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CHAPTER 1
Smart drug delivery nanostructured
systems for cancer therapy
A.M.U.B. Mahfuz
1
, M. Khalid Hossain
2,3
, M. Ishak Khan
4
, Imran Hossain
5
and
Muzahidul I. Anik
6
1
Department of Biotechnology and Genetic Engineering, University of Development Alternative, Dhaka, Bangladesh;
2
Interdisciplinary Graduate School of Engineering Science, Kyushu University, Kasuga, Fukuoka, Japan;
3
Atomic Energy
Research Establishment, Bangladesh Atomic Energy Commission, Dhaka, Bangladesh;
4
Department of Neurosurgery,
University of Pennsylvania, Philadelphia, PA, United States;
5
Institute for Micromanufacturing, Louisiana Tech University,
Ruston, LA, United States;
6
Department of Chemical Engineering, University of Rhode Island, Kingston, RI, United States
1. Introduction
Cancer is the second most common cause of death worldwide. It was estimated that
about 9.6 million people died of cancer in 2018 (Bray et al., 2018). Various treatment
options have emerged in the past century for treating cancer. These include surgery,
chemotherapy, radiation, immunotherapy, hormone therapy, gene therapy, photother-
mal therapy, photodynamic therapy, etc. However, surgery, chemotherapy, radiation
therapy, and their combinations still remain the first lines of cancer treatment (Kumari
et al., 2016). Cancer is caused by unregulated proliferation of cells and chemotherapy tar-
gets to kill these cells. Conventional chemotherapeutic agents fail to distinguish between
cancer and normal cells and thus systemic administration of cancer chemotherapy leads to
off-target adverse effects (Peer et al., 2007). These effects are observed in immediate and
delayed patterns. Immediate effects include chemotherapy-induced nausea and vomiting,
chemotherapy-induced constipation and diarrhea, hypersensitivity, mucositis (chemo-
therapy disrupts repopulation of cells with high physiological turnover such as those lin-
ing mucosa), nephrotoxicity, central and peripheral neurotoxicity, myotoxicity, and so
on (Nurgali et al., 2018). Long-term effects include cardiovascular events such as hyper-
tension, coronary artery disease, ventricular failure, cardiomyopathy (e.g., anthracycline
induced), infertility, psychosocial effects, and more strikingly sometimes chemotherapy-
induced emergence of another type of cancer (examples include therapy-related acute
myeloid leukemia and myelodysplastic syndrome) (Ahmad et al., 2016). Moreover,
some anticancer drugs have low aqueous solubility and conventional chemotherapy is
associated with multiple drug resistance (Kumari et al., 2016). All these barriers, if not
eradicated, can be minimized by targeted drug delivery and different nanostructured sys-
tems are currently being considered as the most important candidates for this purpose.
New Trends in Smart Nanostructured Biomaterials in Health Sciences
ISBN 978-0-323-85671-3, https://doi.org/10.1016/B978-0-323-85671-3.00001-4
©2023 Elsevier Inc.
All rights reserved. 3
Nanostructured systems have already shown great promise in medicine. They can be
utilized for smart drug delivery, gene therapy, photodynamic therapy, disease diagnosis,
and imaging. This chapter will focus only on the recent advancements achieved by nano-
structured systems in smart drug delivery.
2. Nanostructured systems for smart drug delivery
Smart drug delivery can be defined as delivery of drugs to the target site at the desired
concentration so that optimum results can be achieved without any or with minimum
adverse effects arising from off-target actions (Hossain et al., 2021; Hossen et al.,
2019). Different nanostructured systems are the ideal candidates for smart drug delivery.
The concept of targeted delivery is not new. Paul Ehrlich first thought of targeted drug
delivery for killing microbes that he called Zauberkugel (magic bullet) (Heynick, 2009).
Besides targeted delivery, nanostructured systems or nanocarriers are also able to deliver
poorly water-soluble and poorly absorbed drugs (include proteins and peptides), release
drugs in a controlled and sustained pattern, achieve the same therapeutic efficacy with a
decreased amount of drug, accomplish minimum drug wastage, increase dosing interval,
and overcome drug resistance (Singh et al., 2011).
Smart drug delivery for cancer therapy includes the following steps:
1. Identification of target cells: Passive targeting or active targeting methods can be
adopted for targeted delivery but active targeting is far more superior. Passive target-
ing takes the advantage of EPR (Enhanced Permeation and Retention) phenome-
non. Inflammation and/or hypoxia make the endothelium of vessels leaky. These
two phenomena are invariably associated with tumor microenvironment. Moreover,
hypoxia in cancers signals formation of new vessels and engulfment of existing vessels.
Newly formed vessels in cancer tissues are of inconsistent size and shape, highly leaky,
and don’t follow the hierarchy of blood vessels
(Artery /Arteriole /Capillary /Venule /Vein). As a result of the aforemen-
tioned events, cancer vasculature is leakier than any normal vessel and enhances
permeation of macromolecules (such as nanocarriers) weighing more than 40 kDa.
The tumor microenvironment also doesn’t have proper lymphatic drainage which
leads to retention of nanocarriers. However, this EPR effect only increases drug de-
livery to tumors by 20%e30% in comparison with normal tissues and doesn’t facilitate
small molecules delivery which wash away swiftly. Delivery of drug-loaded target-
specific nanocarriers, like guided missiles, can be achieved by surface modification
of nanocarriers with ligands complementary to the receptors overexpressed on cancer
cell membrane. Nanocarriers can be surface modified with antibodies, peptides, pro-
tein, aptamer, small molecules (folate, transferrin, galactose), etc. (Attia et al., 2019).
4New Trends in Smart Nanostructured Biomaterials in Health Sciences
2. Releasing of drugs to the target site: The next step of carrying a drug to the target
site is releasing the drug from the nanocarrier. Smart nanocarriers made from different
stimuli-responsive materials can successfully do this. Endogenous stimuli include low
pH, hypoxia, redox reactions, and high enzymatic activity. Exogenous stimuli include
temperature, light, magnetic field, ultrasound, and electric stimulation (Liu et al.,
2016).
3. Excretion from the body after successful drug delivery: This is the last step in
the smart drug delivery process. The nanocarrier used for drug delivery should leave
the body unchanged or after enzymatic degradation and it shouldn’t accumulate in
any organ. Ideal structure and properties of smart nanostructured drug delivery sys-
tems are schematically presented in Fig. 1.1 (Grund et al., 2011).
It is relevant to discuss the nanostructured systems that are contributing to cancer
therapy in a categorized manner. In this regard, the nanostructured systems can be
broadly categorized as lipid-based, polymer-based, and inorganic.
2.1 Lipid-based nanostructured systems in cancer therapy
In this section, lipid-based nanostructured systems will be discussed in detail. Primarily,
the lipid-based nanosystems consist of liposome, niosome, nanostructured lipid carriers,
and nanoemulsions.
Figure 1.1 Schematic representation of structure and desired properties of smart nanostructured
drug-delivery systems during different stages of drug delivery. (Reprinted with permission from
Grund, S., Bauer, M., &Fischer, D. (2011). Polymers in drug delivery-state of the art and future trends.
Advanced Engineering Materials, 13(3), B61eB87. https://doi.org/10.1002/adem.201080088)
Smart drug delivery nanostructured systems for cancer therapy 5
2.1.1 Liposome
Among all the nanostructured systems dedicated to drug delivery, liposomes deserve spe-
cial attention. It is the longest-serving nanocarrier for drug delivery purpose (Khan et al.,
2022). Liposomes are vesicular spherical structures made of phospholipid bilayer encom-
passing an aqueous core. This bilayer can be either single or multiple (Slingerland et al.,
2012). They were discovered in the early years of 1960s by Alec D. Bangham and R.W.
Horne during their study of phospholipids under electron microscope when they
observed spontaneous self-assembly of phospholipids into vesicular sphericles upon con-
tact with water. The potential of liposomes as a carrier of enzymes and drugs was first
shown by Gregory Gregoriadis and Brenda Ryman in 1971 when they successfully
entrapped an enzyme (amyloglucosidase of Aspergillus niger) inside a liposome for the first
time (Weissig, 2017, pp. 1e15). Since then, liposomes have been considered an attractive
agent for targeted drug delivery, especially in the treatment of malignancies.
Liposomes can be classified as follows (Isalomboto Nkanga et al., 2019):
(i) According to source:
1. Natural: constituent phospholipid is obtained from natural sources such as egg
yolk, soybean, etc. The most common natural phospholipids for liposome syn-
thesis are phosphatidylcholine and phosphatidylethanolamine.
2. Synthetic: constituent phospholipid is obtained from modifications of natural
lipids. Commonly used synthetic phospholipids are modified phosphatidylcho-
lines. These include dipalmitoyl phosphatidylcholine, distearoyl phosphatidyl-
choline, dimyristoyl phosphatidylcholine, and hydrogenated soy
phosphatidylcholine.
(ii) According to number of lipid bilayers:
1. Unilamellar vesicle: consists of a single phospholipid bilayer. These can again
be of small (25e50 nm), large (100 nme1mm), and giant (>1mm) types based
on size.
2. Oligolamellar vesicle: consists of two to five phospholipid bilayers arranged in
a concentric pattern (100 nme1mm).
3. Multilamellar vesicle: consists of >5 concentric phospholipid bilayers
(100 nme15 mm).
(iii) According to number of vesicles:
1. Single vesicle
2. Multivesicular vesicle: multiple small single vesicles get entrapped within a
large vesicle (1.6e10.5 mm).
The stability of liposomes depends on many factors such as constituent lipid, vesicle
size, number of lamellae, charge, surface properties, and temperature (Pattni et al.,
2015;Yan et al., 2020) . These properties are fine-tuned to obtain the desired
liposome.
6New Trends in Smart Nanostructured Biomaterials in Health Sciences
Quite a good number of methods have been invented for synthesis of liposomes. Ex-
amples of some conventional methods are thin film hydration method (the original
Bangham method) for multilamellar vesicles and giant unilamellar vesicles, detergent
removal methods for large unilamellar vesicles, and sonication for small unilamellar ves-
icles (Pattni et al., 2015).
Conventional methods of liposome preparation have many disadvantages for which
they aren’t suitable for commercial production. These disadvantages include poor
mono-dispersion (nonuniform size distribution), unreliable encapsulation efficiency, ve-
sicular instability, difficult sterilization procedures for removing contaminants, increased
amount of residual organic solvent, possible protein payload denaturation, and potential
toxicity to human health and environment by the used organic solvents (Maja et al.,
2020;Pattni et al., 2015). To overcome these obstacles, some novel methods have
been devised. Microfluidics-based methods (Kotoucek et al., 2020), different supercritical
fluid methods (Santo et al., 2013), liposomal lyophilization (Franze et al., 2018), spray
drying of liposomes for topical applications (Maniyar & Kokare, 2019;Rojanarat
et al., 2011), membrane contactor techniques (Pham et al., 2012), crossflow injection
technique (Wagner et al., 2002), and dual asymmetric centrifugation method (Massing
et al., 2008) are some newer additions to the liposome preparation procedure.
Liposomes act as a promising nanocarrier for a wide range of molecules. They can
carry hydrophobic and lipophilic molecules in their lipid bilayer/s and entrap hydrophilic
molecules in the aqueous core. They can also carry vaccines and medications on their sur-
face with the help of electrostatic interactions (Yan et al., 2020). Conventional liposomes
face many barriers before reaching their destinations. Pre-administration concerns
include phospholipid degradation, nonuniform size distribution, inefficient encapsula-
tion, leakage of entrapped drug/vaccine, and fusion among liposomes. These physical
and chemical instabilities cause short shelf lives of liposomes (Çagdas
¸et al., 2014).
Post-administration barriers include rapid engulfment and subsequent clearance by the
reticuloendothelial system (RES), in vivo instability, and nonspecific cargo delivery
(Çagdas
¸et al., 2014).
Opsonization of liposomes leads to clearance of liposomes by RES. To ensure a long-
circulating time by evading opsonization, numerous chemically inert hydrophilic poly-
mers and water-soluble polymers with hydrophobic groups have been conjugated to
the phospholipid head groups. These conjugations form a steric barrier around the lipo-
some and prevent opsonins as well as other liposome vesicles to come in contact. This
solves two important problemsdclearance by RES and liposome aggregation. Although
many polymers have been considered for conjugation, PEG (polyethylene glycol)-
ylation is still the “gold standard”method for liposomal surface modification. These
long-circulating liposomes are known as “sterically stabilized liposome”or “stealth lipo-
some”(Çagdas
¸et al., 2014;Deodhar & Dash, 2018).
Smart drug delivery nanostructured systems for cancer therapy 7
Cationic liposomes are derived from a combination of cationic lipids and neutral
helper lipids. Due to their positive charges, cationic liposomes show an affinity for nega-
tively charged cell membrane, endosomal membrane, and nucleic acids. Despite many
shortcomings in vivo, these liposomes are considered a promising agent for cancer
gene therapy (Liu et al., 2020).
