volume of water. The washed solid was
further puried with ethyl alcohol using Soxhlet
extraction techniques. The ltered NSs acquired are
vacuum-dried and processed correctly until further
loading of drugs (Diego Marestoni et al., 2020; K.
Tiwari & S. Bhattacharya, 2022).
Melt method
Cyclodextrin-based nanosponges are also synthe-
sized by a melt procedure. In this process, NS are
obtained through crosslinking of different types of
CDs with a carbonyl or a dicarboxylate compound
as crosslinker. The different crosslinking agents
dramatically modulate important parameters such
as swellability and hydrophilicity/hydrophobicity
of the nanoporous polymer. In the melt method, the
crosslinker and polymers are transferred around the
bottom ask in specic ratios and react at 100 °C.
The reaction mixture was further allowed to cool
down and washed with desired solvent to remove
the unreacted polymer and phenol crystals followed
by repeated washing with suitable solvents to re-
move unreacted excipients and by-products
Microwave Assisted Synthesis
This is the simplistic method for the synthesis of
cyclodextrin-based NS using microwave irradi-
ation that signicantly reduces the reaction time
(Singireddy et al., 2016). These NS have a high-
er degree of crystallinity. Compared to the con-
ventional heating method, microwave-assisted
synthesis of NS showed a fourfold reduction in
reaction time with homogeneous-sized particle
distribution with uniform crystallinity (Sherje et
al., 2017).
Bubble electrospinning
A conventional and typical electrospinning cong-
uration consists primarily of a syringe, a syringe
pump, as dened in many literatures, a high-volt-
age power, and a grounded collector. However,
one of the major limitations that limits their ap-
plications is the amount of output of nanobers.
In bubble electrospinning, polyvinyl alcohol can
also be used as a polymer. By the addition of dis-
tilled water into it, the solution of polymer (10%)
was organized, which was then moved at 80-90 °C
for 2 h to obtain a one-phase mixture. It was then
left to achieve at room temperature with the poly-
mer solution and then used to prepare nanoporous
bers (Kartik Tiwari & Sankha Bhattacharya,
2022). (Fig. 2).
Drug loading process within nanosponges
The passive drug loading method is preferred
in the case of β-cyclodextrin-based NS. Ex-
perimental investigation requires the weighed
number of blank NS dispersed in the solution
of the drug mixture followed by sonication to
avoid aggregation. The resulting solution was
further stirred for 24 h on a magnetic stirrer at
a speed of 200 rpm and subsequently, the result-
ing mixtures are subjected to centrifugation. The
drug-containing supernatant was separated and
freeze-dried for 24 h to get porous drug-loaded
NS. The structure of NS plays a very important
role in the complexation with drugs. A study re-
vealed that para-crystalline NS showed differ-
ent loading capacities, compared to crystalline
NS. While, in poorly crystalline nanosponges,
the drug loading occurs as a mechanical mixture
rather than an inclusion complex (Shringirishi et
al., 2014).
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3. CHARACTERIZATION TECHNIQUES
FOR NANOSPONGES
Multiple physiochemical tests are required to test
CDNSs strength, level of crosslinking, and rate of
drug delivery that helps to evaluate the characteris-
tic features of formulation. The following evaluation
is deemed necessary to characterize the NS such as
drug content, entrapment efciency, morphological
analysis, phase solubility, thermomechanical analy-
sis, x-ray diffraction, functional group analysis, po-
rosity, swelling index, in vitro release, and stability
studies as given below.
Drug Content and Entrapment Efciency
To determine drug loading, a high concentration of
drug is dissolved in a suitable solvent considering
the solubility of the drug, later CDNSs are suspend-
ed in the mixture. Subsequently, the dispersion is
mixed and shaken at room temperature for a certain
time period and then ltered to get the NS portion.
This portion is then freeze-dried and drug content is
quantied from the resultant mixture. Similarly to
quantify the drug entrapment, the drug-loaded NS is
mixed in drug-soluble liquid and sonicated for dis-
rupting the complex within NSs hence causing the
drug to dissolve in solvent and drug concentration in
the solvent is estimated using analytical techniques
through either UV-Vis spectroscopy or high-perfor-
mance liquid chromatography (Lembo et al., 2018).
Microscopic studies
The microscopic aspects such as morphology and
surface topography of NSs, or the product are im-
aged using scanning electron microscopy or trans-
mission electron microscopy. The difference in
the crystallization state indicates the formation
of inclusion complexes (Jilsha & Viswanad, 2013)
(Fig. 3).
