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REVIEW ARTICLE
Recent advances in electrospun nanofiber-mediated drug
delivery strategies for localized cancer chemotherapy
Meysam Khodadadi
1
| Sepideh Alijani
2
| Maryam Montazeri
3
|
Niloufar Esmaeilizadeh
2
| Shima Sadeghi-Soureh
2
| Younes Pilehvar-Soltanahmadi
2
1
Student Research Committee, Tabriz
University of Medical Sciences, Tabriz, Iran
2
Cellular and Molecular Research Center,
Cellular and Molecular Medicine Institute,
Urmia University of Medical Sciences,
Urmia, Iran
3
Department of Medical Biotechnology,
Faculty of Advanced Sciences and Technology,
Tehran Medical Sciences, Islamic Azad
University, Tehran, Iran
Correspondence
Younes Pilehvar-Soltanahmadi, Cellular and
Molecular Research Center, Cellular and
Molecular Medicine Institute, Urmia University
of Medical Sciences, Urmia, Iran.
Email: ypilehvar@umsu.ac.ir
Abstract
Nanotechnology empowered localized cancer chemotherapy has indicated a promis-
ing performance for targeting and controlled release of anticancer agents over a
period of time to eliminate local-regional recurrence of cancers and also to improve
the tissue regeneration during/after treatment. Electrospun nanofiber-based implant-
able drug-delivery systems have been established as one of the most effective
approaches for localized cancer treatment, allowing the on-site delivery of anticancer
agents and reducing systemic toxicities and side effects to normal cells. The present
review aimed to summarize the latest cutting-edge research on applications of
electrospun-based systems for local chemotherapy. Meantime, in vitro and in vivo
studies conducted using various anticancer agents along with the capability of
electrospun nanofibers for combinatorial/synergistic chemotherapy as well as exis-
ting challenges and the potential dramatic advances in applying this pioneering
approach for clinical transition in localized treatments of cancer is also discussed.
KEYWORDS
chemotherapy, drug delivery, electrospun nanofiber
1|INTRODUCTION
Anticancer agents bring massive cytotoxicity; thus, localized drug
delivery can generate the feasibility of high-quality safety and effec-
tiveness of chemotherapy in various types of cancer. Local drug deliv-
ery approaches first established in the 1960s by using silicone rubber
as a vehicle for extended drug delivery and ensuring deterministic
therapeutic effectiveness (Folkman & Long, 1964). The therapeutic
agent delivery device implanted straight to the tumor site can propose
the following pros in comparison to systemic drug delivery strategies:
(a) enhancing the stability of encapsulated chemotherapeutic agent
and conservation of its chemotherapeutic effect, (b) generating con-
trolled, sustained, and extended drug release behavior to guarantee
appropriate propagation and internalization into the tumor cells during
various stages of tumor cell cycle, while ensuring low systemic drug
concentration, (c) loading and release of poorly soluble chemothera-
peutic agents within the depot, (d) targeted delivery to the tumor site,
leading to decreased medicines waste, (e) single-dose drug delivery, (f)
decreasing the total amount of drug in the formulation, and
(g) minimizing systemic toxicities and adverse effects on normal cells
in relative to micro/nanoparticulate drug delivery approaches due to
the escaping systemic circulation of chemotherapeutics (Farajzadeh,
Zarghami, et al., 2018; Fu, Li, Ren, Mao, & Han, 2018).
Implantation of localized drug delivery devices at the postsurgical
cavity after a tumor has been removed, intending the elimination of
remaining tumor cells and avoiding possible cancer relapse, has been
provided an emerging potential solution in cancer therapy to tackle
the problems related to the present particulate administration of anti-
cancer agents. Also, to treat the tumors such as pancreatic cancer that
are not easily surgically resected and may infiltrate and spread, using
this approach locally be able to eradicate cancer cells through inhibi-
tion of the cell growth with privileged effectiveness.
Currently, various types of drug delivery vehicles including gels,
films, rods, wafers, particles, and fibers with foreseeable and extended
Received: 9 May 2019 Revised: 21 February 2020 Accepted: 24 February 2020
DOI: 10.1002/jbm.a.36912
1444 © 2020 Wiley Periodicals, Inc. J Biomed Mater Res. 2020;108:1444–1458.wileyonlinelibrary.com/journal/jbma
drug discharge kinetics have been explored as localized drug delivery
devices (Dadashpour et al., 2018; Javidfar et al., 2018; Lotfi-Attari
et al., 2017; Nejati-Koshki et al., 2017; Wolinsky, Colson, &
Grinstaff, 2012). Among them, electrospun nanofibers have achieved
particular interest during the past two decades due to unique and
appealing features for use as localized drug delivery devices including
microscale or nanoscale diameters with similar structure to extracellular
matrix (ECM), controllable surface morphology, very high surface area,
high porosity with interconnectivity, high drug-loading capacity and
entrapment efficiency, simultaneous delivery of various biologic thera-
peutics and cost-effectiveness (Deldar et al., 2018; Deldar, Zarghami,
Pilehvar-Soltanahmadi, Dadashpour, & Zarghami, 2017; Pilehvar-
Soltanahmadi, Akbarzadeh, Moazzez-Lalaklo, & Zarghami, 2016).
Pursuing the studies that utilizing electrospun nanofibers in che-
motherapeutic agent delivery, multiple and extensive explorations
concerning the investigation of efficient nanofiber-based local deliv-
ery systems through the combination of chemotherapy with thermal
therapy, gene therapy, and photodynamic therapy, have been con-
ducted in recent years. Thus, the present review has been aimed to
summarize the latest cutting-edge research regarding electrospun
nanofiber-based drug delivery systems and their drug release kinetics.
In the interim, in vitro and in vivo studies conducted applying several
anticancer agents along with the capability of electrospun nanofibers
for combinatorial/synergistic chemotherapy as well as the existing
challenges and the potential dramatic advances in applying this
pioneering approach for clinical transition in localized treatments of
cancer is also presented.
2|ELECTROSPINNING
Several methods available for constructing nanofibers are phase sepa-
ration, self-assembly, drawing, template synthesis, and electrospinning
(Luo, Stoyanov, Stride, Pelan, & Edirisinghe, 2012; Mellatyar
et al., 2018). In comparison to other processes for the fabrication of
nanofibers, electrospinning appears to be an easy, highly efficient
method, cost-effective, smart, and scalable technique to produce
polymeric nanofibers (Farajzadeh, Pilehvar-Soltanahmadi, et al., 2018).
This method can fabricate ultrafine fibers with diameters in between
micrometers and nanometers using different natural and synthetic
biomaterials that have unique characteristics such as interconnected
pore structure, high porosity, high surface area to volume ratio, excel-
lent tensile strength, and many more (Joshi et al., 2015). Also,
electrospun nanofibrous mats can be surface functionalized to tune
the chemical and physical features of the fiber surface while the fiber
structure, morphological dimension, and spatial distribution can be
controlled to attain specific mechanical properties (Son, Kim, &
Yoo, 2014).