Liposome-mediated effective drug delivery cannot rely solely on the passive EPR ef-
fect. Directed delivery of the payload to neoplastic cells can be achieved in two waysd(a)
liposomal ligandecancer cell receptor interactions and (b) stimuli-responsive liposomes
(Upponi & Torchilin, 2014).
Cancer cells significantly overexpress one or more receptor proteins on their surfaces
in comparison with the normal cells of healthy tissues. For example, about 25% of breast
cancer cases overexpress HER2 (human epidermal growth factor receptor 2). Similarly,
ovarian cancer, multiple myeloma, and B cell lymphoma overexpress folate receptor,
VLA-4, and CD19, respectively (Noble et al., 2014). Ligands specific to these receptors
are attached directly to the liposomal surface or with the PEG chains. These ligands can
be an antibody fragment (antigen-binding fragment or single-chain variable fragment),
monoclonal antibody, peptide, protein, glycoprotein, carbohydrate, vitamin, or aptamer
(Deodhar & Dash, 2018;Yan et al., 2020). Liposomes specific for proteins overexpressed
in tumor vasculature endothelial cells (VEGFR, APJ, VCAM1, and a
v
b
3
integrin) have
also shown success in inhibiting tumor angiogenesis (Cheng & Ji, 2019).
The bloodebrain barrier (BBB) is a delicate structure and is an impedance on the way
of drug delivery to the brain. Conjugating transferrin, lactoferrin, glucose, glutathione,
and cyclic peptides with PEG facilitate liposomes to cross the BBB (Fig. 1.2)(Agrawal
et al., 2017). Daunorubicin containing liposomes modified with transferrin and p-
aminophenyl-a-D-mannopyranoside (MAN) have shown improved delivery to the gli-
oma tissue (a type of brain tumor) in an animal model (Ying et al., 2010).
Targeted release of cargo from liposomes to the neoplastic tissue can be achieved using
stimuli-responsive liposomes. Tumor microenvironments have some properties distin-
guishable from the physiological conditions of normal tissues. For example, tumor micro-
environments usually have an extracellular pH (pH ¼6.0e7.0) lower than that of healthy
tissues (pH ¼7.4). This reduced pH is due to either hypoxia in the cancer tissue or War-
burg effect (fermenting glucose to lactate instead of oxidative phosphorylation by cancer
cells and normal proliferating cells even in the presence of adequate O
2
). This decrease
in pH can trigger unloading of drugs from pH-sensitive liposomes to cancer tissues. In
addition to pH, redox potential, enzyme activity, reactive oxygen species, and cancer tissue
hypoxia can also act as intrinsic stimuli for stimulus-sensitive liposomes (Lee & Thompson,
2017). Extrinsic stimuli used for drug release from smart liposomes include light, heat,
magnetic field, electric field, ultrasound wave, and microwave (Lee & Thompson, 2017).
8New Trends in Smart Nanostructured Biomaterials in Health Sciences
Liposomes have also been made smart by increasing their payload capacity. It has been
shown that liposomes can deliver more than one type of cargo simultaneously. These can
be of the same type like two drugs or different types like a drug and a genetic material
(siRNA, shRNA, anti-miRNA, or DNA) or an anticancer metal. This sort of delivery
is known as liposomal co-delivery (Fig. 1.3)(Zununi Vahed et al., 2017).
Although liposomes are an excellent carrier for targeted delivery, there are still issues
that need to be solved. PEG conjugation increases the circulation time of liposomes and
enhances their permeability as well as functionality. However, PEGylation also brings
some disadvantages. PEG chains exert steric hindrance and the target cancer cells may
not efficiently uptake drugs. PEG addition also causes disturbance in effective binding
of the targeting ligands on liposomes to their counterpart cellular receptors (Fang
et al., 2017). PEGylation also causes obstruction in the endosomal escape of liposomes
and thus reduces the efficiency of liposome-based drug delivery (Guo & Huang,
2011). Another serious issue concerning liposomal drug delivery is accelerated blood
clearance (ABC). Repeated administration of PEGylated nanocarriers leads to production
of anti-PEG immunoglobulin M. This anti-PEG antibody and complement activation
result in rapid clearance of PEGylated nano vehicles by the mononuclear phagocyte sys-
tem which is known as the ABC phenomenon (Abu Lila et al., 2013). These issues can be
overcome by using cleavable PEG (Fang et al., 2017).
Figure 1.2 Scheme showing specific targeting by liposome after crossing the bloodebrain barrier
(BBB). Such targeting is relevant to therapeutic application in Alzheimer’s Disease. (Reprinted with
permission from Agrawal, M., Ajazuddin, Tripathi, D. K., Saraf, S., Saraf, S., Antimisiaris, S. G., Mourtas, S.,
Hammarlund-Udenaes, M., &Alexander, A. (2017). Recent advancements in liposomes targeting strategies
to cross blood-brain barrier (BBB) for the treatment of Alzheimer’s disease. Journal of Controlled Release,
260,61e77. https://doi.org/10.1016/j.jconrel.2017.05.019.)
Smart drug delivery nanostructured systems for cancer therapy 9
Because of effective entrapment of nucleic acids, cationic liposomes are preferred for
gene delivery. Besides clearance by RES, they adsorb plasma proteins on their surface
which compromise their efficacy (Liu et al., 2020). Cationic liposomes also face poor
penetration to tumor cells, endosomal entrapment, and unsatisfactory diffusion of the ge-
netic material delivered to the nucleus. Researches are ongoing to solve the aforemen-
tioned obstacles in liposome-based delivery (Fang et al., 2017;Liu et al., 2020;
Sanchez et al., 2017).
2.1.2 Niosome
Niosomes are nano-vesicles made of nonionic surfactants. They were developed in the
1970s for use in cosmetic products (Sanchez et al., 2017). Nonionic surfactants can
self-assemble themselves into niosomes in aqueous media. However, this self-assembly
usually isn’t spontaneous and needs energy input (e.g., heat, physical agitation by shaking,
ultrasound) (Sahin, 2007). Niosomes share common physicochemical characteristics,
medicinal applications, and in vivo interactions with liposomes. Like liposomes, they
can be unilamellar, oligolamellar, or multilamellar and they can carry both hydrophobic
and hydrophilic drugs (Abdelkader et al., 2014;Khan & Irchhaiya, 2016;Muzzalupo &
Mazzotta, 2019). The main difference between these two nanocarriers is in
Figure 1.3 (A) Simplified scheme of liposomal co-delivery fine-tuned for cancer cells. (B) Different
types of liposomal structures and their lamellarity. (Reprinted with permission from Zununi Vahed, S.,
Salehi, R., Davaran, S., &Sharifi, S. (2017). Liposome-based drug co-delivery systems in cancer cells.
Materials Science and Engineering: C, 71, 1327e1341. https://doi.org/10.1016/j.msec.2016.11.073.)
10 New Trends in Smart Nanostructured Biomaterials in Health Sciences
compositiondliposomes are made of phospholipids but for niosomes, the ingredient is
mainly nonionic surfactant. This provides niosomes some advantages over liposomes.
Niosomes are physicochemically as well as biologically more stable than liposomes.
They can entrap drugs effectively, their commercial production cost is less than lipo-
somes, and they have a long shelf-life. They are nontoxic, nonimmunogenic, and biode-
gradable (Bhardwaj et al., 2020;Muzzalupo & Mazzotta, 2019). Niosomes can be
prepared in a good number of ways. Thin-film hydration, Hand Shaking, Bubble
method, ether injection, reverse phase evaporation, sonication, heating, microfluidiza-
tion, freeze and thaw, dehydration-rehydration, transmembrane pH gradient, single-
pass technique or multiple membrane extrusion, niosome derivation from proniosome,
HandjanieVila technique, and supercritical carbon dioxide fluid method are some well-
established methods of niosome preparation (Fig. 1.4 depicts heating method, one com-
mon method of niosome preparation) (Bhardwaj et al., 2020;Khan & Irchhaiya, 2016;
Moghassemi & Hadjizadeh, 2014). The main component of niosome is usually a syn-
thetic, nonionic surfactant having a single chain hydrophobic alkyl tail and a hydrophilic
head group. Nonionic surfactants are specifically preferred for niosome preparation
because they are less toxic and more stable and biocompatible in comparison with ionic
or amphoteric surfactants (Jiao, 2008). Alkyl ethers and crown ethers, alkyl esters and
Figure 1.4 Protocol for one of the methods of preparing niosome (heating method). (Reprinted with
permission from Moghassemi and Hadjizadeh (2014).)
Smart drug delivery nanostructured systems for cancer therapy 11
amides, fatty acids, fatty alcohols, and pluronic block copolymers have been used as
nonionic surfactants for niosome preparation. Among them, alkyl ethers and alkyl esters
are most commonly used because of their low toxicity profile and easy availability
(Abdelkader et al., 2014;Ag Seleci et al., 2016). Not all nonionic surfactants form nio-
some in the aqueous medium. Whether an amphiphile (e.g., nonionic surfactant, block
copolymer) will form a vesicle (niosome, polymersome) or micelle can be predicted from
two important measurementsd(i) Hydrophilic-Lipophilic Balance (HLB) and (ii) Crit-
ical Packing Parameter (CPP).
Nonionic surfactants can have an HLB value from 0 to 20. The more the HLB value
is, the more hydrophilic and less lipophilic the surfactant becomes. Surfactants whose
HLB values lie in the 4e8 range are usually the ideal candidates for niosome preparation.
Surfactants having an HLB value 9.6 usually assemble themselves into micelles or open
lamellar structures instead of noisomes (Abdelkader et al., 2014;Ag Seleci et al., 2016).
The drug entrapment efficiency of a niosome can also be roughly estimated from the
HLB value of its constituent surfactant. It was shown with the drug nimesulide that
the entrapment efficiency of niosomes decreases with the decrease in HLB values of
the surfactants used from 8.6 to 1.8 (Shahiwala & Misra, 2002).
Critical Packing Parameter (CPP) is another predictor of niosome formation proba-
bility of a given surfactant. CPP is expressed as
CPP ¼v=a0lc+(1.1)
where v¼hydrophobic chain volume, a
0
¼hydrophilic head group area, and
l
c
¼hydrophobic chain length.
When the CPP value is 1/3, spherical micelles are formed. Cylindrical micelle,
bilayer micelle (niosome), and inverse micelle are formed when 1/3 CPP 1/2,
1/2 CPP 1, and CPP >1, respectively (Fig. 1.5 depicts different mechanisms of
niosome functionality) (Marianecci et al., 2014).
Recently, another new predictor, “effective area per lipid chain”(i.e., cross-section of
a hydrophobic “tail,”A
c
) has been proposed for determining possible amphiphile aggre-
gation state. It was proposed that with an A
c
value >0.43 nm
2
, an amphiphile tends to
form micelles. An A
c
value below 0.43 nm
2
but close to it ease the formation of bilayer
vesicles (such as niosome), whereas an A
c
value much lower than 0.43 nm
2
(A
c
0.43 nm
2
)
,
usually leads to multilamellar structure formation (Cevc, 2012).
In addition to the above-mentioned factors, monomer concentration, temperature,
aqueous interlayer, length of lipid chain, lipid chain-packing, and asymmetry in mem-
brane also have deterministic roles in niosome formation (Marianecci et al., 2014).
Nonionic surfactants possess the ability to form niosomes in favorable conditions but
these niosomes are usually leaky and easily permeable to the solutes (Abdelkader et al.,
2014). For this reason, cholesterol and charged molecules are used as membrane additives
during niosome preparation.
12 New Trends in Smart Nanostructured Biomaterials in Health Sciences
Cholesterol attaches with the surfactant’s hydrophilic head through hydrogen bonds.
The interposition of cholesterol between adjacent surfactant molecules thus renders sta-
bility to niosomes. Surfactants having an HLB value >6 can’t assemble into a bilayered
vesicle without the addition of cholesterol. The incorporation of cholesterol in niosomes
leads to an increase in gel liquid transition temperature. This increase in transition tem-
perature ensures niosomal stability. Another advantage is increased transition temperature
enhances drug entrapment efficiency (Kumar & Rajeshwarrao, 2011). Cholesterol also
plays important roles in determining shelf-life, cargo release, and in vivo stability (Ag
Seleci et al., 2016).
Charged molecules are introduced in niosomes to inhibit aggregation through electric
repulsion between the same type of charges. Dicetylphosphate, dihexadecyl phosphate,
sodium deoxycholate, phosphatidic acid, and lipoamino acid are commonly used as nega-
tive charge inducers. Sterylamine and cetylpyridinium chloride are examples of positive
charge inducers (Junyaprasert et al., 2008;Khan & Irchhaiya, 2016).