Phase solubility
The phase solubility technique investigates the
effect of NS on drug solubility (Swaminathan
et al., 2007). Experimentally phase solubility
determination requires excess drug addition to
saturated solutions of suitable solvents. Thus,
solubility study involves the addition of vary-
ing concentrations of blank nanosponges and
continuing until equilibrium is obtained. Later
the stability constant values obtained from the
interaction between nanosponges and the drug
can increase the solubility of poorly water-sol-
uble drugs. Such studies have been carried out
for itraconazole loaded cyclodextrin nanospong-
es prepared by Shankar and co-workers (Swa-
minathan et al., 2007). Consequently, NS could
markedly increase the solubility of molecules
with very low aqueous solubility such as antican-
cer drugs, steroids, and anti-inflammatory drugs
(Sawatdee et al., 2016).
Figure 2. Schematic representation of bubble electrospinning method.
Reproduce with permission from (Kartik Tiwari & Sankha Bhattacharya, 2022)
under Creative Commons Attribution (CC BY 4.0) license.
REVIEW ARTICLE Popat Mohite et al.
6 | Nanofabrication (2024) 9 https://doi.org/10.37819/nanofab.009.1823
Figure 3. Scanning electron microscopy images of β-CDNS (I) [curcumin-loaded diphenycarbonate
cross-linked NS (a); curcumin-loaded diphenycarbonate cross-linked NS (b); curcumin-β-CD complex
(c); curcumin-β-CD complex (d)]. Transmission electron microscopy mages of β-CDNS -II [Blank
NS (a) and Babchi Oil-Loaded β-CDNS (b)]. Reproduce with permission from (Kumar e t a l., 2018;
Mashaqbeh et a l., 2021) under Creative Commons Attribution (CC BY 4.0) license.
I
II
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Thermo-analytical methods
Thermo-analytical methods determine whether
the drug substance undergoes some change before
the thermal degradation of the NSs, this change
includes evaporation, decomposition, oxidation, or
polymorphic transition of incorporated drug sub-
stance, which may indicate the complex formation.
The thermogram obtained from differential scan-
ning calorimetry, in case complex formed, broad-
ening, shifting, and appearance of new peaks or
disappearance of certain peaks are observed with
changes in the weight loss (Jagtap et al., 2019).
X-ray diffraction
X-ray powder diffraction (XRPD) has been used
for evaluating the crystallinity of NS and its drug
complexation capacity (Ahmed et al., 2013a).
Changes in crystallinity have a profound effect
on drug loading, solubility, dissolution, and drug
release kinetics. XRPD of β-CD shows an amor-
phous state while the NS may either be crystalline
or para-crystalline (poorly crystalline) depending
on processing conditions. Swaminathan and his
colleagues report this phenomenon, CAM loaded
CD-NS were prepared using two sets of condi-
tions, namely, reacting β-CD and DPC at 90 °C,
with and without using ultrasound. A crystalline
product was obtained using the ultrasound-assist-
ed method while a para-crystalline product was
obtained without ultrasound. The XRPD data of
the para-crystalline product showed an increase
in the peak area while the intensity versus full
width at half maximum ratio decreased (Ahmed
et al., 2013b). The XRPD patterns of crystalline
NS at different β-CD/cross-linking agent ratios are
shown in Fig. 4.
Figure 4. X-ray diagrams of crystalline camptothecin-loaded NS, compared with pure
camptothecin-NS simulated physical mixture and plain camptothecin (a). X-ray diagrams
of crystalline NS at different β-CD/cross-linking agent ratios (b). Reproduce with
permission from (Swaminathan et a l., 2010), Righlink copyright clearance from.
Fourier transform-infrared spectroscopy
Fourier transform-infrared spectroscopy (FTIR)
is the most important technique for structural elu-
cidation, particularly functional group detection.
Monomers get attached to form polymer during
polymerization reaction where functional group
peaks in the spectrum of FTIR are the character-
istic indications of polymerisation. The range of
4000-650 cm−1 is used to take FTIR spectra of drug,
polymer, drug-polymer physical mixture, neat NS,
drug-loaded nanosponges and observed for any
possible interaction. It also shows the hydrophilic
and hydrophobic sites of nanosponges. The disap-
pearance of any functional group peak in the case
of hydrophobic drug is because of its inclusion in
cyclodextrin/NS cavity (Kumar & Rao, 2022).
Raman spectroscopy
Raman spectroscopy is an extremely useful tool in
molecular study as the intensity, width, and wav-
enumber of Raman peaks are quite responsive to
conrmation, molecule environment and intermo-
lecular reactions. Raman spectroscopy explores the
elucidation of CDNS after entering a swollen form
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from a dry state. Moreover, this technique also pro-
vides information about the illustration of the state
of water and dissolved solute inside nanoporous NS
architecture with meticulous importance to diffu-
sion from the gelled condition. Dynamics of hydra-
tion are examined by analyzing vibration modes of
decoupled O-H and C-H groups from bulk water
background (Sherje et al., 2017).
Nuclear magnetic resonance spectroscopy
Nuclear magnetic resonance spectroscopy tech-
niques such as 13C, 1H, 2D NMR, and high-resolu-
tion magic angle spinning techniques help in under-
standing the structure of CD crosslinked polymers.