The uniaxial stretching of a viscoelastic fluid (polymer melt and
solution) through electrostatic forces is the basis of the creation of
electrospun nanofibers. Typical electrospinning equipment briefly
consists of a syringe and capillary needle through which a polymer
solution, sol–gel, particulate melt or suspension is passed; a syringe
pump, an electrical generator (high voltage power supply) and a con-
ductive collector. Using high voltages (usually between 5 and 30 kV)
to a liquid droplet to prevail the polymer solution surface tensions
and allow the formation of an electrified fluid jet is the foundation
of the electrospinning process. Subsequently, the electrostatic repul-
sion causes a continuous elongation in the jet, which is ultimately
deposited on the conductive collector (Jiang, Carbone, Lo, &
Laurencin, 2015). The quality and characteristics of the final product
depend on several variables including concentration, viscosity, poly-
mer conductivity, flow rate, applied voltage, needle tip-collector dis-
tance, humidity and temperature in the chamber, and so forth
(Ahmed, Lalia, & Hashaikeh, 2015).
A broad spectrum of materials and their combinations such as
carbons, polymers, metals, and ceramics have been used to
electrospun into ultrafine uniform fibers. Among them, polymers, both
natural and synthetic, are most common components to supply the
backbone for nanofibrous scaffolds and have attained great interest
recently owing to its extensive applications in numerous fields includ-
ing chemistry, electronics, photonics, biosensors, tissue engineering,
cancer research, and many others (Hu et al., 2014).
Various natural and synthetic materials or a rational combination
of these polymers are being used in the provision of nanofiber-based
drug delivery systems for localized cancer therapy via electrospinning
(Chen et al., 2016).
Naturally derived polymers display excellent biodegradability, bio-
compatibility and low/nontoxicity, and some present inherent broad-
spectrum antimicrobial activity and superior medical functionality.
Natural polymer-based materials such as polysaccharides (alginate,
chitosan, cellulose, etc.), proteins (collagen, gelatin, keratin, silk fibroin,
etc.), DNA and their derivatives and composites as well as their applica-
tions in electrospun nanofiber-based drug delivery systems have been
described or reviewed in some studies (Fu et al., 2018; Hu et al., 2014).
Synthetic biodegradable polymers gained much attention recently
in the fabrication of electrospun nanofibers due to easier
electrospinning, dissolving in a wide range of solvents and relatively
less costly than natural polymer-based materials. Polymers such as
poly(vinyl alcohol) (PVA), polyethylene, poly(lactic acid) (PLA),
poly(ethylene oxide), poly(ε-caprolactone) (PCL), and copolymers, such
as poly(lactic-co-glycolic acid) (PLGA) and poly(L-lactide-co-cap-
rolactone) have been widely examined to produce nanofibers with
favorite attributes as a drug delivery system in engineering strategies
for tissue defect repair and localized cancer chemotherapy
(Hu et al., 2014; Liu et al., 2018; Saei Arezoumand, Alizadeh, Pilehvar-
Soltanahmadi, Esmaeillou, & Zarghami, 2017). In this case, the degrada-
tion rate can be regulated to a certain extent through changing limits
such as the composition of polymer blend and crystallinity degree.
3|ELECTROSPUN NANOFIBERS FOR
CHEMOTHERAPY
Currently, various chemotherapeutic agents and their combination
regimens have been identified as the most widespread and effectual
KHODADADI ET AL.1445
strategy for the treatment of many types of cancer. Side effects are
one of the main issues that occur during chemotherapy treatment,
causing lethal harm to nontumorigenic healthy cells (Chen, Boda,
Batra, Li, & Xie, 2018). Because of the mitigation of adverse reactions
and ease of access efficient doses, electrospun nanofibers have been
broadly studied as a local and sustained anticancer drug-loaded
implants to the tumor site (Wang, Zhao, Shen, & Shi, 2012). Numerous
chemotherapeutic agents such as cisplatin, doxorubicin (DOX), doce-
taxel, paclitaxel (PTX), platinum complexes, dichloroacetate (DCA),
5-fluorouracil, and curcumin have been incorporated into electrospun
nanofibrous mats applied for local chemotherapy after surgical re-
section (Norouzi, Nazari, & Miller, 2017). However, it should be noted
that up to date, all the electrospun nanofiber-mediated drug delivery
strategies for cancer therapy are still in preclinical and clinical trials.
3.1 |Loading and release kinetic of
chemotherapeutic agents from nanofibers drug/
polymer blend nanofibers
The electrospinning of a drug/polymer blend proposes a straightfor-
ward and uncomplicated approach for homogenous encapsulation of
therapeutic agents into nanofibers. However, the physicochemical
features of materials and also their interaction with therapeutic agent
molecules influence the distribution, uniformity, loading capacity, and
release kinetics of drug molecules from electrospun fibers (Norouzi
et al., 2017). Based on the principle of “like dissolves like,”hydrophilic
drugs such as DOX hydrochloride and lipophilic drugs such as PTX
can be facilely loaded in hydrophilic and lipophilic polymers, respec-
tively (Sultanova, Kaleli, Kabay, & Mutlu, 2016).
For blend electrospinning, bioactive molecules are blended with
aqueous polymer solution before electrospinning process, which cau-
ses biomolecule localization on or near the nanofiber surfaces, leading
to often a burst discharge and bioactivity reduction. With the purpose
of achieving sustained drug discharge, mixing of hydrophilic and
hydrophobic biopolymers with different ratios used in numerous stud-
ies demonstrated significantly enhancing in drug encapsulation effi-
ciency and then reducing the drug burst discharge (Zamani,
Prabhakaran, & Ramakrishna, 2013).
3.1.1 |Core–shell nanofibers
In comparison to the blend electrospinning, emulsion electrospinning
and coaxial electrospinning are relatively simple methods to present
more sustained drug discharge patterns and reduce the initial burst
release; however, these approaches still display a minor initial burst
release.
By utilizing coaxial electrospinning process, two or more ingredi-
ents are concurrently electrospun via different individual capillaries to
fabricate core–shell structured fibers (Figure 1) (Rathbone, 2013). As
expected, the presence of the shell layer might decrease the burst dis-
charge, and extend the biomolecules discharge from the core area.
Also, drugs can be encapsulated simultaneously into core–shell
nanofibrous mats with one drug in the core, and the other in the shell
area (Minden-Birkenmaier, Selders, Fetz, Gehrmann, & Bowlin, 2017).
Another privilege of the core–shell nanofibrous scaffold is that it can
temporally protect a certain unstable biological agent from aggressive
environments for example growth factors that essential to be pre-
served for a particular period of time before participating in the early
phases of tissue healing process (Fan, Yung, Huang, & Chen, 2017; Hu
et al., 2014).