Like liposomes, niosomes are also PEGylated to avoid clearance by the RES. PEGy-
lation also provides attachment sites for targeting ligands (Elliott et al., 2009). Smart
niosomes have been modified with whole monoclonal antibodies or their fragments,
cell-penetrating peptides, aptamers, glucose, transferrin, folic acid, N-
palmitoylglucosamine, etc. ( Muzzalupo & Mazzotta, 2019) for guided delivery of
chemotherapy drugs. Niosomes made from pH-sensitive components have also been
Figure 1.5 Different mechanisms of niosome functionality. (A) Drug molecule release,
(B) enhancement of penetration, (C) adsorption to Stratum Corneum, (D) skin penetration, and
(E) pilosebaceous unit penetration. (Reprinted with permission from Marianecci, C., Di Marzio, L.,
Rinaldi, F., Celia, C., Paolino, D., Alhaique, F., Esposito, S., &Carafa, M. (2014). Niosomes from 80s to
present: The state of the art. Advances in Colloid and Interface Science, 205, 187e206. https://doi.org/10.
1016/j.cis.2013.11.018.)
Smart drug delivery nanostructured systems for cancer therapy 13
reported. These niosomes can take advantage of the low pH present in tumor microen-
vironment and inflammation sites. pH-sensitive niosomes can be prepared by adding pH-
sensitive molecules to nonionic surfactants or making the surfactant itself pH-sensitive
(Rinaldi et al., 2017).
Niosomes have been used as a nanocarrier for the delivery of anticancer, antiinflam-
matory, and antifungal drugs as well as hormones, vaccines, genetic materials, natural
compounds, and imaging agents (Guler et al., 2017). Niosomes can be administered
via a variety of routes such as oral, subcutaneous, intravenous, intramuscular, ocular,
inhalational, transdermal, and intraperitoneal (Moghassemi & Hadjizadeh, 2014).
Niosome is a nanocarrier with many promises. It has shown the capabilities to bypass
some of the obstacles faced by liposome. However, until now niosome-based formula-
tions are only under trial for various dermatological conditions (Muzzalupo & Mazzotta,
2019). Currently, data regarding adverse effects related to systemic administration of nio-
somal formulations are insufficient. Large-scale toxicological studies can hasten the tran-
sition from laboratory research to clinical administration of niosomal formulations
(Marianecci et al., 2014).
2.1.3 Solid lipid nanoparticle and nanostructured lipid carrier
Solid lipid nanoparticles (SLNs) are colloids composed of a lipid matrix that remain solid
at body temperature and are stabilized with surfactants and sometimes with a co-
surfactant. The diameter of an SLN can be between 10 and 1000 nm (Pink et al.,
2019). The history of SLN can be traced back to the early 90s when they were prepared
by Muller and Lucks using high-pressure homogenization technique and by Gasco using
microemulsion technique (M€uller et al., 2002). SLNs are biocompatible, maintain stabil-
ity of the loaded drugs, capable of controlled and targeted release of cargo, can carry both
lipophilic and hydrophilic drugs and increase their bioavailability, don’t require any
organic solvent, and can be easily scaled-up and sterilized (Hanumanaik et al., 2013).
However, SLNs have some disadvantages. They crystallize at a high temperature with
many imperfections in the crystal lattice that accommodate the drug but at storage tem-
perature these nanocrystals convert into low energy, more stable, and ordered state. This
results in expulsion of the entrapped drug. Other disadvantages of SLNs are a high ten-
dency to form gel, an increase in particle size during shelf life, and presence of high-water
content in SLN dispersions (70%e99.9%) (M€uller et al., 2002;Hanumanaik et al., 2013).
To bypass the problems faced by SLNs, second generation of lipid particleebased nano-
carriers were developed. These are known as nanostructured lipid carriers (NLC). In
NLC, the matrix is created by blending liquid lipids with solid lipids in such proportion
that the mixture remains solid at body temperature but its melting point becomes lower
than the solid lipid used. The inclusion of liquid lipid allows more imperfections in the
14 New Trends in Smart Nanostructured Biomaterials in Health Sciences
matrix which in turn provide enough space for the payload and prevent the problem of
drug repulsion by inhibiting formation of an ordered crystal structure. Like SLNs, the size
of NLCs remains within 10e1000 nm and their size varies with the variation of constit-
uent lipid and manufacturing method (García-Pinel et al., 2019).
NLCs can be of three types depending on their method of preparation and
composition:
1. Imperfect type (the lipid matrix is a disorganized crystal and can’t order itself to a per-
fect crystal),
2. Amorphous type (the matrix is an amorphous solid, not crystalline), and
3. Multiple type (liquid lipid-in-solid lipid-in-water dispersion) (M€uller et al., 2002).
Many methods have been devised for preparing NLCs over the past years. Fig. 1.6
shows some commonly adopted methods of preparing NLCs (Hanumanaik et al., 2013).
Smart NLCs for guided delivery of chemotherapy agents have been prepared by
attaching lactoferrin, small peptide (Zhang et al., 2018), N-acetyl-D-glucosamine (Liang
et al., 2017), hormone (Taratula et al., 2013), and aptamer (Liang et al., 2018) on their
surface. Liang et al. developed a smart NLC containing epigallocatechin gallate against
HER2 (human epithelial growth factor receptor) positive breast cancer. Here they
used aptamers for two stage targetingdHB5 aptamer for specifically binding to the
HER2 receptor and ATP aptamer for drug release after entry into the cancer cells (Liang
et al., 2018). Functionality and distribution of smart NLCs in the biological system are
depicted in Fig. 1.7.
2.1.4 Nanoemulsion
An emulsion is a mixture of two immiscible liquids where one lipid disperses in the other
liquid in the form of spherical droplets. The spherical droplets form the dispersed phase
(also called “internal”or “discontinuous”phase) and the other liquid forms the contin-
uous phase (or “external phase”or “dispersion medium”) of emulsion.
The two most common liquids that form emulsions are water and oil. Emulsions can
be broadly classified into three types:
1. Oil-in-water (o/w) emulsion [oil is the dispersed phase and water is the continuous
phase]
2. Water-in-oil (w/o) emulsion [water is the dispersed phase and oil is the continuous
phase]
3. Bicontinuous emulsion [coexistence of o/w and w/o emulsions in the same system]
Instead of just 2 phases, emulsions can be more complexdthey can contain upto 3
phases (o/w/o or w/o/w) where oil is dispersed in water droplets which are again
dispersed in oil or vice versa, respectively.
An emulsion can be a coarse emulsion (droplet size >200 nm), microemulsion
(droplet size <100 nm), and nanoemulsion (droplet size <600 nm). At first glance, it
Smart drug delivery nanostructured systems for cancer therapy 15
seems contradictory because by definition nano (10
9
) is a smaller entity than micro
(10
6
). The reason behind this is historical. The term “microemulsion”is older (first
used in 1959) than “nanoemulsion”(first used in 1996) and the universally accepted clas-
sification of fine emulsions is yet to be established. The main difference between a
Figure 1.6 Different preparation methods of nanostructured lipid carriers.
16 New Trends in Smart Nanostructured Biomaterials in Health Sciences
micro- and a nanoemulsion is the former one is thermodynamically stable, whereas the
latter one is thermodynamically unstable.
A nanoemulsion can’t form without an input of external energy. The reason is when a
nanoemulsion is formed, an increase in the surface area occurs because of the formation of
droplets. This increase in surface area doesn’t happen without energy input.
The required energy input for a nanoemulsion formation, DG¼increase in the con-
tact area between the two liquids (DA)surface tension (g)entropy of dispersion
(TDS).
A nanoemulsion breaks over time due to Ostwald ripening phenomenon (dissolution
of tiny droplets and their subsequent deposition on larger droplets, because larger droplets
are energetically favorable), flocculation (clumping of smaller droplets), coalescence (merg-
ing of 2 small droplets to form a larger one), creaming, phase separation, and sedimen-
tation. To make nanoemulsions stable, different stabilizers are also added. Emulsifiers,
ripening retarders, texture modifiers, and weighting agents are used as stabilizers (Aswatha-
narayan & Vittal, 2019;Jaiswal et al., 2015).
Triglycerides are commonly used to derive the dispersion phase of nanoemulsions.
The droplet size of nanoemulsions is dependent on the chain length of triglycerides.
Long-chain triglycerides form larger droplets, while small-chain triglycerides form
smaller droplets. Small droplets are favorable against flocculation, Brownian motion,
and gravitational force. However, small droplets are prone to Ostwald ripening because
triglycerides with small chains are highly water-soluble. For this reason, long-chain tri-
glycerides (common source is soybean oil) or a mixture of long and medium-chain tri-
glycerides (common source is coconut oil) are usually used for nanoemulsion preparation.
Nonionic surfactants (Tween80, Tween20, Span80, PEG, sucrose monostearate, etc.),
anionic (sodium dodecyl sulfate), and amphiphilic (whey protein and egg yolk powder)
molecules have been tried as emulsifiers in nanoemulsions. Sodium chloride and sodium
Figure 1.7 Depiction of diverse functionality of nanostructured lipid carriers (NLCs) and their distribu-
tion in different organs. (Reprinted with permission from Taratula, O., Kuzmov, A., Shah, M., Garbuzenko,
O. B., &Minko, T. (2013). Nanostructured lipid carriers as multifunctional nanomedicine platform for
pulmonary co-delivery of anticancer drugs and siRNA. Journal of Controlled Release, 171(3), 349e357.
https://doi.org/10.1016/j.jconrel.2013.04.018.)
Smart drug delivery nanostructured systems for cancer therapy 17
alginate have been used as ripening retardant and texture modifier, respectively (Aswa-
thanarayan & Vittal, 2019).
Depending on energy input, the methods of nanoemulsion preparation are mainly of
two types (Jaiswal et al., 2015):
1. High energy method: External force is applied to break down dispersed droplets to
the nanometer size. Examples: high-pressure valve homogenization technique,
microfluidization method, ultrasonication technique, high-energy stirring method,
membrane emulsification method, etc.
2. Low energy methods: required energy is supplied from chemical potential of the
ingredients. It can again be classified into two types:
(a) Phase inversion emulsification method:
- Transitional phase inversion method
- Emulsion inversion point technique
(b) Self-nanoemulsification method
Nanoemulsions are now being investigated as a potential lipid-based nanocarrier for
the delivery of cancer therapeutics. Lipophilic drugs can be loaded in o/w emulsions and
hydrophilic drugs can be loaded in w/o emulsions (Chime et al., 2014). Smart nanoe-
mulsions have been prepared from stimuli-sensitive components and through surface
modifications. Liu et al. (2014) have developed a smart pH-sensitive nanoemulsion for
controlled release of doxorubicin (Fig. 1.8 shows the mechanism of such release in a
simplistic manner). Jia et al. (2020) have reported a pH-sensitive smart Pickering nano-
emulsion for delivery of doxorubicin and immune checkpoint inhibitor HY19991.
Chongprakobkit & Tachaboonyakiat have developed a thermosensitive nanoemulsion
carrying naproxen (Chongprakobkit & Tachaboonyakiat, 2013). Rapoport et al.
(2009) have reported an ultrasound-sensitive paclitaxel loaded nanoemulsion for the
treatment of pancreatic, breast, and ovarian malignancies. Loureiro et al. (2015) have re-
ported a smart nanoemulsion incorporating folic acid as the guide for directed delivery of
bovine serum albumin conjugated methotrexate (antineoplastic) and vancomycin (anti-
biotic). Bazan Henostroza and colleagues have developed mucoadhesive cationic nano-
emulsions intended for prolonged delivery of rifampicin in ocular tuberculosis patients
(Bazan Henostroza et al., 2020).
A special variant of nanoemulsion is self-nanoemulsifying drug delivery systems
(SNEDDSs). Nanoemulsions, although having some clear advantages, usually are not
suitable for long-term preservation because of the instabilities discussed before.
SNEDDSs can help overcome these shortcomings of nanoemulsions. SNEDDSs are pre-
pared from the desired drug and other nanoemulsion forming components without add-
ing water. After ingestion, SNEDDSs come in contact with water in the stomach where
gastric motility provides the required mechanical agitation for forming a nanoemulsion.
SNEDDSs can be made as solid and manipulated for extended-release. Encapsulated
18 New Trends in Smart Nanostructured Biomaterials in Health Sciences
SNEDDSs ensure palatability, good patient compliance, and increased bioavailability of
hydrophobic drugs (Date et al., 2010). Various antineoplastic drug-loaded SNEDDSs
such as docetaxel (Seo et al., 2013), doxorubicin (Usmani et al., 2019), cisplatin (Osman
et al., 2017), paclitaxel (Cho et al., 2016), sunitinib (Alshahrani et al., 2018), erlotinib and
a glycyrrhetinic acid analog, CDODA-Me combination (Nottingham et al., 2020), sor-
afenib (Sandhya et al., 2020), brigatinib (Ansari et al., 2021), flutamide (Jeevana Jyothi &
Sreelakshmi, 2011), etc., have been found superior over conventional delivery systems.