The shift in chemical shift values (δ) indicates the
transfer of proton among species in reaction and
hence ascertains the structure of the NSs (Kartik
Tiwari & Sankha Bhattacharya, 2022).
Particle size analysis
Mean particle size, zeta potential, and polydis-
persity index of nanosponges are analyzed using
dynamic light scattering using a zetasizer instru-
ment, at room temperature. Experimentally, the
samples are dispersed in Milli-Q water to develop
a monodisperse system and assessed. Zeta poten-
tial is a measure of the level of the surface charge
and serves as an indicator of the relative magni-
tude of the repulsion force between colloidal par-
ticles in aqueous suspension. A high zeta potential
prevents particle-particle agglomeration, whereas
the zeta potential is greater than 30mV, then the
dispersion is stable, which is measured using addi-
tional electrode in particle size equipment (Anwer
et al., 2022). Moreover, the mean hydrodynamic
diameter and polydispersity index of the particles
are calculated using the cumulated analysis after
averaging the total measurements (Shringirishi et
al., 2014).
Void fraction/porosity,
swelling, and water uptake
Void fraction investigations are performed to test the
width of the nanoholes and nanopores that are de-
veloped after freeze-drying. Experimentally, a heli-
um pycnometer measures the porosity of NS, since
helium gas can invade associate- and intra-specic
channels of fabric. The genuine amount of the fabric
is measured by means of the helium uprooting cycle
due to its permeable presence, nanosponges display
more noteworthy porosity relative to the guardian
polymer utilized to make the gadget (Prabhu et
al., 2020). The NS was developed using swellable
polymers like polyamidoamine, the water uptake is
quantied by soaking the prepared nanosponges in
aqueous solvent (Prabhu et al., 2020).
In-vitro release and release kinetics
The release behavior of the drug from NS is as-
sessed using in vitro release study. Multi-compart-
ment rotating cell in which donor compartment is
lled with an aqueous dispersion of NS fortied
with active moiety and receptor compartment lled
with phosphate buffer of appropriate pH. The com-
partments are separated with a hydrophilic dialysis
membrane and samples are withdrawn at a xed
time and replaced with fresh buffer to maintain
the sink condition. Later using a suitable analyti-
cal technique the amount of drug is determined and
drug release is calculated. Further, to investigate
the mechanism of drug release from nanosponge
the release data could be analyzed using Zero or-
der, First order, Higuchi, Peppas, Hixon-Crowell,
Kopcha and Makoid-Banakar models. The data set
obtained is further used to estimate the parameters
of a non-linear function that provides the closest t
between experimental observations and non-lin-
ear function (Kumar & Rao, 2022). Furthermore,
the Nanosponges are tested for stability according
to ICH guidelines (Venkateswarlu et al., 2022).
A summary of characterization performed over
β-CDNS for various drugs is presented in Table 1.
4. FACTORS AFFECTING
THE SYNTHESIS OF NANOSPONGE
Cross-linkers and polymer types
The performance and development of NSs are
impacted by the type of polymer employed. The
amount of cross-linker is responsible for getting the
desired three-dimensional cross-linked structure
(Table 2). Molecular nanocavities are transformed
into three-dimensional nanoporous structures that
are capable of cross-linkers. The ratio of polymer:
crosslinker plays a vital role as they encapsulate the
drug which affects the solubility of the drug (Kar-
tik Tiwari & Sankha Bhattacharya, 2022). The use
of different polymers for the preparation of nano-
sponges is reported in Table 2.
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Drug Polymer Fabrication
technique Characterization Critical attribute Reference
Flutamide cyclodextrin Freeze-drying
Particle size,
zeta potential,
and morphology
Small size (82.53 ± 42.32 and
99.10 ± 22.15 nm) and high zeta
potential (43.0 ± 9.89 and 24.1
± 10.1 mV) could indicate the
stabilization of NS suspension due
to reduced aggregation probability
of particles.
(Allahyari
et a l.,
2021)
In-vitro release
studies
In-vitro release pattern of FLT
showed complete release in 180
min from NS complexes without
burst effect. A dramatic increase
observed in the rate and amount
of drug release due to the wetta-
bility of utamide. By comparing
the release proles of CDNS at
different composition 1:2 and 1:4,
experimentally observed that the
release can be modied by chan-
ging the cross-linking degree of
CD molecules.