Generally, controlled discharge of biomolecules loaded in the core
of coaxially electrospun nanofibers only occurs when the nanofiber
shell materials are nonhygroscopic. Once the shell area of the
nanofibers is hygroscopic through either applying hygroscopic poly-
mers or integrating hydrophilic biomolecules, multiple channels
between the nanofiber core and the outer milieu were created with
water molecules, resulting in fairly fast drug release from the core
with features similar to burst discharge in a lieu-controlled release.
This problem has limited the majority of in vivo uses of core–shell
nanofiber-mediated drug delivery systems since essentially hygro-
scopic biomaterials (collagen, gelatin, glycosaminoglycans, peptides,
etc.) are preferred to choose as the shell layer because of their
supreme biocompatibility (Aytac & Uyar, 2018; Han & Steckl, 2013).
In an effort to resolve this issue, triaxial structured electrospun
nanofibrous mats were introduced for controlled dual release of bio-
molecules in which the core area comprised of Polyvinylpyrrolidone
(PVP) and one drug, the middle layer consisted of PCL, and the shell
area comprised of a hygroscopic material and the second therapeutic
agent (Figure 2) (Han & Steckl, 2013). With the middle region as a
buffer area between the interior core and the exterior shell, an about
24-fold slower discharge relative to that from core–shell nanofibers
was attained. In the interim, an initial burst release of about 80% dura-
tion 1 hr was supplied by the hygroscopic region. The triaxial
nanofibrous mats were remarkably appealing since the middle region
was able to serve as an encapsulation layer between core and shell
areas. This permits for the encapsulating hydrophilic therapeutic
agents in the shell area without triggering a burst discharge from the
biomolecules loaded in the core area.
3.1.2 |Nanoparticles-in-nanofibers
Loading nanospheres/micelles into the core–sheath structured
electrospun nanofibrous mats can improve the micelle stability and an
extended release in comparison to micellar formulations. In a study by
Yang et al., an active-targeting micellar system was combined with
polymeric nanofibrous mats to develop an implantable localized drug
delivery device for effectual and reliable cancer therapy (Yang
et al., 2015). As shown in Figure 3, this system was attained applying
a coaxial electrospinning process with a mixture of PVA and DOX-
loaded active-targeting micelles assembled from a folate-conjugated
PCL/Poly(ethylene glycol) (PEG) copolymer as the core component
and cross-linked gelatin as the shell layer. As a result of the degrada-
tion of the electrospun nanofibrous matrix, the active-targeting
1446 KHODADADI ET AL.
micelles were sustainably discharged from the system, quickly accu-
mulated around the cancer cells through interstitial transport and
enhanced permeation and retention (EPR) effect, and specifically
internalized by cancer cells through Folate receptor-mediated
endocytosis.
3.1.3 |Multilayered 3D electrospun nanofibers
To effectively meet the requirements of clinical application, the multi-
layered 3D electrospun nanofibers-based drug delivery devices, which
applies a high level of regulation during drug discharge kinetics have
been devolved in recent years. The nanofibrous layer without inte-
grating biomolecules supply a physical obstacle to block water diffu-
sion and therefore, postpone drug discharge from the other drugs-
loaded nanofibrous layers.
According to this approach, Grinstaff and colleagues designed a
trilayered superhydrophobic electrospun mesh composed of PCL and
poly(glycerol monostearate-co-ε-caprolactone) (PGC-C18) incorpo-
rated with a chemotherapeutic agent, 7-ethyl-10-hydroxy-camp-
tothecin (SN-38), in the core layer, between two protective layers of
the mat without drugs (Figure 4) (Falde et al., 2015). This bulky mat
has a wetting-resistant surface owing to the noticeable hydrophobic
nature arising from PGC-C18 polymer. These mats displayed slow
initial drug discharge during 10 days in parallel to the infiltration of
media from the protective layers, pursued by markedly delayed and
prolonged drug discharge upon 30 days with wetting of SN-
38-incorporated core layer. The in vitro cytotoxicity findings of the
implantable drug-loaded trilayered system against Lewis Lung Carci-
noma (LLC) cells over 20 days were consistent with the release profile,
longer than the unlayered version.
To obtain a drug delivery system that allows time-programmed
dual-drug sustained discharge in a single formula, asymmetric multi-
layered drug-encapsulated poly(L-lactide-co-ε-caprolactone) (PLCL)
nanofibrous meshes were designed using consecutive electrospinning
in four layers: first drug-encapsulated mat (top), shield mat, second
drug-encapsulated mat, and basement mat (bottom) (Figure 5) (Okuda
et al., 2010). The nondrug-encapsulated PLCL mat with appropriate
morphological features and thickness act as a barrier mat. Therefore,
retarded drug release—controlled timed release—was attained. The
time-programmed dual-drug sustained release via the tetra-layered
electrospun nanofibrous mats was confirmed as a convenient strategy
for innovative multidrug combinatorial chemotherapy requiring
regiospecific administration of various drugs at different times. Never-
theless, some concerns remain vague with the abovementioned multi-
layered nanofibrous stacks. These meshes are mostly manually
stacked, therefore, present impediments in the scale-up fabricating
process. Furthermore, the stacked mats principally act as a physical
FIGURE 1 Schematic diagram of a
coaxial electrospinning process.
Reproduced with permission, Bentham
Science (Farajzadeh, Pilehvar-
Soltanahmadi, et al., 2018)
FIGURE 2 A schematic illustration
of triaxial electrospun nanofiber
membranes in which the core area
comprised of PVP and one drug, the
middle layer included poly
(ε-caprolactone), and the shell area
comprised of a hygroscopic material
and the second therapeutic agent.
Reproduced with permission,
American Chemical Society (Han &
Steckl, 2013)
KHODADADI ET AL.1447
FIGURE 3 The implantable
doxorubicin loaded micelle-in-
nanofiber platform synthesized by
coaxial electrospinning. Reproduced
with permission, American Chemical
Society (Yang et al., 2015)
FIGURE 4 A trilayered superhydrophobic electrospun meshes composed of poly(ε-caprolactone) and poly(glycerol monostearate-co-
ε-caprolactone) (PGC-C18) incorporated with an anticancer agent, SN-38, in core layer, between two protective layers of mat without drugs.
These meshes exhibit slow initial drug discharge during 10 days in parallel to the infiltration of media from the protective layers, pursued by
markedly delayed and prolonged drug discharge upon 30 days with wetting of SN-38-incorporated core layer. Reproduced with permission,
Elsevier (Falde et al., 2015)
1448 KHODADADI ET AL.
barrier for the bottom or top surfaces but not for the side surfaces,
which might cause issues for the accurate control of drug discharge.
3.1.4 |Superhydrophobic materials based
electrospun nanofibers
The chemistry of the nanofibers, which is the decisive element in fiber
wettability and degradability, has a prevailing function in control of
drug release. Adding hydrophilic and hydrophobic materials to
electrospun nanofibers considerably influence on fiber wettability,
leading to regulating the drug discharge from the fibers. Grinstaff and
colleagues constructed a 3D superhydrophobic material composed of
PCL electrospun fibers containing PGC-C18 as a hydrophobic doping
agent loaded with SN-38, in this platform, entrapped air serves as a
hindrance component in a porous nanofibrous mat to regulate the
rate at which SN-38 is discharged (Yohe, Colson, & Grinstaff, 2012).