However, toxicological studies about SNEDDSs are still insufficient and this area de-
serves special attention to bring SNEDDSs in regular clinical prescriptions (Rehman
et al., 2017).
2.2 Polymer-based nanostructured systems in cancer therapy
Polymer-based nanosystems are also a prime type of nanostructured system that are
contributing to cancer therapy. Their main types include polymeric nanoparticles, poly-
meric micelle, polymersome, dendrimer, and nanogels (Biswas et al., 2022; Parvej et al.,
2022).
Figure 1.8 Mechanism of nanoemulsion mediated controlled chemotherapy release (doxorubicin) in
a pH-responsive manner. (Reprinted with permission from Liu, F., Lin, S., Zhang, Z., Hu, J., Liu, G., Tu, Y.,
Yang, Y., Zou, H., Mo, Y., &Miao, L. (2014). pH-responsive nanoemulsions for controlled drug release.
Biomacromolecules, 15(3), 968e977. https://doi.org/10.1021/bm4018484.)
Smart drug delivery nanostructured systems for cancer therapy 19
2.2.1 Polymeric nanoparticles
Polymeric nanoparticles (PN) intended for drug delivery are synthesized from biocom-
patible and biodegradable polymers and can be designed as nanospheres (contain colloidal
matrix) or nanocapsules (vesicle containing an aqueous or oleaginous core). Drugs can be
loaded in the matrix (nanosphere) or inner core (nanocapsules) or adsorbed on the surface
of PNs. Nanospheres are commonly prepared by solvent evaporation, nanoprecipitation,
emulsification followed by either reverse salting-out or solvent diffusion techniques.
Nanocapsules can be prepared by nanoprecipitation or emulsification followed by sol-
vent diffusion (for insight into the structure of nanocapsules, refer to Fig. 1.9)(Zielinska
et al., 2020). PNs for drug delivery are prepared from FDA and European Medicine
Agency approved natural polymers like polysaccharides (chitosan, dextran, pullulan), gly-
cosaminoglycans (heparin, hyaluronic acid), alginate, and biodegradable synthetic poly-
mers like poly (lactic acid) (PLA), poly(glycolic acid) (PGA), poly(lactic-co-glycolide)
(PLGA), poly-ε-caprolactone (PCL), polyethylene glycol (PEG), etc. (Taghipour-
Sabzevar et al., 2020;Zielinska et al., 2020). Extensive deacetylation of chitin renders
a linear cationic polymer, chitosan. Presence of eNH
2
and eOH groups on chitosan
make it amenable to various chemical modifications for attaching targeting ligands.
Figure 1.9 Simplified representation of nanocapsules and nanospheres. (Reprinted with permission
from Zieli
nska A., Carreir
o F., Oliveira A.M., Neves A., Pires B., Venkatesh D.N., Durazzo A., Lucarini M., Eder
P., Silva A.M., Santini A., &Souto E.B. (2020). Polymeric nanoparticles: Production, characterization,
toxicology and ecotoxicology. Molecules, 3731.)
20 New Trends in Smart Nanostructured Biomaterials in Health Sciences
Dextran is a polymer of glucose molecules connected through a-(1 /6) [predominant]
and a-(1 /3) glycosidic linkages and has a highly variable molecular weight
(3e2000 kDa). Dextrans with a molecular weight between 40 and 70 kDa are usually
used as therapeutic nanocarriers. Numerous eOH groups present on dextran are suitable
targets for conjugation and can be exploited for guided delivery, increased solubility, and
circulation time. Maltotriose is formed when three glucose molecules attach through
a-(1 /4) glycosidic linkages. These maltotriose units again connect through
a-(1 /6) glycosidic linkages to form pullulan. Low molecular weight pullulans are
toxic, inflammatory, and subject to rapid renal clearance, but high molecular weight pul-
lulans show much less toxicity. Pullulans have a natural affinity to lectin and asialoglyco-
protein receptors and can be utilized for targeting cancerous organs expressing these
receptors like liver, spleen, and lung. When glucuronic acid connects through alternating
b-(1 /4) and b-(1 /3) glycosidic linkages with N-acetyl-D-glucosamine, hyaluronic
acid forms. It has a natural affinity for CD44 receptor and can be exploited to target can-
cer cells overexpressing this receptor such as lung, gall bladder, pancreatic, prostate, and
triple-negative breast cancers. Due to its targeting property, hyaluronic acid has been
used for preparing drug-conjugates, nanogels as well as surface modification of other
nanocarriers. Another natural polymer, alginate’s nanoparticles are pH-sensitive which
makes them suitable for smart cancer drug delivery. Properties of synthetic polymer
nanoparticles are dependent on molecular weight, crystallinity, and constituent isomers.
These parameters can be changed for obtaining desired properties and these polymeric
nanoparticles can be adorned with various ligands (He et al., 2018;Taghipour-
Sabzevar et al., 2020).
2.2.2 Polymeric micelle
Micelle, like liposome, is a self-assembling nanosystem. Upon contacting water, double
chain phospholipids form bilamellar liposomes, whereas phospholipids with a single chain
aggregate their polar headgroups in the outer region and hydrophobic tails in the core to
form unilamellar micelles. For the formation of micelles, a minimum concentration of
the respective amphiphile (containing both hydrophilic and hydrophobic regions)
must be present, which is called critical micelle concentration (Crayton et al., 2017).
Polymeric micelle size can vary in the range of 10e100 nm (Kulthe et al., 2012). Micelles
are generally spherical; however, they can be ellipsoid or cylindrical (Wisniewska-Becker
& Gruszecki, 2013). Commonly used methods of micelle preparation are simple dissolu-
tion method, dialysis, lyophilization (also known as freeze-drying), solvent evaporation,
and oil in water emulsion (Cholkar et al., 2012). Conventional micelles are made from
surfactants (polysorbates, Cremophor EL, etc.) and polymeric micelles are made using
newer amphiphilic polymers. Polymeric micelles can be classified into four typesd(i)
block copolymer, (ii) grafted polymer, (iii) noncovalently bonded, and (iv) polyelectro-
lyte. Among the polymeric micelles, block copolymer micelles are widely used, where
the block copolymers are composed of a hydrophobic and a hydrophilic block (diblock)
Smart drug delivery nanostructured systems for cancer therapy 21
or alternating hydrophobic and hydrophilic blocks (polyblock) (Kulthe et al., 2012;Xu
et al., 2013). Polymeric micelles offer increased stability, minimal cytotoxicity, longer cir-
culation time, and improved bioavailability over conventional micelles (Xu et al., 2013).
The hydrophilic corona of micelles provides steric protection from opsonization, thus
ensuring evasion from RES clearance and long enough circulation time. The hydropho-
bic core acts as an effective carrier of water-insoluble or poorly soluble drugs (Kulthe
et al., 2012). Poly (lactic acid), poly (lactic-co-glycolic acid), and poly(ε-caprolactone)
(PCL) are some common polymers that constitute the hydrophobic core of block copol-
ymer micelles and polyethylene glycol or oxide is used for the outer corona. However,
many other new combinations of hydrophobic and hydrophilic polymers are currently
under research (Majumder et al., 2020). Guided delivery of a drug/gene via smart mi-
celles can be achieved by attaching tissue-specific ligands (different sugar moieties, folate,
transferrin, monoclonal antibody, peptides, etc.) to their water-exposed hydrophilic
termini. Targeted release of drug is achieved by preparing micelles using stimuli
(increased temperature or decreased pH of the target site, redox potential, ultrasound
wave, magnetic field, light, and so on)-sensitive materials (Kulthe et al., 2012). Currently
block copolymer micelles carrying doxorubicin, paclitaxel, docetaxel, epirubicin, and
cisplatin targeting different cancers are under clinical trial. Genexol-PM, a block copol-
ymer micelle consisting of PEG as the hydrophilic block and Poly (D,L-lactide) as the
hydrophilic block and carrying paclitaxel as the cargo, has gained approval in South Ko-
rea (Majumder et al., 2020). Micelles have also been found as an efficient medium of
multiple drug co-delivery (enhancement of drug delivery by such implementation is clar-
ified in Fig. 1.10)(Jo et al., 2020).
2.2.3 Polymersome
Polymersomes are the polymeric counterparts of liposomes. They are bilayered nanove-
sicles made mainly of synthetic amphiphilic block copolymers encompassing a watery
core. The polymer chains in polymersomes are larger than the lipid chains of liposomes
and these polymer chains form a thicker, more viscous, and less permeable shell in com-
parison with liposomes (Fisher et al., 2010). They were first prepared by Bohdana and
coworkers in 1999 (Discher, 1999). Besides synthetic copolymers, polypeptide, and
polysaccharide-based amphiphilic block copolymers are also currently being investigated
to obtain polymersomes with more tunable properties (Zhao et al., 2014). Their diameter
can be from 100 nm to >10 mm. Synthesis of polymersomes with a diameter below
100 nm is difficult because of the energetic constraints arising from dense hydrophobic
domains. Polymersomes are more stable than liposomes and they can be made from
biodegradable copolymers with high renal clearance. The hydrophilic block used in
most diblock copolymers is PEG which helps avoid phagocytosis by RES and ensures
long circulatory time (Crayton et al., 2017). Polymersomes can be prepared by film
rehydration, solvent exchange, electroformation, and double emulsion methods
22 New Trends in Smart Nanostructured Biomaterials in Health Sciences
(Anajafi& Mallik, 2015). Smart polymersomes for triggered release of cargo are prepared
from different stimuli-sensitive block copolymers.
For precise delivery to cancer cells, surface modification of polymersomes with
different molecules, namely, antibodies (anti-intercellular adhesion molecule-1 antibody
(Lin et al., 2006;Robbins et al., 2010), antiepidermal growth factor receptor antibody
(Lee et al., 2011), antibiotin IgG, trastuzumab (Egli et al., 2011)), peptides (PR-b peptide
(Demirgöz et al., 2009), RGD peptide (Lai et al., 2012), CGRGDS peptide (Petersen
et al., 2010), G23 peptide (Stojanov et al., 2012)), protein (lactoferrin (Gao et al.,
2010), transferrin (Gao et al., 2010)), hormone (Des-octanoyl ghrelin), vitamin (folate
(Chen, Chiang, Chen, Liang, et al., 2014)), carbohydrate (sialyl Lewis X (Robbins
et al., 2010)), etc., have been reported. Targeted drug delivery by polymersomes can
be visualized in Fig. 1.11.
2.2.4 Dendrimer
The name dendrimer is derived from “dendron”(means tree in Greek) and they are
highly branched (like a tree) polymeric nanoparticles. They were first synthesized in
1978 by Vogtle and colleagues and named by Donald Tomalia (Avti & Kakkar, 2013).
Figure 1.10 Enhancement of drug delivery by incorporating multiple drugs in polymeric micelle.
(Reprinted with permission from Jo, M. J., Jin, I. S., Park, C.-W., Hwang, B. Y., Chung, Y. B., Kim, J.-S., &
Shin, D. H. (2020). Revolutionizing technologies of nanomicelles for combinatorial anticancer drug de-
livery. Archives of Pharmacal Research, 43(1), 100e109. https://doi.org/10.1007/s12272-020-01215-4.)
Smart drug delivery nanostructured systems for cancer therapy 23
They assume a spherical shape in three dimensions. Dendrimers are composed of three
partsda central core, polymeric branches spreading from the core, and functional groups
at the outer end of the branches. Two basic methods are generally adopted for dendrimer
synthesisddivergent and convergent methods. In the divergent approach, the dendrimer
grows outward from the core and in the convergent approach, dendrons with terminal
groups are prepared first which later chemically join the core to attain the full structure
(Chen & Cooper, 2000). Poly(amidoamine) or PAMAM is the most used polymer for
dendrimer preparation (Ambekar et al., 2020). In the past years, different dendrimer var-
iants such as hybrid dendrimers (e.g., Poly(propylene-imine) core-PAMAM shell den-
drimer) (Majoros et al., 2008), dendrimers containing silicone and phosphorus at all
branching points (Caminade, 2017), peptide dendrimers (Sadler & Tam, 2002), multilin-
gual dendrimer (multiple copies of the same functional group are conjugated to the sur-
face), amphiphilic dendrimers, polyamidoamine organosilicon dendrimers, tecto
dendrimer (a dendrimer forms the core to which other dendrimers are attached), chiral
dendrimers, Frechet-type dendrimers (bears eCOOH group as the terminal group),
metallo dendrimers, micellar dendrimers, liquid crystalline dendrimers, etc., have been
reported. For their highly ordered size and shape, low molecular weight, low polydisper-
sity index, micellar nature, and highly modifiable surfaces, dendrimers are an attractive
nanocarrier for drug delivery. Dendrimers can carry hydrophobic drugs in the core
Figure 1.11 Polymersome mediated drug delivery by systematic targeting. (1,2) passive localization
of Polymersome, (3) endocytosis regulated by antibodies, (4,5) enzymatic degradation, (6) dissociation
of Polymersome. (Reprinted with permission from Lee, J. S, Groothuis, T., Cusan, C., Mink, D., &Feijen, J.