Loading of uta-
mide into CDNSs
Moreover, NS (1:4) showed higher
encapsulation of drug, compared
with NS 1:2 might be due to a high
cross-linker ratio and an increase
in cavities number. The encapsu-
lation capacity CDNSs might be
affected by different factors such
as the cross-linker ratio of CD-
NSs, size, and chemical structure
of a guest molecule
Econazole
Nitrate
(EN)
β-Cyclo-
dextrin,
N,N-car-
bonyldi
imidazole
Melt method Surface
morphology
The scan electron microscopy of
β-CD showed a compact struc-
ture whereas the of placebo NSs
demonstrated a spongy structure
of the formulation. In case of dug
loaded NS the desired porosity not
seen as the porosity was partly
occupied by the drug in the drug-
loaded nanosponges due to the
formation of inclusion complexes
(Srivastava
et a l.,
2021)
FTIR
The broadening of peaks of car-
boxylate stretching in structural
analysis at 1535 cm–1 to higher
wavelength suggested the develo-
pment of hydrogen bonds between
the groups of econazole nitrate
and the hydroxyl groups of β-CD
along with the desertion of the
peaks at 3250 cm–1 (asymmetric
O-H stretching) indicated entrap-
ment of the drug into NS.
DSC
While the disappearance of peak
disappeared in EN-CDNS signifying
a change of the drug crystalline
form into an amorphous state in
the NS formulation demonstrating
assimilation of the drug within the
NS as inclusion or non-inclusion
complexes.
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Drug Polymer Fabrication
technique Characterization Critical attribute Reference
XRD
The XRD pattern of EN showed a
prominent sharp peak at 2θ angles
10.1, 17, 21.2, 26.8, and 29.1
which specify the crystalline natu-
re. The XRD diffractogram of the
drug in NS shows diffused peaks
with low intensities indicating that
the drug crystallinity was remar-
kably reduced indicating loading of
drug into nanosponges in unstruc-
tured or solid-state solubilized
form or disarrayed crystalline
phase inside the polymeric matrix.
Curcumin β-CD Freeze-dr-
ying method
Phase solubility
studies
The solubility of curcumin enhan-
ced as a feature of β-CD level in-
creases, displaying the AN type of
solubility phase prole. Meanwhile,
the curcumin complex with NS
exhibits the BS type of solubility
phase diagram. Total curcumin
solubility was enhanced by the
formation of β-CD inclusion com-
plexes up to 2.34-fold, compared
to the inherent solubility
(Mashaq-
beh e t a l.,
2021)
Molecular
modeling
The molecular docking conferred
that the interaction between cross
linker and polymer which is desired
for preparation of NS. The docking
results showed that complexation
schemes have comparable binding
afnities with binding interactions
at ratio of 1:1 complex.
In-vitro release
prole
The in vitro release prole of curcu-
min loaded NSs showed an enhance-
ment in curcumin release and cur-
cumin was released from the NS4
sample faster than from the physical
mixture and the raw curcumin.
Vitamin D β-cyclodex-
trin
Complexation
method Thermostability
The study demonstrates for the
rst time the ability of CDNS com-
plexes to improve the thermos-
tability, chemical, and biological
function of Vit D3.
(Uberti
et a l.,
2023b)
6-Gingerol CD Complexation
method
Thermogravime-
tric analysis
HP β-CD had two stages of ther-
mal weight loss. The rst stage
demonstrated weight loss of 3.5%
due to vaporization of residual wa-
ter. While the second stage was
the apparent thermal weight loss
caused by HP β-CD decomposition,
with 81.8% weight loss.
(Uberti
et a l.,
2023a)
Scanning elec-
tron microscopy
The SEM micrograph quantied
the morphological characters of
the 6-Gingerol CDNS. Within the
aqueous medium, a closed etho-nio-
somal bilayer developed that tends
to minimize their surface free ener-
gy by the development of spherical
trans-ethoniosomal vesicles.
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Drug Polymer Fabrication
technique Characterization Critical attribute Reference
zeta potential
The zeta potential reects the
charge and the stability of the
CDNS. The higher zeta potential
value of optimized formulation
indicated the stability of the
nano-dispersion within CDNS due
to repulsive force between the
trans-ethoniosomal nanovesicles
and the presence of a high-energy
barrier between them that inhibits
their aggregation.
Antican-
cer Hy-
drophobic
Agents,
Naringe-
nin (NG)
hydroxypro-
pyl-β-cyclo-
dextrin
Cross linking
method/
complexation
method
Phase solubility
studies
The Higuchi–Connors prole
demonstrated that the complex
formation of HPβ-CD with NG has
a tremendous effect on the water
solubility of NG, and a saturated
concentration of HPβ-CD in water
(almost 322 mM) could increase
the NG aqueous solubility by about
2375-fold.
(Peiman-
fard e t a l.,
2022)
1H NMR and
13C cross-pola-
rization Magic
angle spinning
solid-state NMR
NMR spectroscopy has been
widely used to study CD comple-
xes, the results obtained from
the experimental 1H NMR spectra
and the Higuchi–Connors method
suggested that HPβ-CD formed
a host–guest complex with NG
through an inclusion phenomenon.
Table 1. Summary of characterization performed β-CDNS for various drugs.