The obtained fibers had a large surface area to volume ratio and obvi-
ous contact angles as high as 153. It was found that the high obvious
contact angle limits penetration of water and decelerates the replace-
ment of air from the high porous fibers, so reducing drug discharge
into the aqueous solution. The discharge rates of SN-38 are extremely
different in relative to those of the melted, degassed electrospun con-
trols and also the nonporous analogues. The melted and electrospun
PCL fibers displayed identical discharge profiles, while the 10% PGC-
C18-doped electrospun fibers compared with their melt controls
showed meaningfully slower drug release. The melted 10% PGC-
C18-doped PCL fibers stopped discharging the drug before 28 days,
while the electrospun fibers persisted to discharge drug out to
70 days. Due to the more porous and higher surface area, 10% PGC-
C18-doped PCL fiber released the drug more slowly. The 30 and 50%
PGC-C18-doped mats displayed alone 10% SN-38 discharge in
more than 9 weeks. The drug-encapsulated 10% PGC-C18-doped
PCL fiber had cytotoxicity to LLC cells in the presence of serum and
acted for a prolonged time period. It was inferred that such a drug
release platform would be of medical interest, for instance, in the pre-
vention of cancer local recurrence and pain management.
In their follow-up study, cisplatin was encapsulated in electrospun
fibers composed of PCL and 30% PGC-C18, and a prolonged dis-
charge in a linear mode over about 90 days was attained (Kaplan
et al., 2016). Remarkably, in comparison to >95% of cisplatin dis-
charge from neat PCL fiber in 24 hr, less than 1% of cisplatin release
was documented within the same period of time. The in vivo assess-
ment of the drug-encapsulated superhydrophobic fibers in a LLC sur-
gical resection mouse indicated a remarkable upsurge (p= 0.0006) in
median recurrence-free survival to >23 days, in relative to standard
intraperitoneal cisplatin treatment of equal dose.
3.1.5 |Stimuli-responsive (smart) nanofibers
The abovementioned devices commonly propose prolonged drug dis-
charge, but with restricted control over the discharge rate, mainly
through passive diffusion of therapeutic agents from the electrospun
nanofibrous mats. Interestingly, the use of smart materials, called also
intelligent or responsive materials allows the on-demand release of
loaded biomolecules since the chemical or physical features of poly-
mer considerably changed in response to the variability in the milieu,
resulting in microstructure alteration and drug discharge (Han, Yu,
Chai, Ayres, & Steckl, 2017).
The stimuli were divided into endogenous and endogenous stim-
uli. Endogenous stimuli are the inherent circumstances of the cancer
cells, for instance, an acidic circumstance, a tough redox circumstance,
and specified enzymes. The exogenous stimuli may be alteration in
temperature, light, electric fields, and ultrasound (Mura, Nicolas, &
Couvreur, 2013). Thermo-responsive nanocarriers are the most inves-
tigated stimulus-triggered delivery approach in cancer treatment. The
system is considered to ideally preserve the therapeutic agents at
37C (body temperature), and quickly release the drug molecules
under 40–42C (hyperthermic circumstances). The temperature varia-
tion can be perceived through heat treatment directly using light on
gold nanoparticles based approaches, and or using magnetic field
hyperthermia (Cheng, Gu, Ren, & Liu, 2014).
Temperature-responsive drug-loaded electrospun nanofibers
have earned their place among “smart”electrospun fibers for
programmed and controlled drug discharge rate. Li and colleagues
designed a nanogel-in-microfiber device with on/off switchable drug
release in conditions of temperature variation through coaxial
electrospinning (Li et al., 2015). As illustrated in Figure 6, the internal
core area consists of polyethylene oxide encapsulated with a drug
model, Methyl orange, and the external shell layer composed of a mix-
ture of PCL and temperature stimuli-responsive nanogels (NGs).
Thermo-responsive PNIPAAm-co-acrylic acid copolymer was used to
fabricate the NGs. In conditions of environmental temperature
FIGURE 5 Graphical schematic of overview (a) and cross-
sectional view (b) of tetra-layered nanofibrous mats applied. Tetra-
layered nanofibrous mats composed of (i) first drug-encapsulated mat
(top), (ii) shield mat, (iii) second drug-encapsulated mat, and
(iv) basement mat (bottom). Reproduced with permission, Elsevier
(Okuda, Tominaga, & Kidoaki, 2010)
KHODADADI ET AL.1449
changes, these NGs inserted in PCL matrix shrink and swell, leading to
the nanochannels formation between the PCL and NGs, and therefore
a change in shell penetrability. The NGs inserted the outer shell area
could serve as a valve for controlling the release of the loaded drugs,
presenting the nanogel-in-microfiber system with a trustworthy tem-
perature responsivity. Also, according to the in vitro cytotoxicity
assessment, it was verified that the rate of drug discharged in the
opened mode of the device is much greater relative to that in the
closed mode, allowing a substantial reducing influence to the prolifer-
ation of cancer cells.
Aoyagi and coworkers described a smart hyperthermia on/off
switchable electrospun fiber with concurrent heat generation and
drug release via alternating magnetic field (AMF) to induce apoptosis
in skin cancer cells (Kim, Ebara, & Aoyagi, 2013). The temperature-
responsive copolymer of N-hydroxymethylacrylamide (HMAAm) and
N-isopropylacrylamide (NIPAAm) was used to load DOX, as a chemo-
therapeutic agent and magnetic nanoparticles (MNPs), as the heat
resource through electrospinning. With 5 min exposure to AMF, The
DOX/MNPs nanofibrous mats caused 70% apoptosis in human mela-
noma cells because of a synergistic effect of hyperthermia and
chemotherapy.
The slight acidic microenvironment of the cancer tissues because
of a higher metabolic rate and the over-production of lactide is the
basis of designing pH-responsive drug delivery devices.
Xie and coworkers designed a pH-responsive drug-releasing sys-
tem using polydopamine-coated PCL electrospun nanofibers in which
a mussel inspired protein polydopamine coating could tune the encap-
sulating and liberating percentage of charged biomolecules from poly-
meric nanofibrous mats in solutions with different pH values (Jiang
et al., 2014). It was found that the positive charged anticancer agents
(such as DOX) discharge from the composite fibers were considerably
faster in acidic environments compared to those in basic and neutral
conditions, leading to a remarkable decrease in viability of H1299
cell line.