(2011). Lysosomally cleavable peptide-containing polymersomes modified with anti-EGFR antibody for
systemic cancer chemotherapy. Biomaterials, 32(34), 9144e9153. https://doi.org/10.1016/j.biomaterials.
2011.08.036.)
24 New Trends in Smart Nanostructured Biomaterials in Health Sciences
and in the voids between the branches, and hydrophilic drugs after conjugation on the
surface (Munavalli et al., 2019, pp. 289e345). Besides drugs, dendrimers can also be
used for gene delivery since they are immunogenic. It was found that glycosylated den-
drimers can more effectively deliver genes than plain dendrimers (Kesharwani et al.,
2017). Dendrimers can be PEGylated to avoid removal by the body’s immune system
and conjugated with folic acid, amino acid, peptide, protein, carbohydrates, fatty acid,
antibody, N-acetylcysteine, biotin, Phosphonates, sulfate, P-hydroxyl benzoic acid, hy-
aluronic acid, etc. for site-specific drug delivery (Choi et al., 2005). Stimuli-responsive
polymers have been used to exercise more control on dendrimer-mediated delivery.
Smart dendrimers synthesized from pH, enzyme, oxidation, reduction, temperature,
light, ultrasound, and magnetic field-sensitive polymers have been reported for chemo-
therapy delivery (specifically, the mechanism of cancer chemotherapy delivery by multi-
stimuli-responsive dendrimer is shown in Fig. 1.12)(Le et al., 2019). Although
dendrimers have shown great promises in targeted delivery in cancer, it is still in its early
stage. The biocompatibility of dendrimer nanocarriers is still not so well established and
this field requires more research to bring dendrimers into clinical application (Munavalli
et al., 2019).
2.2.5 Nanogels
Nanogels are three-dimensional nano-sized networks (20e250 nm) of polymers (may be
hydrophilic or amphiphilic, ionic or nonionic, natural or synthetic). Chitosan, dextran,
dextrin, pullulan, mannan, poly-L-lysine, poly (g-glutamic acid), hyaluronic acid,
Figure 1.12 The mechanism of multi-stimuli-responsive dendrimer in cancer, which is fine-tuned by
surface modification and addition of linker agent. (Reprinted with permission from Le N.T.T., Nguyen
T.N.Q., Cao V.D., Hoang D.T., Ngo V.C., &Hoang Thi T.T. (2019). Recent progress and advances of multi-
stimuli-responsive dendrimers in drug delivery for cancer treatment. Pharmaceutics, 591.)
Smart drug delivery nanostructured systems for cancer therapy 25
alginate, and heparin are some natural polymers used for nanogel preparation. Synthetic
polymers used for nanogels are poly (methyl methacrylate), PLA, PGA, PLGA, poly(ε-
caprolactone), etc. Sometimes a combination of natural and synthetic polymers is used
(Kabanov & Vinogradov, 2009). Nanogels can be fine-tuned for a specific biological sys-
tem to achieve smart application, such as targeted drug delivery to tumor tissue by remote
triggering (Fig. 1.13)(Hang et al., 2017).
Nanogels are prepared by four approaches (Kabanov & Vinogradov, 2009):
1. Physical self-assembly of interactive polymers
2. Polymerization of monomers in homogeneous phase or micro- or nanoheterogene-
ous environment
3. Chemical cross-linking of preformed polymers and
4. Template-assisted nanofabrication of nanogel particles
Among these strategies, physical self-assembly (1) and chemical cross-linking (2) are
the commonest approaches. Physical self-assembly occurs due to various noncovalent in-
teractions such as hydrophobic-hydrophobic or hydrophilic-hydrophilic interactions,
Figure 1.13 Scheme of targeted and remotely triggered delivery of doxorubicin by nanogel.
(Reprinted with permission from Hang, C., Zou, Y., Zhong, Y., Zhong, Z., &Meng, F. (2017). NIR and
UV-responsive degradable hyaluronic acid nanogels for CD44-targeted and remotely triggered intracel-
lular doxorubicin delivery. Colloids and Surfaces B: Biointerfaces, 158, 547e555. https://doi.org/10.1016/
j.colsurfb.2017.07.041.)
26 New Trends in Smart Nanostructured Biomaterials in Health Sciences
ionic interactions, van der Waals forces, hydrogen bonds, and hosteguest interactions.
For cross-linking polymerization, inverse emulsion, RAFT (Reversible Addition-
Fragmentation Chain Transfer), click chemistry, and photo-induced polymerization
methods are applied (Yin et al., 2020). Nanogels are one of the most tunable nanocarriers.
Their particle size, shape, and porous structure can be modified according to need. They
can be made responsive to a wide range of intrinsic and extrinsic stimuli such as temper-
ature, pH, ionic concentration, redox potential, light, dual stimuli-responsive (pH/tem-
perature), and triple stimuli-responsive (pH/temperature/redox). They can encapsulate
both hydrophobic and hydrophilic drugs, oligonucleotides, proteins, and imaging agents,
and can be utilized for a wide range of therapeutic, diagnostic, and theranostic purposes.
Nanogels can be modified with folic acid, transferrin, peptides (such as tumor homing
peptide LyP-1, RGD peptide), and antibodies for targeted delivery. Smart nanogels
loaded with many antineoplastic drugs such as doxorubicin, cisplatin, temozolamide,
5-flurouracil, and fludarabine have been reported (Hajebi et al., 2019). Although with
great promise, nanogels like other nanocarriers have limitations. Failure to completely
remove residual solvents, surfactants, and monomers during nanogel preparation may
cause adverse effects. Toxicity and immunogenicity may also arise from nanogel degra-
dation products and the pharmacokinetic behavior of nanogels may be uncertain. Com-
mercial preparation of nanogels and maintaining desired properties during preparation are
also challenging (Suhail et al., 2019).
2.3 Inorganic nanostructured systems in cancer therapy
Inorganic nanostructured systems for drug delivery can be broadly divided into two
categoriesdmetallic and nonmetallic (Hossain et al., 2021; Khan & Hossain, 2022; Mah-
mud et al., 2022).
2.3.1 Metallic nanoparticles
Since their discovery in the 1970s, metallic nanocarriers have been used in biomedical
applications in general and for drug delivery applications in particular. Metallic nanopar-
ticles of 10e100 nm size have been used as drug carriers (Irfan et al., 2020). Gold and
silver nanoparticles have electronic and optical properties (Afzal et al., 2017,2018),
whereas iron and calcium phosphate nanoparticles have unique magnetic properties
(Hoque et al., 2018;Rahman, Asadul Hoque, et al., 2019;Rahman, Hoque, Rahman,
Azmi, et al., 2019;Rahman, Hoque, Rahman, Gafur, et al., 2019). These unique prop-
erties can be manipulated to make effective drug nanocarriers. Gold nanoparticles
(AuNPs) are easy to prepare and they are biocompatible and nontoxic. They can be easily
conjugated with probe molecules like antibodies, enzymes, nucleotides, etc., and loaded
with anticancer drugs like doxorubicin (Kumari et al., 2016). They have been function-
alized with diverse chemical agents like polyethylene glycol, folic acid, glutathione,
bovine serum albumin, Cyclic Arg-Gly-Asp-Lys peptide, trans-activating transcriptional
Smart drug delivery nanostructured systems for cancer therapy 27
activator (TAT) peptide, etc. (Beik et al., 2019). To date,numerous anticancer drugs like
doxorubicin, cisplatin, imatinib mesylate, oxaliplatin, paclitaxel, methotrexate, sunitinib
malate, bleomycin, etc. have been loaded on AuNPs. AuNPs have shown success in
breast tumor, melanoma, prostate cancer, and colorectal cancer cell lines/animal models
(Beik et al., 2019). Silver nanoparticles (AgNPs) show cytotoxicity against different can-
cer cell lines as well as can protect against DNA damage and oxidative damage. AgNPs
have been conjugated with known anticancer drugs like salinomycin, gemcitabine, and
camptothecine (Ghiut
¸a & Cristea, 2020). As an example, Zeng et al. designed AgNP
with nanosized graphene oxide and used it to conjugate with doxorubicin (Zeng
et al., 2018). This is a facile, one-step process to design a nanocarrier system that is capable
not only of drug delivery but also intracellular biosensing. Additionally, the biocompat-
ibility of these nanocarriers can be further increased by modifying with suitable polymers
and targeting ligands to enhance drug delivery performance (Zeng et al., 2018). Another
kind of nanoparticles that are of particular interest for their magnetic properties are super-
paramagnetic iron oxide nanoparticles (SPIONs) (Anik et al., 2021; Rubel & Hossain,
2022). SPIONs are particularly useful because they can be conjugated with biomolecules
like antibodies, transferrin, aptamers, hyaluronic acid, folate, and peptides (Zhi et al.,
2020). SPIONs hold a special place among nanomaterials because their magnetic prop-
erties allow them to move to a target site in presence of an external magnetic field
(Fig. 1.14)(Anik et al., 2021). Calcium phosphate nanoparticles (CaP NPs) have diverse
applications as a drug delivery platform (Yang et al., 2021). As an example, Wang et al.
reported polyacrylic acid/calcium phosphate nanoparticles as a pH-responsive drug de-
livery platform. These nanocarriers combined with doxorubicin showed enhanced inhi-
bition of tumor growth when compared with the free doxorubicin group (Wang et al.,
2017). Other metallic nanocarriers include quantum dots consisting of group IIeIV (Sn,
Zn, Te, Cd) or IIIeV (IN, As, P) atoms. For example, ZnS-capped CdSe quantum dot-
peptide conjugate has been used for in vivo tumor vasculature targeting (Chamundees-
wari et al., 2019).
2.3.2 Nonmetallic nanoparticles
Nonmetallic nanocarriers are mostly carbon and silica-based nanoparticles. Among the
carbon-based NPs, carbon nanotubes (CNTs), nanodiamonds (NDs), and graphene
quantum dots (GQDs) are the most prevalent, whereas for silica-based NPs, mesoporous
silica and clay nanotubes are the most ubiquitous (Fig. 1.15 shows implementation of
GQD as a theragnostic agent (Ding et al., 2017)). CNTs have some properties like
high aspect ratio, high surface area with low weight, needle structure in the nanosize
range (0.4e100 nm diameter), distinct mechanical, chemical, thermal, and electrical
characteristics which make them desirable in drug delivery applications. Stable structure
and amenability to diverse surface modifications make them a suitable agent to target can-
cer cells. Along these lines, CNTs have been used to encapsulate various anticancer drugs
28 New Trends in Smart Nanostructured Biomaterials in Health Sciences
like paclitaxel, mitomycin, doxorubicin, methotrexate, etc. (Chamundeeswari et al.,
2019). Graphene is another carbon-based nanocarrier that has efficient drug delivery
characteristics. In particular, GQDs, which are graphene blocks with 2D transverse size
(<100 nm), can be used in different drug delivery applications. GQDs have been used
in different drug delivery modes such as enhanced permeability and retention
(EPR)-pH responsive delivery, targeting ligand and pH mediated delivery, EPR-
photothermal responsive delivery, core/shell-photothermal/magnetic thermal respon-
sive delivery, etc. A commonstep involved in delivering anticancer drugs via GQDs to
the target cells is manipulation of the EPR effect. Once uptaken by the cells, these
Figure 1.14 Schematic showing synergistic drug delivery and heat generation in cancer cells by mag-
netic nanoparticles. (Reprinted with permission from Anik, M. I., Hossain, M. K., Hossain, I., Mahfuz, A. M.
U. B., Rahman, M. T., &Ahmed, I. (2021). Recent progress of magnetic nanoparticles in biomedical ap-
plications: A review. Nano Select, nano.202000162-nano.202000162. https://doi.org/10.1002/nano.
202000162.)
Smart drug delivery nanostructured systems for cancer therapy 29
absorbed drugs are released in the cytoplasm by diffusion and adsorption (Zhao et al.,
2020). Like CNTs, NDs also have a high surface area and diverse functionalities which
make them an ideal candidate for conjugation with active anticancer pharmaceutical
agents. NDs have been conjugated with doxorubicin and epirubicin to treat various can-
cer cell lines. One important feature of NDs is they have a strong affinity toward biomol-
ecules like proteins and antibodies and they are water soluble. So, there is no need to
apply the extra step of oxidative modification (Chauhan, Jain, & Nagaich, 2020).