Cross-linkers
Diarylcarbonates, carbonyldiimidazoles, pyromellitic
anhydride, carboxylic acid dianhydrides, glutaraldehyde,
epichloridrine, 2,2-bis (acrylamide) acetic acid, Diphenyl
carbonate, and di-isocyanates
Polyvinyl alcohol, ethyl cellulose, Hyper-cross-
linked polystyrene, cyclodextrins and its deriva-
tives, including methyl-CD, alkyloxy carbonyl-CD,
and 2-hydroxy propyl-CD, as well as copolymers
such poly ( allylvalerolactone-allylvalerolactone),
poly(allylvalerolactone-allylvalerolactoneoxepanedione)
Table 2. Chemicals frequently used in the synthesis of NS.
Epichlorohydrin is used as a cross-linker to de-
velop hydrophilic NSs. An effective drug carrier
can be employed in formulations for immediate re-
lease with such an NS, which also improves drug
absorption across biological barriers. Diphenyl-
carbonate treatment can create a hydrophobic NS.
Carbonyldiimidazoles pyromellitic anhydride,
diisocyanates as cross-linkers, and they could serve
as a vehicle for the sustained release drug delivery
of hydrophilic medicines, such as proteins and pep-
tides. Considering recent investigations, various
examples of polymers employed with NS prepara-
tion methods are presented in Table 3 along with
prospective applications.
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Polymer Fabrication technique Size Use References
β-CD and different
crosslinkers Cross-linking using polymers Not quoted
Removing toxic
molecules from the
body
(Varan
et a l., 2020)
CD and their
derivatives
Simple thermal desorption,
extraction with solvents and/
or use of microwave and ul-
trasound techniques (diphen-
ylcarbonate or pyromellitic
anhydride as crosslinkers)
Below 500 nm
Solubility enhan-
cement, cytotoxi-
city, hemolytic,
antifungal, antiviral
activity
(Cavalli
et a l., 2010;
Osmani
et a l., 2018b)
β-CD and
copolyvidonum
Simple thermal desorption,
extraction with solvents
and/or use of microwaves
and ultrasounds
Not quoted Saturation
solubility study
(Mele
et a l., 2 011)
β-cyclodextrin with
diphenyl carbonate
(DPC), pyromellitic
dianhydride (PMDA) and
epichlorohydrin (EP)
Simple thermal desorption,
extraction with solvents 166-673 nm herbicide (Liu e t a l.)
β-Cyclodextrin-ba-
sed carbamate
nanosponges
Cross-linking using polymers Not quoted NSAIDS (Pawar
et a l., 2019)
Table 3. Cyclodextrin Nanosponges prepared by diverse methods and their potential applications.
Type of drugs and medium
used for crosslinking
The solvent system employed demonstrates a signif-
icant impact on the production of NS, in addition to
the type and nature of the polymer and cross-linker
utilized. To encapsulate the maximum quantity
of drug crosslinked with nanostructure, the phys-
iochemical properties of drug were considered.
Moreover, a molecular weight of less than 500 Da is
a basic prerequisite and preferred for encapsulation.
To be properly entrapped within nanocavities,
drug molecules are required to comply with specif-
ic properties such as simple to trap molecules, mo-
lecular mass between 100 and 400 Da, and fewer
than ve condensed rings. Additionally, the mole-
cules should possess a melting point of around or
less than 250 °C with solubility in water of not more
than 10 mg/mL (Osmani et al., 2018a). Higher melt-
ing points of pharmaceuticals make it difcult to
develop stable complexes between medicines and
niacin due to the need to maintain higher stability
constant values after loading in the NS. Moreover,
the loading of the drug is signicantly impacted by
a greater drug melting point. Additionally, due to
the stiffness of the compound’s structural makeup,
melting of compounds at higher temperatures re-
sults in reduced drug loading. A hydrophilic media
forces organic guest molecules into the hydrophobic
cavities, while an organic solvent tends to release
the organic molecules trapped in NS. Therefore, the
medium has a signicant impact on how targeted
compounds interact with NS cavities. Furthermore,
optimized physical and chemical interactions, such
as structural characteristics, size, mutual polarity
matching, and hydrophobic environment drive the
strong attraction between host and guest molecules
(Osmani et al., 2018a).
Degree of substitution
The quantity, position, and type of the substituent
on the polymeric molecule demonstrate a signicant
impact on a NSs capacity to complex (Jagtap et al.,
2019). As the β-CD derivatives are widely available
in major three forms due to variations in the func-
tional groups present on the surface of CD deriva-
tives, the kind of substitution is essentially different.
Different types of complexed material (β-CD NSs,
CD-carbonate NSs, and CD-carbamate NSs,) can be
developed with different functional groups when
they are complexed together using cross-linker.