In another study, Zhang et al. established an implantable prodrug
micelle/small drug coencapsulated electrospun fiber for dual drug
release (Zhang et al., 2017). Via copper-free click polymerization of
PEG2k units and Pt(IV) prodrug, the amphiphilic Pt(IV) prodrug-
backbone copolymer, (PEG2kPt(IV))n, was fabricated. Then, the self-
assembled Pt(IV) micelle was incorporated into biocompatible PVA
nanofibers with DCA through coelectrospinning. After in vivo
implantation, fast discharge of DCA and Pt(IV) micelle could be
attained at the tumor site by gradually dissolving of PVA fibers. The
liberated DCA diffused into cells quickly and leading to apoptosis in
cancer cells via pyruvate dehydrogenase kinase inhibition. In the
meantime, the accumulated Pt(IV) micelles around cancer cells were
internalized into cancer cells via EPR effect and endocytosis and
reduced into bioactive Pt(II) to exhibit their anticancer activities.
Because of the less intracellular and extracellular pH and also higher
levels of reducing substances, Pt(IV) could be reduced into the bioac-
tive Pt(II) and break the micelle, therefore reducing the Pt accumula-
tion in normal tissues.
An electric field can initiate redox reactions as well as the ionization
process that can result in swelling, bending, or shrinking of the poly-
meric drug-delivery vehicles, permitting controlled drug discharge. Yun
and colleagues designed a drug-loaded electro-responsive fiber through
electrospinning of PVA/Polyacrylic acid/multiwalled carbon nanotubes
(MWCNTs) (Yun, Im, Lee, & Kim, 2011). It was found that the swelling
ratio of the fibers enhanced at the high voltage owing to induced elec-
trostatic repulsion through the ionization of the carboxylate groups in
the polymer under the used voltages, which then leads to the swelling
of electrospun nanofibers. Therefore, faster drug discharge was
FIGURE 6 Schematic illustration of the fabrication of a nanogel-in-microfiber device with on/off switchable drug release in conditions of
temperature variation through coaxial electrospinning. Reproduced with permission, John Wiley and Sons (Li et al., 2015)
1450 KHODADADI ET AL.
detected from the electrospun mat by the enhancing of used electric
voltage.
Ultrasonically triggered drug release devices have been received
particular attention due to its noninvasive or slightly invasive perfor-
mance. Having triggered drug release, ultrasound-based drug delivery
systems increase penetration of drugs into tumor volume with mini-
mum tissue thermal damage.
Grinstaff and colleagues developed a 3D superhydrophobic
nanofibrous mat through electrospinning of PGC-C18 (30 wt%) and
PCL, in which air was trapped both within the 3D structure and at the
surface (Yohe, Kopechek, Porter, Colson, & Grinstaff, 2013). It was
found that the release of SN-38 from superhydrophobic fibers could
be triggered by sound wave diffusion via the medium to the fiber
through the use of enough acoustic pressure utilizing high-intensity
focused ultrasound.
The smart drug release devices suggest a promising prospect for
precision cancer treatment with preventing normal tissue damage,
resulting from the regulating drug discharge at defined sites and times.
Nevertheless, though the proof of concept has been victoriously verified
in vitro, limited in vivo investigations have been conducted. The intricacy
of system design and slight penetration depth of the externally used
stimuli are amongst the great limitations that should be considered.
3.1.6 |Surface-modified nanofibers
Nanofiber surface modification is another approach to incorporate
the drug to the nanofibers that would aid to regulate the release rate
at the targeted site and allow the functionality of the immobilized
anticancer drugs to be conserved. This can aid to resolve the issue of
short term release and also initial burst discharge.
Jiang et al. showed that a mussel inspired protein polydopamine
coating can modulate the encapsulating and liberating rate of charged
biomolecules from electrospun PCL fibers at various pHs (Figure 7)
(Jiang et al., 2014). Coating polydopamine on the PCL nanofibers
occurs in two steps. First, oxidation and rearrangement of dopamine
take place at pH 8.5 which leads to form 5,6-dihydroxyindole, the
monomer for polymerization in the subsequent stage. Then, cycliza-
tion of NH
2
group occurs and −OH groups remain after this reaction.
Compounds comprising −OH groups can liberate +H. Therefore, the
polydopamine modified PCL fibers released +H ions and produce neg-
ative charges on the surfaces in basic and neutral circumferences.
Likewise, −OH groups were protonated, and the charges at the sur-
faces of fibers were changed to neutral in acid. Thus, the loading effi-
ciency of positive charged DOX HCl and rhodamine 6G HCl was
increased with enhanced pHs. The discharge kinetic was contrary to
the loading manner, in which, the biomolecules were liberated further
fast in an acidic milieu in relative to those at the high pHs. The MTT
assay demonstrated that cancer cell death has been induced by the
DOX liberated at low pHs which indicated pH-responsive release.
Liu et al. developed a functionalized fibrous drug release system
with near-infrared (NIR)-initiated and optics-monitored drug dis-
charging based on Calcium titanate (CaTiO3) nanomaterials for person-
alized tumor chemotherapy (Liu et al., 2016). In this work, Yb, Er
codoped CaTiO
3
(CTO:Er,Yb) fibers functionalized with poly(acrylic
acid) was successfully synthesized via electrospinning. Owing to
poly(acrylic acid) surface modification and the electrostatic interaction
between DOX and poly(acrylic acid), the loading capacity of DOX was
noticeably augmented from about 9 to 54%. Moreover, DOX displayed
a pH-dependent discharge pattern because of the carboxyl groups of
poly(acrylic acid) undergo protonation with the reduced pH, and the
amount of DOX liberated was optically checked by upconversion
photoluminescence spectra under 980 nm NIR excitation due to the
fluorescence resonance energy transfer effect between the fibers and
DOX molecules. Furthermore, under 808 nm NIR irradiation, CTO:Yb,-
Er nanofibers exhibited a remarkably augmented DOX discharging
FIGURE 7 (a) SEM image displaying polydopamine tubes. (b) TEM image presenting the same sample as in (a). The tubes were achieved by
soaking the poly(ε-caprolactone)–polydopamine core–sheath nanofibers in Dichloromethane to selectively eliminate the cores. Reproduced with
permission, Elsevier (Jiang et al., 2014)
KHODADADI ET AL.1451
because of the weak temperature increase and consequent vibration of
poly(acrylic acid) chains and subsequently enhanced in vitro anticancer
efficacy. Though complete in vivo works and clinical trials remain
ahead, such surface-functionalized nanofibers might inspire a promising
implantable localized drug delivery device with smart functionalities
such as optics-monitored and NIR-triggered drug releasing for person-
alized cancer chemotherapy.