Another group of nonmetallic molecules that are widely used as drug carriers are
silica-based NPs. Mesoporous silica NPs, which possess a large porous honeycomb struc-
ture, can be used to encapsulate various kinds of anticancer drugs. The unique character-
istics of mesoporous silica NPs include high pore volume, high surface area,
biocompatibility, and high loading capacity. By utilizing these unique features, mesopo-
rous silica NPs have been conjugated with antineoplastic drugs like camptothecin and
methotrexate and have been delivered efficiently (Chamundeeswari et al., 2019).
Another widely available type of silica-based NP is clay nanoparticle. These clay nano-
particles also have biocompatibility, chemical inertness, colloidal nature, and thixotropy
that make them suitable as drug carriers. Additionally, intercalation of clay ions and sur-
face modification of clay minerals can tune these drug carriers for effective loading/
release of a drug (Khatoon et al., 2020). Other types of inorganic nanocarriers include
hybrid nanocarriers. Some examples of hybrid nanocarriers are lipid-polymer hybrid
nanocarriers; ceramic-polymer hybrid nanocarriers, etc.
Figure 1.15 Simplified schematic of graphene quantum dot (GQD) as a theragnostic agent. (Reprinted
with permission from Ding, H., Zhang, F., Zhao, C., Lv, Y., Ma, G., Wei, W., &Tian, Z. (2017). Beyond a
carrier: Graphene quantum dots as a probe for programmatically monitoring anti-cancer drug delivery,
release, and response. ACS Applied Materials and Interfaces, 9(33), 27396e27401. https://doi.org/10.
1021/acsami.7b08824.)
30 New Trends in Smart Nanostructured Biomaterials in Health Sciences
3. Conclusions
Drug delivery itself is a highly enriched and diversified topic. Especially, methodologies
associated with cancer-related drug delivery have seen significant improvement over the
last few decades. Therefore, an organized discussion of smart nanostructured drug deliv-
ery systems in an organized manner will facilitate the readers to obtain an overall scenario
of the state of the art in this field. To satisfy such an objective, this chapter provides with
the grounds of smart drug delivery by pinpointing the critical steps of drug delivery and
the relevance of nanostructured systems to them. Furthermore, this chapter discusses syn-
thesis, functionalities from biochemical and biological perspectives, and specific applica-
bilities of lipid-based, polymer-based, and inorganic nanostructured drug delivery
systems. Despite being brief, the topic-wise discussions give idea about the diverse appli-
cations and prospects of such smart drug delivery systems and the feasibility of nanostruc-
tured designs and substantiate their utility in cancer therapy.
References
Abdelkader, H., Alani, A. W. G., & Alany, R. G. (2014). Recent advances in non-ionic surfactant vesicles
(niosomes): Self-assembly, fabrication, characterization, drug delivery applications and limitations. Drug
Delivery, 21(2), 87e100. https://doi.org/10.3109/10717544.2013.838077
Abu Lila, A. S., Kiwada, H., & Ishida, T. (2013). The accelerated blood clearance (ABC) phenomenon: Clin-
ical challenge and approaches to manage. Journal of Controlled Release, 172(1), 38e47. https://doi.org/
10.1016/j.jconrel.2013.07.026
Afzal, M., Ashraf, M., Tayyaba, S., Hossain, M., & Afzulpurkar, N. (2018). Sinusoidal microchannel with
descending curves for varicose veins implantation. Micromachines, 9(2), 59. https://doi.org/10.3390/
mi9020059
Afzal, M., Tayyaba, S., Ashraf, M., Hossain, M., Uddin, M., & Afzulpurkar, N. (2017). Simulation, fabrica-
tion and analysis of silver based ascending sinusoidal microchannel (ASMC) for implant of varicose veins.
Micromachines, 8(9), 278. https://doi.org/10.3390/mi8090278
Ag Seleci, D., Seleci, M., Walter, J.-G., Stahl, F., & Scheper, T. (2016). Niosomes as nanoparticular drug
carriers: Fundamentals and recent applications. Journal of Nanomaterials,1e13. https://doi.org/
10.1155/2016/7372306
Agrawal, M., Ajazuddin, Tripathi, D. K., Saraf, S., Saraf, S., Antimisiaris, S. G., Mourtas, S., Hammarlund-
Udenaes, M., & Alexander, A. (2017). Recent advancements in liposomes targeting strategies to cross
blood-brain barrier (BBB) for the treatment of Alzheimer’s disease. Journal of Controlled Release, 260,
61e77. https://doi.org/10.1016/j.jconrel.2017.05.019
Ahmad, S. S., Reinius, M. A., Hatcher, H. M., & Ajithkumar, T. V. (2016). Anticancer chemotherapy in
teenagers and young adults: Managing long term side effects. BMJ, 354, i4567. https://doi.org/
10.1136/bmj.i4567
Alshahrani, S. M., Alshetaili, A. S., Alalaiwe, A., Alsulays, B. B., Anwer, M. K., Al-Shdefat, R., Imam, F., &
Shakeel, F. (2018). Anticancer efficacy of self-nanoemulsifying drug delivery system of sunitinib malate.
AAPS PharmSciTech, 19(1), 123e133. https://doi.org/10.1208/s12249-017-0826-x
Ambekar, R. S., Choudhary, M., & Kandasubramanian, B. (2020). Recent advances in dendrimer-based
nanoplatform for cancer treatment: A review. European Polymer Journal, 126, 109546. https://doi.org/
10.1016/j.eurpolymj.2020.109546
Anajafi, T., & Mallik, S. (2015). Polymersome-based drug-delivery strategies for cancer therapeutics. Ther-
apeutic Delivery, 6(4), 521e534. https://doi.org/10.4155/tde.14.125
Anik, M. I., Hossain, M. K., Hossain, I., Ahmed, I., & Doha, R. M. (2021). Biomedical applications of mag-
netic nanoparticles. In A. Ehrmann, T. A. Nguyen, M. Ahmadi, A. Farmani, & P. Nguyen-Tri (Eds.),
Smart drug delivery nanostructured systems for cancer therapy 31
Magnetic Nanoparticle-Based Hybrid Materials (1st ed., pp. 463e497). Elsevier. https://doi.org/10.1016/
B978-0-12-823688-8.00002-8
Anik, M. I., Hossain, M. K., Hossain, I., Mahfuz, A. M. U. B., Rahman, M. T., & Ahmed, I. (2021). Recent
progress of magnetic nanoparticles in biomedical applications: A review. Nano Select.https://doi.org/
10.1002/nano.202000162. nano.202000162-nano.202000162.
Ansari, M. J., Alnakhli, M., Al-Otaibi, T., Meanazel, O. A., Anwer, M. K., Ahmed, M. M.,
Alshahrani, S. M., Alshetaili, A., Aldawsari, M. F., Alalaiwe, A. S., Alanazi, A. Z., Zahrani, M. A., &
Ahmad, N. (2021). Formulation and evaluation of self-nanoemulsifying drug delivery system of briga-
tinib: Improvement of solubility, in vitro release, ex-vivo permeation and anticancer activity. Journal of
Drug Delivery Science and Technology, 61, 102204. https://doi.org/10.1016/j.jddst.2020.102204
Aswathanarayan, J. B., & Vittal, R. R. (2019). Nanoemulsions and their potential applications in food
industry. Frontiers in Sustainable Food Systems, 3, 95. https://doi.org/10.3389/fsufs.2019.00095
Attia, M. F., Anton, N., Wallyn, J., Omran, Z., & Vandamme, T. F. (2019). An overview of active and pas-
sive targeting strategies to improve the nanocarriers efficiency to tumour sites. Journal of Pharmacy and
Pharmacology, 71(8), 1185e1198. https://doi.org/10.1111/jphp.13098
Avti, P. K., & Kakkar, A. (2013). Dendrimers as anti-inflammatory agents. Brazilian Journal of Pharmaceutical
Sciences, 49(spe), 57e65. https://doi.org/10.1590/S1984-82502013000700006
Bazan Henostroza, M. A., Curo Melo, K. J., Nishitani Yukuyama, M., Löbenberg, R., & Araci Bou-
Chacra, N. (2020). Cationic rifampicin nanoemulsion for the treatment of ocular tuberculosis. Colloids
and Surfaces A: Physicochemical and Engineering Aspects, 597, 124755. https://doi.org/10.1016/
j.colsurfa.2020.124755
Beik, J., Khateri, M., Khosravi, Z., Kamrava, S. K., Kooranifar, S., Ghaznavi, H., & Shakeri-Zadeh, A.
(2019). Gold nanoparticles in combinatorial cancer therapy strategies. Coordination Chemistry Reviews,
387, 299e324. https://doi.org/10.1016/j.ccr.2019.02.025
Bhardwaj, P., Tripathi, P., Gupta, R., & Pandey, S. (2020). Niosomes: A review on niosomal research in the
last decade. Journal of Drug Delivery Science and Technology, 56, 101581. https://doi.org/10.1016/
j.jddst.2020.101581
Biswas, M. C., Chowdhury, A., Hossain, M. M., & Hossain, M. K. (2022). Applications, drawbacks and
future scope of nanoparticles-based polymer composites. In M. R. Sanjay, J. Parameswaranpillai,
T. G. Yashas Gowda, I. H. S. Siengchin, & M. €
O. Seydibeyoglu (Eds.), Metal Nanoparticle-Based Polymer
Composites (1st ed.). Elsevier. https://doi.org/10.1016/B978-0-12-824272-8.00002-6
Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A., & Jemal, A. (2018). Global cancer statistics
2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
CA: A Cancer Journal for Clinicians, 68(6), 394e424. https://doi.org/10.3322/caac.21492
Çagdas
¸, M., Sezer, A. D., & Bucak, S. (2014). Liposomes as potential drug carrier systems for drug delivery.
In Application of nanotechnology in drug delivery (pp. 1e100). InTech. https://doi.org/10.5772/58459
Caminade, A.-M. (2017). Phosphorus dendrimers for nanomedicine. Chemical Communications, 53(71),
9830e9838. https://doi.org/10.1039/C7CC04949H
Cevc, G. (2012). Rational design of new product candidates: The next generation of highly deformable
bilayer vesicles for noninvasive, targeted therapy. Journal of Controlled Release, 160(2), 135e146.
https://doi.org/10.1016/j.jconrel.2012.01.005
Chamundeeswari, M., Jeslin, J., & Verma, M. L. (2019). Nanocarriers for drug delivery applications. Envi-
ronmental Chemistry Letters, 17(2), 849e865. https://doi.org/10.1007/s10311-018-00841-1
Chauhan, S., Jain, N., & Nagaich, U. (2020). Nanodiamonds with powerful ability for drug delivery and
biomedical applications: Recent updates on in vivo study and patents. Journal of Pharmaceutical Analysis,
10(1), 1e12. https://doi.org/10.1016/j.jpha.2019.09.003
Chen, Y.-C., Chiang, C.-F., Chen, L.-F., Liang, P.-C., Hsieh, W.-Y., & Lin, W.-L. (2014). Polymersomes
conjugated with des-octanoyl ghrelin and folate as a BBB-penetrating cancer cell-targeting delivery
system. Biomaterials, 35(13), 4066e4081. https://doi.org/10.1016/j.biomaterials.2014.01.042
Chen, C. Z., & Cooper, S. L. (2000). Recent advances in antimicrobial dendrimers. Advanced Materials,
12(11), 843e846. https://doi.org/10.1002/(SICI)1521-4095(200006)12:11<843::AID-
ADMA843>3.0.CO;2-T
Cheng, Y., & Ji, Y. (2019). RGD-modified polymer and liposome nanovehicles: Recent research progress
for drug delivery in cancer therapeutics. European Journal of Pharmaceutical Sciences, 128,8e17. https://
doi.org/10.1016/j.ejps.2018.11.023
32 New Trends in Smart Nanostructured Biomaterials in Health Sciences
Chime, S. A., Kenechukwu, F. C., & Attama, A. A. (2014). Nanoemulsionsdadvances in formulation, char-
acterization and applications in drug delivery. In Application of nanotechnology in drug delivery (Vol. 3)
InTech. https://doi.org/10.5772/58673
Choi, Y., Thomas, T., Kotlyar, A., Islam, M. T., & Baker, J. R. (2005). Synthesis and functional evaluation
of DNA-assembled polyamidoamine dendrimer clusters for cancer cell-specific targeting. Chemistry and
Biology, 12(1), 35e43. https://doi.org/10.1016/j.chembiol.2004.10.016
Cho, H.-Y., Kang, J.-H., Ngo, L., Tran, P., & Lee, Y.-B. (2016). Preparation and evaluation of solid-self-
emulsifying drug delivery system containing paclitaxel for lymphatic delivery. Journal of Nanomaterials,
1e14. https://doi.org/10.1155/2016/3642418
Cholkar, K., Patel, A., Dutt Vadlapudi, A., & Mitra, K. (2012). Novel nanomicellar formulation approaches
for anterior and posterior segment ocular drug delivery. Recent Patents on Nanomedicinee, 2(2), 82e95.
https://doi.org/10.2174/1877912311202020082
Chongprakobkit, S., & Tachaboonyakiat, W. (2013). A thermal controlled release of naproxen from sodium
phosphorylated chitosan nanoemulsion. Advanced Materials Research, 701, 217e221. https://doi.org/
10.4028/www.scientific.net/AMR.701.217
Crayton, S. H., Chen, A. K., Liu, J. F., Higbee-Dempsey, E. M., Huang, C.-H., Tsourkas, A., & Cheng, Z.