The number of substitutions and cross-linking are
directly proportional to one another, which shows
that exhibiting more substituents may increase the
likelihood of higher levels of cross-linking, which
can produce highly porous NSs as a result of more
linkages between polymers and the establishment of
a mesh-like network. In addition, the various condi-
tions of system production also signicantly affect
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the position of substitution. This might be because
the functional group on the parent compound may
occupy a different location as a result of a change
in the production method, new materials with dif-
ferent physicochemical properties are. developed.
For instance, if produced under different production
conditions, samples of hydroxypropyl β-cyclodex-
trin with the same degree of substitution might not
demonstrate similar physicochemical characteris-
tics. This could be explained by the likelihood that
the hydroxypropyl groups on the parent CD mole-
cule reside in different locations. Thus, the degree of
polymer substitution is crucial and has a consider-
able impact on the ultimate quality of NSs, as shown
by the production process and material purity.
Swaminathan and co-worker utilized ultraso-
nography and loaded Camptothecin (CAM) within
NSs in three different molar ratios of 1:2, 1:4 and 1:8
(β-CD: cross-linker). Experimental investigation
demonstrated high drug loading, compared to the
traditional method (reux heating), which showed
just 10% w/w with para-crystalline NS. Additional-
ly, the type of NS employed had a signicant impact
on the release kinetics of CAM after complexation
in NS. This may be attributable to optimal levels of
cross-linking and greatest drug loading. Whereas a
low drug loading at the 1:8 molar ratio was most
likely caused by inadequate NS network develop-
ment as a result of the steric obstructions mentioned
above (Ahmed et al., 2013a).
Complexation temperature
As was previously noted, the type and nature of
the polymer dene the type of NSs that are to be
manufactured; several varieties of NSs can be con-
structed and developed based on the polymer used.
Several prominent instances of NS include silicon
NS particles, titanium-based NSs, CD-based NSs
and hyper-cross-linked polystyrene NSs. Among
all the different forms of NSs, CD-based NSs have
attracted the most attention and have therefore been
extensively explored.
Temperature
The complexation of the drug is greatly impacted by
temperature changes, due to a potential reduction in
drug NSs contact forces, Vander Waals forces, and
hydrophobic forces with rising temperature and ap-
parent stability of the NS complex that diminishes
with temperature change.
Fabrication techniques
Drug/NSs complexation plagues the drug loading in
NSs, which depends on the strategy used to entrap
the drug inside of them. The physiochemical prop-
erties of the medicine and chemicals also reduce the
method’s productivity. In most instances, the poten-
cy of the drug’s complexation was discovered by
drying up (Allahyari et al., 2021). As a result, β-CD
is typically chosen over other ingredients when
making NS. There are numerous methods for fabri-
cating NS using various suitable grades of polymer-
ic substance are covered in the next section.
5. CYCLODEXTRIN BASED
NANOSPONGES FOR THERAPY
AND DIAGNOSTIC APPLICATIONS
The use of CDNS is widespread in various thera-
peutic applications and can modify the physiolog-
ical properties of drugs for various ailments. Saei-
deh and his colleagues developed the CDNS of
utamide (FLT) with solubility improvement abil-
ity as a novel delivery system. The CDNS at dif-
ferent ratios was introduced as a non-toxic delivery
system for FLT with dissolution rate improvement
characteristics. However, the number of cavities
in nanosponge structure might affect the loading
percentage and dissolution rate of FLT (Allahy-
ari et al., 2021). Hadeia and co-workers examined
curcumin’s complexation stability and solubiliza-
tion with β-CD and β-CDNS. NSs were fabricated
through cross-linking of β-CD with different mo-
lar ratios of diphenyl carbonate. Experimentally
developed β-CD complexes enhanced curcumin
solubility up to 2.34 fold, compared to the inherent
solubility and 2.95-fold increment in curcumin sol-
ubility when loaded in β-CDNSs. Interestingly, the
stability constant for curcumin NS was (4972.90
M–1), which was 10 times higher than that for the
β-CD complex, where the value was 487.34 M–1.
The study results indicated a decrease in the com-
plexation efciency and solubilization effect with
the increased cross-linker amount. Cyclodextrin
polymers and CDNSs have been widely investigat-
ed for improving the drug bioavailability. The in-
vestigation indicated the negative effect of further
increasing the molar ratio of diphenyl carbonate by
more than 1:4 of β‐CD: cross‐linker (Mashaqbeh
et al., 2021). Currently, there is a need for the de-
velopment effective drug delivery system for colon
cancer. The NS-based drug delivery system helps
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14 | Nanofabrication (2024) 9 https://doi.org/10.37819/nanofab.009.1823
to overcome the side effects of conventional drug
delivery systems. Novel broad spectrum was used
for treatment but, they show instability in gastric pH
to overcome these problem encapsulations this type
of drug is a better alternative. Nisin is a polycyclic
antibacterial peptide widely used for the treatment
of colon cancer; however, demonstrates degrada-
tion and remains unstable at gastric pH to overcome
this problem Yousef, and co-workers developed two
different types of CDNSs using carbonyl di-imid-
azole and pyro-metallic dianhydride. The antican-
cer activity was compared using MCF-7 cells other
physiochemical properties and release kinetics were
successfully studied. The important aspect for ni-
sin is stability which was studied using tricin-SDS-
PAGE electrophoresis. The cell line studies revealed
signicant cell damage by nisin with improvement
in stability (Fig. 5) (Khazaei Monfared et al., 2022).