3.2 |Multidrug-loaded electrospun nanofibers
In the tumor-treating field, the use of a single drug delivery system is
uncommon because of the drug toxicity at higher doses, the heteroge-
neity of cancer cells, and the development of chemoresistance after
prolonged chemotherapy. Nanofiber-based multidrug delivery
approach is a promising approach to rise the therapeutic
TABLE 1 Local chemotherapy through multidrug-loaded electrospun nanofibers
Polymer Drugs Method Type of cancer (in vitro)
Type of cancer
(in vivo) References
PLA Sodium DCA and
diisopropylamine
dichloroacetate (DADA)
Blend electrospinning C26 colon carcinoma cells Colorectal cancer Liu, Wang, Yue,
Jing, and
Huang (2015)
PLA 5-Fluorouracil and oxaliplatin Blend electrospinning HCT-8 human colorectal cancer
cells and C26 colon carcinoma
cells
Colon cancer Zhang, Wang, Liu,
Liu, and
Jing (2016)
PCL Curcumin-aloe vera,
curcumin-neem extract
Blend electrospinning MCF-7 human breast cancer
cells and human lung
adenocarcinoma A549 cells
–Sridhar et al. (2014)
PEG–PLA PTX and DOX hydrochloride Emulsion
electrospinning
Murine glioma C6 cells –Xu, Chen, Wang,
and Jing (2009)
PLA Cyclophosphamide and
oxaliplatin
Blend electrospinning Human hepatocellular cancer
HCC cells
Subcutaneous and
orthotopic HCC
Liu et al. (2015)
PVA DCA and Pt(IV)
prodrug-backboned micelle
Blend electrospinning HeLa human cervical cancer cells Cervical cancer Zhang et al. (2017)
PLGA Hydroxycamptothecin @
hydroxyapatite nanoparticles
(CPT @HANPs) and DOX@
mesoporous silica
nanoparticles (DOX@MSNs)
Blend electrospinning HeLa human cervical cancer cells –Chen et al. (2014)
PLGA/GE Camptothecin and DOX-loaded
mesoporous ZnO
(DOX@mZnO)
Blend electrospinning Human liver carcinoma HepG2
cells
–Wei, Hu, Li, Chen,
and Chen (2014)
PVA DOX and curcumin loaded
mPEG-PCL micelles
Blend electrospinning Human cervical cancer HeLa
cells
–Yang, Wang, Li,
Ding, and
Zhou (2014)
PLLA DOX and DOX-loaded
mesoporous silica
(MSN/DOX)
Blend electrospinning Triple negative human breast
cancer cell line MDA-MB-231
Residual breast
cancer model
Yuan et al. (2016)
PLLA IBU and DOX/SB loaded MSNs Blend electrospinning Human hepatocellular carcinoma
cell line (HuH-7)
–Yuan et al. (2015)
PEO-PCL Niclosamide and AgNPs Blend electrospinning Human lung adenocarcinoma
A549 cells and MCF-7 human
breast cancer cells
–Dubey and
Gopinath (2016)
PCL/GE Dox-loaded NaGdF
4
:Yb/
Er@NaGdF
4
:Yb@mSiO
2
-
polyethylene glycol (UCNPS)
nanoparticles and
indomethacin
Blend electrospinning –Hepatoma H22
tumor
Chen et al. (2015)
PLA/PEO Cisplatin and curcumin Blend electrospinning Human cervical cancer HeLa
cells
Cervical carcinoma Ma et al. (2015)
PPC PTX-loaded ca-alginate
microparticles and TMZ
Emulsion
electrospinning
Murine glioma C6 cells –Ni, Fan, Wang, Qi,
and Li (2014)
Abbreviations: DCA, dichloroacetate; DOX, doxorubicin; IBU, Ibuprofen; PCL, poly(ε-caprolactone); PEO, Poly(ethylene oxide); PLA, poly(lactic acid); PLGA,
poly(lactic-co-glycolic acid); PPC, Poly(propylene carbonate); PTX, paclitaxel; PVA, poly(vinyl alcohol); SB, sodium bicarbonate; TMZ, temozolomide.
1452 KHODADADI ET AL.
effectiveness, minimize the drug doses and reduce the side effects, as
a result of a synergistic activity excreted by various therapeutic mole-
cules (Rasouli et al., 2020). Some reports on local chemotherapy
through multidrug-loaded electrospun nanofibers are summarized in
Table 1.
In a work by Grinstaff and colleagues, chemotherapeutic agents,
Hydroxycamptothecin (CPT)-11 and SN-38, were encapsulated into
electrospun PCL doped with 10% PGC-C18 and confirmed their
favorable mechanical properties for surgical buttressing of the anasto-
mosis (Yohe, Herrera, Colson, & Grinstaff, 2012). Besides, a sustained
discharge over 90 days of SN-38 and CPT-11 was attained, leading to
substantial and long-term toxicity on human colon carcinoma cells
(HT-29). In another study, ultrafine PLA–PEG fibers incorporated with
both hydrophilic and hydrophobic anticancer agents (DOX and PTX)
were successfully electrospun from W/O emulsions, in which the oily
phase included a chloroform solution containing PTX and PLA–PEG
and the aqueous phase was DOX (Xu et al., 2009). Because of its high
hydrophilicity of the fiber, DOX was easily diffused, and the rate of its
discharge was faster in relative to that of hydrophobic PTX. Further-
more, the PTX discharge rate was facilitated through the discharge of
DOX. It was found that the dual drug-loaded electrospun nanofibers
displayed a greater growth inhibition and apoptosis induction on rat
Glioma C6 cells compared to a single drug-loaded nanofiber, which
proposes the promising potential of electrospun nanofiber-based
multidrug delivery systems for combinatorial chemotherapy.
In addition to multidrug delivery through the use of emulsion and
coaxial electrospinning approaches, sequential delivery of two or mul-
tiple drugs also were capable to elicit a pronounced antitumor effi-
cacy. For a notable example, a bilayered electrospun PLGA
nanofibrous membrane loaded with chemotherapeutic and anti-
angiogenic agents displayed a sequential drug-eluting manner with
the high drug discharge rate of chemotherapeutic irinotecan, car-
mustine, and cisplatin from the third day, pursued by the of high con-
centration release of the antiangiogenic combretastatin from day
21 (Tseng et al., 2017). Also, the in vivo drug discharge profiles of the
mats revealed discharging high concentrations of drugs over 8 weeks
in the rat cerebral parenchyma, suggesting a high antitumor efficiency
of the biodegradable multiagent nanofibrous membranes against glio-
blastoma multiforme.
Due to the some limitations in core–shell and core-sheath struc-
tured nanofibers for multidrug delivery, such as considerable optimi-
zation of the electrospinning circumstances in coaxial electrospinning
and difficulty to eliminate the emulsifier used in emulsion
electrospinning which might introduce biocompatibility issues
(Qi et al., 2010), nano- and microscale carriers such as halloysite nano-
tube, hydroxyapatite, mesoporous nanoparticles, and polymeric
nanoparticles have been used to load into electrospun fibers for local
multidrug therapy (Qi et al., 2010; Wei et al., 2014). For instance, Wei
et al. mixed DOX-encapsulated mesoporous ZnO (DOX@mZnO) with
CPT and PLGA/gelatin solution to construct an electrospun composite
nanofibrous scaffold which exhibited robust cell growth inhibition
against HepG-2 cells (Wei et al., 2014).
3.3 |Multifunctional electrospun nanofibers for
anticancer drug delivery
The striking structural features of electrospun nanofibers accelerate
developing multifunctional localized drug delivery systems for cancer
treatment.