(2017). 3.20 molecular imaging. In Comprehensive biomaterials II (pp. 424e466). Elsevier. https://doi.org/
10.1016/B978-0-12-803581-8.10222-X
Date, A. A., Desai, N., Dixit, R., & Nagarsenker, M. (2010). Self-nanoemulsifying drug delivery systems:
Formulation insights, applications and advances. Nanomedicine, 5(10), 1595e1616. https://doi.org/
10.2217/nnm.10.126
Demirgöz, D., Pangburn, T. O., Davis, K. P., Lee, S., Bates, F. S., & Kokkoli, E. (2009). PR_b-targeted
delivery of tumor necrosis factor-aby polymersomes for the treatment of prostate cancer. Soft Matter,
5(10), 2011. https://doi.org/10.1039/b814217c
Deodhar, S., & Dash, A. K. (2018). Long circulating liposomes: Challenges and opportunities. Therapeutic
Delivery, 9(12), 857e872. https://doi.org/10.4155/tde-2018-0035
Ding, H., Zhang, F., Zhao, C., Lv, Y., Ma, G., Wei, W., & Tian, Z. (2017). Beyond a carrier: Graphene
quantum dots as a probe for programmatically monitoring anti-cancer drug delivery, release, and
response. ACS Applied Materials and Interfaces, 9(33), 27396e27401. https://doi.org/10.1021/
acsami.7b08824
Discher, B. M. (1999). Polymersomes: Tough vesicles made from diblock copolymers. Science, 284(5417),
1143e1146. https://doi.org/10.1126/science.284.5417.1143
Egli, S., Nussbaumer, M. G., Balasubramanian, V., Chami, M., Bruns, N., Palivan, C., & Meier, W. (2011).
Biocompatible functionalization of polymersome surfaces: A new approach to surface immobilization
and cell targeting using polymersomes. Journal of the American Chemical Society, 133(12), 4476e4483.
https://doi.org/10.1021/ja110275f
Elliott, J. A., Flam, B., Muffly, K., Strom, J. A., Hood, E., & VanAuker, M. D. (2009). Targeted drug delivery
with PEGylated immuno-niosomes. In 25th southern biomedical engineering conference 2009, 15e17 May 2009
(pp. 363e366). Miami, Florida, USA: Springer. https://doi.org/10.1007/978-3-642-01697-4_124
Fang, Y., Xue, J., Gao, S., Lu, A., Yang, D., Jiang, H., He, Y., & Shi, K. (2017). Cleavable PEGylation: A
strategy for overcoming the “PEG dilemma”in efficient drug delivery. Drug Delivery, 24(2), 22e32.
https://doi.org/10.1080/10717544.2017.1388451
Fisher, O. Z., Khademhosseini, A., & Peppas, N. A. (2010). Drug delivery: Nanoscale devices. In Encyclo-
pedia of materials: Science and technology (pp. 1e9). Elsevier. https://doi.org/10.1016/B978-008043152-
9.02233-8
Franze, S., Selmin, F., Samaritani, E., Minghetti, P., & Cilurzo, F. (2018). Lyophilization of liposomal for-
mulations: Still necessary, still challenging. Pharmaceutics, 10(3), 139. https://doi.org/10.3390/
pharmaceutics10030139
Gao, H., Pang, Z., Fan, L., Hu, K., Wu, B., & Jiang, X. (2010). Effect of lactoferrin- and transferrin-
conjugated polymersomes in brain targeting: In vitro and in vivo evaluations. Acta Pharmacologica Sinica,
31(2), 237e243. https://doi.org/10.1038/aps.2009.199
García-Pinel, B., Porras-Alcala, C., Ortega-Rodríguez, A., Sarabia, F., Prados, J., Melguizo, C., & Lopez-
Romero, J. M. (2019). Lipid-based nanoparticles: Application and recent advances in cancer
treatment. Nanomaterials, 9(4), 638. https://doi.org/10.3390/nano9040638
Ghiut
¸a, I., & Cristea, D. (2020). Silver nanoparticles for delivery purposes. In Nanoengineered biomaterials for
advanced drug delivery (pp. 347e371). Elsevier. https://doi.org/10.1016/B978-0-08-102985-5.00015-2
Smart drug delivery nanostructured systems for cancer therapy 33
Grund, S., Bauer, M., & Fischer, D. (2011). Polymers in drug delivery-state of the art and future trends.
Advanced Engineering Materials, 13(3), B61eB87. https://doi.org/10.1002/adem.201080088
Guler, E., Demir, B., Guler, B., Demirkol, D. O., & Timur, S. (2017). BiofuNctionalized nanomaterials for
targeting cancer cells. In Nanostructures for cancer therapy (pp. 51e86). Elsevier. https://doi.org/10.1016/
B978-0-323-46144-3.00003-9
Guo, S., & Huang, L. (2011). Nanoparticles escaping RES and endosome: Challenges for siRNA delivery for
cancer therapy. Journal of Nanomaterials, 2011,1e12. https://doi.org/10.1155/2011/742895
Hajebi, S., Rabiee, N., Bagherzadeh, M., Ahmadi, S., Rabiee, M., Roghani-Mamaqani, H., Tahriri, M.,
Tayebi, L., & Hamblin, M. R. (2019). Stimulus-responsive polymeric nanogels as smart drug delivery
systems. Acta Biomaterialia, 92,1e18. https://doi.org/10.1016/j.actbio.2019.05.018
Hang, C., Zou, Y., Zhong, Y., Zhong, Z., & Meng, F. (2017). NIR and UV-responsive degradable hyal-
uronic acid nanogels for CD44-targeted and remotely triggered intracellular doxorubicin delivery. Col-
loids and Surfaces B: Biointerfaces, 158, 547e555. https://doi.org/10.1016/j.colsurfb.2017.07.041
Hanumanaik, M., Patel, S. K., & Sree, K. R. (2013). Solid lipid nanoparticles: A review. International Journal of
Pharmaceutical Sciences and Research, 4(3), 928e940.
He, Y., Xue, C., Yu, Y., Chen, J., Chen, X., Ren, F., Ren, Z., Cui, G., & Sun, R. (2018). CD44 is over-
expressed and correlated with tumor progression in gallbladder cancer. Cancer Management and Research,
10, 3857e3865. https://doi.org/10.2147/CMAR.S175681
Heynick, F. (2009). The original ‘magic bullet’is 100 years old. British Journal of Psychiatry, 195(5), 456.
https://doi.org/10.1192/bjp.195.5.456
Hoque, Md A., Ahmed, M. R., Rahman, G. T., Rahman, M. T., Islam, M. A., Khan, M. A., &
Hossain, M. K. (2018). Fabrication and comparative study of magnetic Fe and a-Fe2O3 nanoparticles
dispersed hybrid polymer (PVA þChitosan) novel nanocomposite film. Results in Physics, 10, 434e443.
https://doi.org/10.1016/j.rinp.2018.06.010
Hossain, M. K., Khan, M. I., & El-Denglawey, A. (2021). A review on biomedical applications, prospects,
and challenges of rare earth oxides. Applied Materials Today, 24, 101104. https://doi.org/10.1016/
j.apmt.2021.101104
Hossen, S., Hossain, M. K., Basher, M. K., Mia, M. N. H., Rahman, M. T., & Uddin, M. J. (2019). Smart
nanocarrier-based drug delivery systems for cancer therapy and toxicity studies: A review. Journal of
Advanced Research, 15,1e18. https://doi.org/10.1016/j.jare.2018.06.005
Irfan, F., Iqbal, T., Malik, N., & Ijaz, M. (2020). A review on nanocarriers for cancer targeted drug delivery.
Pakistan Journal of Scientific and Industrial Research Series A: Physical Sciences, 63(3), 239e246.
Isalomboto Nkanga, C., Murhimalika Bapolisi, A., Ikemefuna Okafor, N., & Werner Maçedo Krause, R.
(2019). General perception of liposomes: Formation, manufacturing and applications. In Liposomes - ad-
vances and perspectives. IntechOpen. https://doi.org/10.5772/intechopen.84255
Jaiswal, M., Dudhe, R., & Sharma, P. K. (2015). Nanoemulsion: An advanced mode of drug delivery system.
3 Biotech, 5(2), 123e127. https://doi.org/10.1007/s13205-014-0214-0
Jeevana Jyothi, B., & Sreelakshmi, K. (2011). Design and evaluation of self-nanoemulsifying drug delivery
system of Flutamide. Journal of Young Pharmacists, 3(1), 4e8. https://doi.org/10.4103/0975-1483.76413
Jiao, J. (2008). Polyoxyethylated nonionic surfactants and their applications in topical ocular drug delivery.
Advanced Drug Delivery Reviews, 60(15), 1663e1673. https://doi.org/10.1016/j.addr.2008.09.002
Jia, L., Pang, M., Fan, M., Tan, X., Wang, Y., Huang, M., Liu, Y., Wang, Q., Zhu, Y., & Yang, X. (2020).
A pH-responsive pickering nanoemulsion for specified spatial delivery of immune checkpoint inhibitor
and chemotherapy agent to tumors. Theranostics, 10(22), 9956e9969. https://doi.org/10.7150/
thno.46089
Jo, M. J., Jin, I. S., Park, C.-W., Hwang, B. Y., Chung, Y. B., Kim, J.-S., & Shin, D. H. (2020). Revolu-
tionizing technologies of nanomicelles for combinatorial anticancer drug delivery. Archives of Pharmacal
Research, 43(1), 100e109. https://doi.org/10.1007/s12272-020-01215-4
Junyaprasert, V. B., Teeranachaideekul, V., & Supaperm, T. (2008). Effect of charged and non-ionic mem-
brane additives on physicochemical properties and stability of niosomes. AAPS PharmSciTech, 9(3), 851.
https://doi.org/10.1208/s12249-008-9121-1
Kabanov, A. V., & Vinogradov, S. V. (2009). Nanogels as pharmaceutical carriers: Finite networks of infinite
capabilities. Angewandte Chemie International Edition, 48(30), 5418e5429. https://doi.org/10.1002/
anie.200900441
34 New Trends in Smart Nanostructured Biomaterials in Health Sciences
Kesharwani, P., Amin, M. C. I. M., Giri, N., Jain, A., & Gajbhiye, V. (2017). Dendrimers in targeting and
delivery of drugs. In Nanotechnology-based approaches for targeting and delivery of drugs and genes (pp.