Figure 5. Microscopical characterization of nisin loaded NS (I). Cell viability results for colon cancer (HT-29)
and breast cancer (MCF-7) cells exposed to nisin-Z and loaded on NS (II-A,B) and plain nanosponges (II-C,D)
for 24 h. Tricine-SDS-PAGE analysis of nisin with different treatments. Lane 1: Nisin (4 mg/mL); Lane 2:
Nisin (4 mg/mL) and pepsin (7.5 mg/mL); Lane 3: pyromellitic dianhydride-NSs (15 mg/mL); Lane 4: carbonyl
diimidazole-NSs (15 mg/mL); Lane 5: Marker; Lane 6: Nisin and pyromellitic dianhydride-NS; Lane 7: Nisin
and carbonyl diimidazole-NSs; Lane 8; Nisin, carbonyl diimidazole-NSs and pepsin (7.5 mg/mL) (III-A). Lane 1:
Marker; Lane 2: Nisin, pyromellitic dianhydride-NSs and pepsin (7.5 mg/mL) (III-B). Reproduce with permission
from (Khazaei Monfared e t a l., 2022) under Creative Commons Attribution (CC BY-4.0) license.
Hamid Shah et al (2023) reported the anticancer
activity of S. nigrum extract encapsulated in β-cy-
clodextrin and cross-linked with arabinoxylan was
examined by Hamid Saeed Shah et al., using the
MCF-7 breast cancer cell line. It has been reported
that different medications and biomolecules can be
carried on nanosponges. Nanosponges with a mor-
phological spherical, smooth, and 226 nm size were
III
III
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created. The SN extract had enhanced anticancer
potential as demonstrated by its greater bioavail-
ability and stability in the target site, as revealed by
cytotoxic studies. Additionally, in vivo, anticancer
activity showed that the SN extract that was en-
capsulated caused a decrease in tumor volume and
weight, which increased the likelihood of survival
by up to 85%. The current study’s ndings validat-
ed the delivery of synthetic and natural anticancer
medicines using cyclodextrin-based nanosponges
to increase their respective bioavailability and sta-
bility (Shah et al., 2023).
Ferulic acid (FA) was effectively encapsulated
into NSs by Atefe Rezaei et al., (2019), which led to
a notable increase in FA solubility of up to 15 times
when compared to the free form of FA. FTIR, XRD,
and DSC physicochemical and structural charac-
terizations showed that FA was appropriately en-
capsulated into the NS structures. The MTT assay
demonstrated that FA-NS had a greater antiprolif-
eration effect against MCF7 and 4T1 breast cancer
cell lines than free FA did. FA was released from
NSs slowly and under control, according to in vitro
release data. According to our ndings, FA can be
delivered by CD-NS, a viable nano-delivery meth-
od that may improve FA’s cytotoxicity, solubility,
and anticancer potential (Rezaei et al., 2019).
Two different CD-NS formulations were created
by Sally Abou Taleb et al., to load QCT and improve
its aqueous solubility to increase its biological ac-
tivities, specically its anti-proliferative and anti-
SARS-CoV-2 properties. With PS in the nanosize
range, the produced QCT loaded CD-NS showed a
high EE% of QCT (94.17-99.31%). FT-IR spectros-
copy demonstrated that QCT-loaded CD-NSs were
formed. The results of the in vitro release investi-
gation showed that the created formulations’ QCT
release was enhanced, suggesting better solubiliza-
tion. The IC50 of free QCT against the lung cancer
cell line A549 was 1.57-5.35 times greater than that
of the developed QCT-loaded CD-NS formulations.
In terms of SARS-CoV-2 activity, the IC50 values of
free QCT were 5.95-26.95 times greater than those
of the developed QCT loaded CD-NS formulations.
It is noteworthy that QCT-loaded CD-NS using
2-HPβCD (QCT-HPBCD/DPC 1:3) outperformed
QCT-loaded CD-NS using βCD (QCT-BCD/DPC
1:3) in terms of the entrapped QCT’s anti-prolifera-
tive and anti-SARS-CoV-2 activities in vitro. This
could be explained by 2-HPβCD’s superior wetting
ability and increased water solubility over βCD
(Abou Taleb et al., 2022).