Hou and colleagues fabricated a multifunctional (porous structure
and upconversion luminescence properties) NaYF
4
:Yb
3+
,Er
3+
decorated
SiO
2
composite nanofibers as chemotherapeutic agent carriers via the
electrospinning (Hou et al., 2012). The prepared NaYF
4
:Yb
3+
,Er
3+
@SiO
2
composite nanofibers showed the attracting features of specified
nanofiber-like porous morphology, high biocompatibility, and
upconversion emission, that were appropriate for DOX storage/release.
It was revealed that the DOX release from NaYF
4
:Yb
3+
,Er
3+
@SiO
2
had
a pH-sensitive liberation profile. DOX released from porous NaYF
4
:Yb
3+
,
Er
3+
@SiO
2
carriers was internalized inside Hela cells through endocyto-
sis, and exhibited similar cytotoxicity with free DOX. Furthermore,
upconversion luminescent microscopy images of NaYF
4
:Yb
3+
,Er
3+
@SiO
2
uptake by cells displays bright NIR up-conversion emission, making the
NaYF
4
:Yb
3+
,Er
3+
@SiO
2
as a multifunctional vehicle for concurrently bio-
imaging and treating cancer.
A similar study was also reported that a dual-drug delivery system
using multifunctional electrospun composite meshes kills hepatoma cells
(Fu et al., 2018). DOX-encapsulated NaGdF
4
:Yb/Er@NaGdF
4
:Yb@mSiO
2
-
PEG nanoparticles with a core–shell structure and up-conversion lumines-
cent properties were integrated into indomethacin-encapsulated
PCL/gelatin nanofibers via electrospinning. This dual drug-loaded compos-
ite nanofibrous mat surgically was implanted at the tumor area, exhibited
controlled discharge of DOX from mesoporous SiO
2
and enhanced tumor
inhibition. Furthermore, upconversion fluorescence/magnetic resonance
dual-model imaging through NaGdF
4
:Yb/Er@NaGdF
4
:Yb incorporated into
the nanocomposite fibers exhibited effective monitoring of the
nanoparticles diffusion inside the tumor and in vivo drug release.
4|ELECTROSPUN NANOFIBERS FOR
COMBINATORIAL/SYNERGISTIC CANCER
CHEMOTHERAPY
Recent remarkable advances in treatment of cancer have progres-
sively moved from monotherapy to a focus on combination therapy,
in which two or more various treatment modalities are capable to be
integrated into a single nanoplatform to produce superadditive thera-
peutic effects via cooperative enhancement interactions that are
much stronger in relative to the theoretical combination of the
corresponding individual treatments (Mokhtari et al., 2017).
Compared with potential side effects and confined treatment
effectiveness of monotherapy, combinatorial therapy in combating can-
cer through the progress of multifunctional nanofiber-based delivery
systems can harbor the plural qualities of relevant individual treatments
and cause greater antitumor effectiveness at a lower dose of drugs,
therefore avoiding unwanted side effects resulting from high doses.
KHODADADI ET AL.1453
4.1 |Combination of thermal therapy and
chemotherapy
Hyperthermia is a special type of medical modality for targeted cancer
therapy through a selective tumor response under an artificially
induced heat, usually in the area of 42–45C for about 30 min. Cancer
cells are more thermo-sensitive compared to their healthy counter-
parts. Hyperthermia is able to trigger irreversible cancer cell destruc-
tion through denaturing proteins and loosening cancer cell membrane,
whereas the damage to normal cells is reversible (Chatterjee,
Diagaradjane, & Krishnan, 2011). Therefore, the combination of ther-
mal therapy with chemotherapy might be capable of enhancing the
cancer cell inactivation. It was found that high temperature alters the
capillary blood flow and speed up drug discharge, therefore altering
the distribution and deeper penetration of drug in cancer tissue. Also,
hyperthermia debilitates the cancer cell stability, upsurges the cell
membrane permeability, and consequently accelerates drug cellular
uptake. In the interim, the high temperature induces dysfunctions in
the cell membrane, hypoxia, and anaerobic glycolysis, thus, decreasing
the pH value and increasing drug activity in an acidic milieu (Liu
et al., 2015).
Photo-hyperthermia and magnetic-hyperthermia are the most
common clinical protocols used as coadjuvant therapy for cancer
therapy. NIR light is mostly used in photo-hyperthermia technology
owing to its relatively deep tissue penetration, safety, non-
invasiveness, simplicity, remote-controllable and oxygen indepen-
dence properties (Cheng, Wang, Feng, Yang, & Liu, 2014). Lately,
NIR photothermal factors such as metal sulfides, carbon nanotubes,
quantum dots, and gold (Au) nanorods, have been used in combina-
tion with nanofiber-based chemotherapy and lead to increased effi-
cacy of treatment.
In the related studies, Zhang and coworkers integrated MWCNT,
as an effective photothermal agent, and DOX into electrospun Poly-L-
lactic acid (PLLA) nanofibers to combine photo-hyperthermia and che-
motherapy (Zhang et al., 2015). It was confirmed that NIR illumination
control displayed a typical switch on/off effect on the drug discharge
manners and the 808 nm NIR irradiation could not only trigger DOX
burst discharge from the nanofibers because of the comparatively low
glass transition temperature of PLLA, but also considerably enhanced
the temperature of nanofibers-covering tumor site, resulting in
increased in vitro and in vivo cytotoxicity through the combination of
MWCNTs prompted hyperthermia and chemotherapy with DOX.
Similarly, Chen et al. developed a multifunctional electrospun
PCL/gelatin nanofibrous mat incorporated with DOX loaded core–
shell structured Cu9S5@mSiO
2
nanoparticles for surgically implanta-
tion into the tumor site to realize the synergistic chemo- and
photothermal tumor therapy (Chen et al., 2015). The in vivo results
revealed that the DOX encapsulated Cu9S5@mSiO
2
composite
nanofibers has significantly enhanced tumor inhibition effect under
980 nm laser irradiation, compared with either photothermal or che-
motherapy treatment.
Magnetic thermal therapy, which applies iron oxide nanoparticles
(IONPs) as a heating source under an AMF, has recently gained
substantial interest. Similar to photothermal agents, IONPs in combi-
nation with nanofiber-based drug delivery systems induce regional
thermal therapy to boost drug discharge and increase intracellular
drug concentration for better effectiveness of chemotherapy, leading
to synergistic magnetic-hyperthermia/chemotherapy.
GhavamiNejad et al. fabricated an smart nanofiber via
electrospinning of a mussel-inspired copolymer, poly(methyl
methacrylate-codopamine methacrylamide) p(MMA-co-DMA) capable
of binding IONPs and the anticancer agent Bortezomib for the possi-
ble using hyperthermic chemotherapy (Figure 8) (GhavamiNejad
et al., 2015). The catechol moieties of surface-functionalized fibers
were utilized for binding and liberating Bortezomib in a pH-dependent
behavior and IONPs for repetitive treatments of hyperthermia. It was
found that the mussel-inspired magnetic fibers showed an effective
heating capability upon the use of an AMF, and a long-lasting cyclic
heating performance under the presence of the AMF. in vitro research
showed that the drug-bound catecholic magnetic fibers presented an
outstanding synergistic therapeutic efficiency for the treatment of
cancer. In a follow-on work from this team, IONPs were incorporated
into PLGA electrospun nanofibers functionalized with dopamine for
conjugating and liberating of Bortezomib via a catechol metal binding
in a pH-sensitive behavior (Sasikala, Unnithan, Yun, Park, &
Kim, 2016). The Bortezomib-encapsulated mussel-inspired magnetic
nanofibrous scaffolds displayed a synergistic therapeutic efficiency
because of the simultaneous use of hyperthermia and controlled drug
release.
Kim et al. loaded DOX and MNPs into the poly(NIPAAm-
coHMAAm) copolymer using electrospinning (Kim et al., 2013). In high
temperatures, the methylol group in HMAAm is crosslinked through
self-condensation. A mixture of Fe
3
O
4
(magnetite) and γ-Fe
2
O
3
(maghemite) MNPs were used since Fe
3
O
4
has instability alone in
extensive acid/base solvents, a spectrum of temperature and oxida-
tion. The chemically crosslinked MNP/DOX incorporated nanofibrous
scaffolds displayed the switchable and reversible alterations in the
swelling ratio in response to interchanging “on”and “off”switches of
AMF and, the resulting “on–off”DOX discharge from the nanofibers
was detected. By synergistic combined effects of hyperthermia and
chemotherapy in the presence of the DOX and MNPs loaded fibers,
about 70% of melanoma cells death was detected under only 5 min of
AMF application.
4.2 |Combination of gene therapy and
chemotherapy
Gene therapy due to target oncogenic pathways at a molecular level
has great potential for application in the safe and effective treatment
of cancer. Gene therapy comprises the therapeutic delivery of plasmid
DNA to substitute supplement or mutated downregulated genes,
and/or nucleic acid fragments like hairpin RNAs, microRNAs, or
siRNAs to hinder any target gene expression (Teo, Cheng, Hedrick, &
Yang, 2016). Because of the presence of different biological molecules
in the blood circulation such as nucleases, the degradation of naked
1454 KHODADADI ET AL.
nucleic acids occurs. While the distance between delivered therapeu-
tic genes and tumor cells has been decreased by the ECM like the
structure of nanofibers, it is capable to retain a high number of thera-
peutic genes at the tumor site, guaranteeing particular gene activity
and lower systemic toxicity. Recently, the strategy combining the
gene delivery technologies and chemotherapy with electrospun
nanofibers have been considered as a highly versatile approach for
the increased treatment of cancer.
Lei et al. developed a dual-encapsulated nanofibrous scaffold
loaded with PTX and RNAi plasmids capable to efficiently and specifi-
cally suppressing the endogenous Matrix metalloproteinase (MMP)-2
gene expression engaged in regulating brain tumor invasion and
angiogenesis complexed with polyethylenimine (PEI) (Lei, Cui, Zheng,
Chow, & Wang, 2013). Both PEI/DNA nanoparticles and PEI/DNA
nanoparticles embedded in fibers exhibited inhibitory effects on the
expression levels of MMP-2, subsequently, tumor angiogenesis and
invasion. It was demonstrated that the gene/drug dual delivery fibers
revealed an improved synergistic therapeutic efficacy relative to
applying a single drug delivery system.
Sukumar and Packirisamy designed a core–shell nanofibers in
which presynthesized suicide gene-bPEI polyplexes were encapsulated
in the fiber shell believing that they are mainly released during the ini-
tial incubation stage, and transfected into the A549 human lung cancer
cells in the vicinity, afterward sustained discharge of prodrug
(5-fluorocytosine) encapsulated in the fiber core (Sukumar &
Packirisamy, 2015). Through a cascade effect commencing from suicide
gene-bPEI polyplexes liberation from the shell part of the nanofibrous
scaffold, transfection, and the expression of suicide gene (cytosine
deaminase-uracil phosphoribosyl transferase in the cells; following
5-fluorocytosine discharge from the core part of the scaffold; cellular
uptake and its metabolic alteration into toxic intermediates drastically
enhanced the anticancer efficacy in a time-dependent manner.
In another study, nanoparticles fabricated of disulfide crosslinked
branched PEI (ssPEI) and miRNA-145, as an anticancer therapeutic
gene, were coated onto the PTX encapsulated PCL (PTX/PCL)
nanofibers and exhibited a time-dependent and sustained release of
PTX and miR-145, enhancing uptake in neighboring cells (Che
et al., 2015). A synergistic antiproliferative effect on the hepatocellu-
lar carcinoma cells was detected through this nanofiber-mediated
codelivery of gene and drug.
5|CONCLUSION AND FUTURE
DIRECTIONS
In recent decades, electrospun nanofibrous scaffolds have received
much attraction for application as effectual and implantable
multifunctional drug delivery platforms for localized and postsurgical
cancer therapy. Nevertheless, some challenges remain to be
addressed for fully implementation in industrial production and medi-
cal application. Relative toxicity of solvents used in electrospinning of
polymeric nanofibers, poor mechanical strength and flexibility of
ceramic nanofibers, lack of compatibility among matrix materials, ther-
apeutic agents and optimized drug release, and depth in vivo studies
are the common challenges to be tackled before this approach is
entered into medical purposes.
FIGURE 8 FE-SEM images of
electrospun (a) Poly(methyl methacrylate-
codopamine methacrylamide) (MADO)
nanofibers, (b) MADO–Fe
3
O
4
nanofibers,
(c) MADO–Fe
3
O
4
–Bortezomib (BTZ)
nanofibers, and (d) TEM image of MADO–
Fe
3
O
4
–BTZ nanofibers. Reproduced with
permission, John Wiley and Sons
(GhavamiNejad et al., 2015)
KHODADADI ET AL.1455
To meet future clinical demands, the development of biodegrad-
able nanofibers, which can be degraded progressively in the body
after running its therapeutic roles to avoid repeated resection to
remove them is essential. Also, the applications of electrospun
nanofibrous scaffolds require to be expanded to emerging alternatives
like immunotherapy. Furthermore, the administration of radio-
sensitizing drugs and phytochemicals with potent and safe anticancer
properties through nanofiber-based drug delivery systems can
improve the anticancer therapeutic effectiveness.
ACKNOWLEDGMENTS
The authors would like to thank the “Cellular and Molecular Medicine
Institute, Urmia University of Medical Sciences”for their kind
cooperation.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
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How to cite this article: Khodadadi M, Alijani S, Montazeri M,
Esmaeilizadeh N, Sadeghi-Soureh S, Pilehvar-Soltanahmadi Y.
Recent advances in electrospun nanofiber-mediated drug
delivery strategies for localized cancer chemotherapy.
J Biomed Mater Res. 2020;108:1444–1458. https://doi.org/10.
1002/jbm.a.36912
1458 KHODADADI ET AL.