The cytotoxicity investigation demonstrated
that the formulations incorporating CAM were
more cytotoxic than pure CAM, and the in vitro
experiments suggested delayed and prolonged
drug release over 24 hours. In 2012, Mognetti
and colleagues synthesized β-cyclodextrin nano-
sponges loaded with paclitaxel, a colloidal system
that is stable in water and prevents paclitaxel from
recrystallizing. According to the in vitro release
trials, there was no early burst impact and full
drug release was achieved in two hours. By de-
creasing the paclitaxel IC50 and increasing the
amount of paclitaxel that entered cancer cells,
the administration of paclitaxel via nanosponges
improved its pharmacological action (Mognetti et
al., 2012).
6. FUTURE PERSPECTIVES
The future perspectives of CDNSs in CC treat-
ment offer exciting possibilities for advancements
in personalized medicine, integration with emerg-
ing technologies, and overcoming challenges for
widespread implementation. One signicant future
perspective is the application of personalized med-
icine in CC treatment. Researchers can focus on
developing CDNS that are tailored to deliver spe-
cic therapeutic agents based on individual patient
characteristics. By considering factors such as tu-
mor heterogeneity and molecular proling, NS can
be designed to optimize treatment outcomes and
minimize side effects, leading to more precise and
effective colon cancer therapy. The integration of
CDNSs with emerging technologies holds immense
potential. Future studies can explore the combina-
tion of NSs with imaging modalities, such as mag-
netic resonance imaging or near-infrared imaging,
to enable real-time monitoring of drug delivery and
tumor response. This integration can provide valu-
able insights into drug distribution and effective-
ness, enabling clinicians to adjust treatment plans
accordingly. Additionally, incorporating stimuli-re-
sponsive materials into nanosponges can allow for
on-demand drug release triggered by specic phys-
iological or environmental cues, further enhanc-
ing the therapeutic efcacy and reducing systemic
toxicit y.
Another promising future perspective is the
use of cyclodextrin-based NSs as carriers for novel
therapeutic agents. Researchers can focus on en-
capsulating emerging targeted therapies, such as
small interfering RNA (siRNA) or gene-editing
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16 | Nanofabrication (2024) 9 https://doi.org/10.37819/nanofab.009.1823
tools, within NS. This approach can facilitate the
efcient delivery of these agents to CC cells, en-
abling precise and targeted treatment modalities
that hold promise for revolutionizing colon cancer
therapy. To fully realize the potential of CDNSs in
CC treatment, it is crucial to address challenges re-
lated to scalability, manufacturing processes, and
regulatory considerations. Future research efforts
should be directed toward developing scalable pro-
duction methods for nanosponges, ensuring repro-
ducibility, and establishing robust quality control
protocols. Additionally, researchers and regulatory
agencies need to collaborate to address regulatory
requirements and obtain necessary approvals for
clinical use, enabling the widespread implementa-
tion of these innovative nanosponges in colon can-
cer therapy.
7. CONCLUSION
Cyclodextrin-based NSs show great promise in
treating CC in the future. Exciting opportunities to
improve treatment outcomes arise from integrating
personalized medicine, combining it with emerging
technologies, and using them as carriers for nov-
el therapeutic agents. Colon cancer treatment can
move towards personalized medicine by tailoring
nanosponges to match individual patient charac-
teristics, which can enhance therapy and decrease
side effects. By combining NSs with imaging mo-
dalities and stimuli-responsive materials, it is pos-
sible to monitor drug delivery in real-time and have
precise control over drug release. Moreover, by
encapsulating emerging targeted therapies, we can
expand treatment options and open doors for preci-
sion medicine approaches. Cyclodextrin-based NSs
widespread adoption in clinical practice causes ad-
dressing scalability, manufacturing processes, and
regulatory considerations. To revolutionize colon
cancer therapy for better patient outcomes, it is cru-
cial to continue researching and developing these
nanosponges.
Abbreviations
CC: Colon cancer; BCD: β-cyclodextrin; NS: nano-
sponges; BCDNS: β-cyclodextrin nanosponges;
NT: Nanotechnology.
Declaration of Competing Interest
The authors declare no conict of interest.
Author Contributions
Conceptualization, PM; Methodology, SM and AP;
Validation, PM and SS; Formal analysis, Resourc-
es, SM; Data curation, SM and AP; writing original
draft preparation, SM and AP; Writing review and
editing, PM and SS.; Supervision, PM; Project ad-
ministration, PM, and SS;. All authors have read and
agreed to the published version of the manuscript.
Funding
This research received no external funding.
Acknowledgments
The authors are highly thankful to Management
Aldel Education Trust for providing the required
infrastructure to carry out the work. Moreover, this
work was partially supported by CMU Proactive
Researcher Scheme (2023), Chiang Mai University
“Contract No. 933/2566” for Sudarshan Singh. ♦
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