363e388). Elsevier. https://doi.org/10.1016/B978-0-12-809717-5.00013-0
Khan, S., & Hossain, M. K. (2022). Classification and properties of nanoparticles. In M. R. Sanjay,
J. Parameswaranpillai, T. G. Yashas Gowda, I. H. S. Siengchin, & M. €
O. Seydibeyoglu (Eds.), Metal
Nanoparticle-Based Polymer Composites (1st ed.). Elsevier. https://doi.org/10.1016/B978-0-12-824272-
8.00009-9
Khan, M. I., Hossain, M. I., Hossain, M. K., Rubel, M. H. K., Hossain, K. M., Mahfuz, A. M. U. B., &
Anik, M. I. (2022). Recent progress in nanostructured smart drug delivery systems for cancer therapy:
A review. ACS Applied Bio Materials, 5, 971e1012. https://doi.org/10.1021/acsabm.2c00002
Khan, R., & Irchhaiya, R. (2016). Niosomes: A potential tool for novel drug delivery. Journal of Pharmaceutical
Investigation, 46(3), 195e204. https://doi.org/10.1007/s40005-016-0249-9
Khatoon, N., Chu, M. Q., & Zhou, C. H. (2020). Nanoclay-based drug delivery systems and their thera-
peutic potentials. Journal of Materials Chemistry B, 8(33), 7335e7351. https://doi.org/10.1039/
D0TB01031F
Kotoucek, J., Hubatka, F., Masek, J., Kulich, P., Velínska, K., Bezdekova, J., Fojtíkova, M.,
Bartheldyova, E., Tomeckova, A., Straska, J., Hrebík, D., Macaulay, S., Kratochvílova, I., Raska, M.,
& Turanek, J. (2020). Preparation of nanoliposomes by microfluidic mixing in herring-bone channel
and the role of membrane fluidity in liposomes formation. Scientific Reports, 10(1), 5595. https://
doi.org/10.1038/s41598-020-62500-2
Kulthe, S. S., Choudhari, Y. M., Inamdar, N. N., & Mourya, V. (2012). Polymeric micelles: Authoritative
aspects for drug delivery. Designed Monomers and Polymers, 15(5), 465e521. https://doi.org/10.1080/
1385772X.2012.688328
Kumari, P., Ghosh, B., & Biswas, S. (2016). Nanocarriers for cancer-targeted drug delivery. Journal of Drug
Targeting, 24(3), 179e191. https://doi.org/10.3109/1061186X.2015.1051049
Kumar, G. P., & Rajeshwarrao, P. (2011). Nonionic surfactant vesicular systems for effective drug deliveryd
an overview. Acta Pharmaceutica Sinica B, 1(4), 208e219. https://doi.org/10.1016/j.apsb.2011.09.002
Lai, M., Jeong, J. H., DeVolder, R. J., Brockman, C., Schroeder, C., & Kong, H. (2012). Ellipsoidal poly-
aspartamide polymersomes with enhanced cell-targeting ability. Advanced Functional Materials, 22(15),
3239e3246. https://doi.org/10.1002/adfm.201102664
Lee, Jung S., Groothuis, T., Cusan, C., Mink, D., & Feijen, J. (2011). Lysosomally cleavable peptide-
containing polymersomes modified with anti-EGFR antibody for systemic cancer chemotherapy. Bio-
materials, 32(34), 9144e9153. https://doi.org/10.1016/j.biomaterials.2011.08.036
Lee, Y., & Thompson, D. H. (2017). Stimuli-responsive liposomes for drug delivery. Wiley Interdisciplinary
Reviews: Nanomedicine and Nanobiotechnology, 9(5), e1450. https://doi.org/10.1002/wnan.1450
Le, N. T. T., Nguyen, T. N. Q., Cao, V. D., Hoang, D. T., Ngo, V. C., & Hoang Thi, T. T. (2019). Recent
progress and advances of multi-stimuli-responsive dendrimers in drug delivery for cancer treatment.
Pharmaceutics, 11(11), 591. https://doi.org/10.3390/pharmaceutics11110591
Liang, Y., Tian, B., Zhang, J., Li, K., Wang, L., Han, J., & Wu, Z. (2017). Tumor-targeted polymeric nano-
structured lipid carriers with precise ratiometric control over dual-drug loading for combination therapy
in non-small-cell lung cancer. International Journal of Nanomedicine, 12, 1699e1715. https://doi.org/
10.2147/IJN.S121262
Liang, T., Yao, Z., Ding, J., Min, Q., Jiang, L., & Zhu, J.-J. (2018). Cascaded aptamers-governed multistage
drug-delivery system based on biodegradable envelope-type nanovehicle for targeted therapy of HER2-
overexpressing breast cancer. ACS Applied Materials and Interfaces, 10(40), 34050e34059. https://
doi.org/10.1021/acsami.8b14009
Lin, J. J., Ghoroghchian, P. P., Zhang, Y., & Hammer, D. A. (2006). Adhesion of antibody-functionalized
polymersomes. Langmuir, 22(9), 3975e3979. https://doi.org/10.1021/la052445c
Liu, F., Lin, S., Zhang, Z., Hu, J., Liu, G., Tu, Y., Yang, Y., Zou, H., Mo, Y., & Miao, L. (2014). pH-
responsive nanoemulsions for controlled drug release. Biomacromolecules, 15(3), 968e977. https://
doi.org/10.1021/bm4018484
Liu, D., Yang, F., Xiong, F., & Gu, N. (2016). The smart drug delivery system and its clinical potential.
Theranostics, 6(9), 1306e1323. https://doi.org/10.7150/thno.14858
Smart drug delivery nanostructured systems for cancer therapy 35
Liu, C., Zhang, L., Zhu, W., Guo, R., Sun, H., Chen, X., & Deng, N. (2020). Barriers and strategies of
cationic liposomes for cancer gene therapy. Molecular TherapydMethods and Clinical Development, 18,
751e764. https://doi.org/10.1016/j.omtm.2020.07.015
Loureiro, A., Abreu, A. S., Sarria, M. P., Figueiredo, M. C. O., Saraiva, L. M., Bernardes, G. J. L.,
Gomes, A. C., & Cavaco-Paulo, A. (2015). Functionalized protein nanoemulsions by incorporation
of chemically modified BSA. RSC Advances, 5(7), 4976e4983. https://doi.org/10.1039/C4RA13802C
Mahmud, N., Anik, M. I., Hossain, M. K., Khan, M. I., Uddin, S., Ashrafuzzaman, M., & Rahaman, M. M.
(2022). Advances in nanomaterial-based platforms to combat COVID-19: Diagnostics, preventions,
therapeutics, and vaccine developments. ACS Applied Bio Materials.https://doi.org/10.1021/
acsabm.2c00123
Maja, L.,
Zeljko, K., & Mateja, P. (2020). Sustainable technologies for liposome preparation. The Journal of
Supercritical Fluids, 165, 104984. https://doi.org/10.1016/j.supflu.2020.104984
Majoros, I. J., Williams, C. R., Tomalia, D. A., & Baker, J. R. (2008). New dendrimers: Synthesis and char-
acterization of POPAMPAMAM hybrid dendrimers. Macromolecules, 41(22), 8372e8379. https://
doi.org/10.1021/ma801843a
Majumder, N., G Das, N., & Das, S. K. (2020). Polymeric micelles for anticancer drug delivery. Therapeutic
Delivery, 11(10), 613e635. https://doi.org/10.4155/tde-2020-0008
Maniyar, M. G., & Kokare, C. R. (2019). Formulation and evaluation of spray dried liposomes of lopinavir
for topical application. Journal of Pharmaceutical Investigation, 49(2), 259e270. https://doi.org/10.1007/
s40005-018-0403-7
Marianecci, C., Di Marzio, L., Rinaldi, F., Celia, C., Paolino, D., Alhaique, F., Esposito, S., & Carafa, M.
(2014). Niosomes from 80s to present: The state of the art. Advances in Colloid and Interface Science, 205,
187e206. https://doi.org/10.1016/j.cis.2013.11.018
Massing, U., Cicko, S., & Ziroli, V. (2008). Dual asymmetric centrifugation (DAC)da new technique for
liposome preparation. Journal of Controlled Release, 125(1), 16e24. https://doi.org/10.1016/
j.jconrel.2007.09.010
Moghassemi, S., & Hadjizadeh, A. (2014). Nano-niosomes as nanoscale drug delivery systems: An illustrated
review. Journal of Controlled Release, 185,22e36. https://doi.org/10.1016/j.jconrel.2014.04.015
M€uller, R. H., Radtke, M., & Wissing, S. A. (2002). Solid lipid nanoparticles (SLN) and nanostructured lipid
carriers (NLC) in cosmetic and dermatological preparations. Advanced Drug Delivery Reviews, 54,
S131eS155. https://doi.org/10.1016/S0169-409X(02)00118-7
Munavalli, B. B., Naik, S. R., Torvi, A. I., & Kariduraganavar, M. Y. (2019). Dendrimers. Springer Interna-
tional Publishing. https://doi.org/10.1007/978-3-319-95987-0_9
Muzzalupo, R., & Mazzotta, E. (2019). Do niosomes have a place in the field of drug delivery? Expert
Opinion on Drug Delivery, 16(11), 1145e1147. https://doi.org/10.1080/17425247.2019.1663821
Noble, G. T., Stefanick, J. F., Ashley, J. D., Kiziltepe, T., & Bilgicer, B. (2014). Ligand-targeted liposome
design: Challenges and fundamental considerations. Trends in Biotechnology, 32(1), 32e45. https://
doi.org/10.1016/j.tibtech.2013.09.007
Nottingham, E., Sekar, V., Mondal, A., Safe, S., Rishi, A. K., & Singh, M. (2020). The role of self-
nanoemulsifying drug delivery systems of CDODA-me in sensitizing erlotinib-resistant nonesmall
cell lung cancer. Journal of Pharmaceutical Sciences, 109(6), 1867e1882. https://doi.org/10.1016/
j.xphs.2020.01.010
Nurgali, K., Jagoe, R. T., & Abalo, R. (2018). Editorial: Adverse effects of cancer chemotherapy: Anything
new to improve tolerance and reduce sequelae? Frontiers in Pharmacology, 9, 245. https://doi.org/
10.3389/fphar.2018.00245
Osman, M., Al-Kreathy, H. M., Al-Zahrani, A., Ahmed, O. A., Ramadan, W. S., ElShal, M. F., Al-
Hart, S. E., Ali, A. S., & Khan, M. L. (2017). Enhancement of efficacy and reduced toxicity of cisplatin
through self nanoemulsifying drug delivery system (SNEDDS). International Journal of Pharmacology,
13(3), 292e302. https://doi.org/10.3923/ijp.2017.292.302
Parvej, M. S., Khan, M. I., & Hossain, M. K. (2022). Preparation of nanoparticles-based polymer composites.
In M. R. Sanjay, J. Parameswaranpillai, T. G. Yashas Gowda, I. H. S. Siengchin, & M. €
O. Seydibeyoglu
(Eds.), Metal Nanoparticle-Based Polymer Composites (1st ed.). Elsevier. https://doi.org/10.1016/B978-0-
12-824272-8.00013-0
Pattni, B. S., Chupin, V. V., & Torchilin, V. P. (2015). New developments in liposomal drug delivery.
Chemical Reviews, 115(19), 10938e10966. https://doi.org/10.1021/acs.chemrev.5b00046
36 New Trends in Smart Nanostructured Biomaterials in Health Sciences
Peer, D., Karp, J. M., Hong, S., Farokhzad, O. C., Margalit, R., & Langer, R. (2007). Nanocarriers as an
emerging platform for cancer therapy. Nature Nanotechnology, 2(12), 751e760. https://doi.org/
10.1038/nnano.2007.387
Petersen, M. A., Yin, L., Kokkoli, E., & Hillmyer, M. A. (2010). Synthesis and characterization of reactive
PEOePMCL polymersomes. Polymer Chemistry, 1(8), 1281. https://doi.org/10.1039/c0py00143k
Pham, T. T., Jaafar-Maalej, C., Charcosset, C., & Fessi, H. (2012). Liposome and niosome preparation using
a membrane contactor for scale-up. Colloids and Surfaces B: Biointerfaces, 94,15e21. https://doi.org/
10.1016/j.colsurfb.2011.12.036
Pink, D. L., Loruthai, O., Ziolek, R. M., Wasutrasawat, P., Terry, A. E., Lawrence, M. J., & Lorenz, C. D.
(2019). On the structure of solid lipid nanoparticles. Small, 15(45), 1903156. https://doi.org/10.1002/
smll.201903156
Rahman, M. T., Asadul Hoque, Md, Rahman, G. T., Gafur, M. A., Khan, R. A., & Hossain, M. K. (2019).
Study on the mechanical, electrical and optical properties of metal-oxide nanoparticles dispersed unsat-
urated polyester resin nanocomposites. Results in Physics, 13, 102264. https://doi.org/10.1016/
j.rinp.2019.102264
Rahman, M. T., Hoque, Md A., Rahman, G. T., Azmi, M. M., Gafur, M. A., Khan, R. A., &
Hossain, M. K. (2019). Fe
2
O
3
nanoparticles dispersed unsaturated polyester resin based nanocomposites:
Effect of gamma radiation on mechanical properties. Radiation Effects and Defects in Solids, 174(5e6),
480e493. https://doi.org/10.1080/10420150.2019.1606809
Rahman, M. T., Hoque, M. A., Rahman, G. T., Gafur, M. A., Khan, R. A., & Hossain, M. K. (2019). Eval-
uation of thermal, mechanical, electrical and optical properties of metal-oxide dispersed HDPE
nanocomposites. Materials Research Express, 6(8), 085092. https://doi.org/10.1088/2053-1591/ab22d8
Rapoport, N. Y., Kennedy, A. M., Shea, J. E., Scaife, C. L., & Nam, K.-H. (2009). Controlled and targeted
tumor chemotherapy by ultrasound-activated nanoemulsions/microbubbles. Journal of Controlled Release,
138(3), 268e276. https://doi.org/10.1016/j.jconrel.2009.05.026
Rehman, F. U., Shah, K. U., Shah, S. U., Khan, I. U., Khan, G. M., & Khan, A. (2017). From nanoemul-
sions to self-nanoemulsions, with recent advances in self-nanoemulsifying drug delivery systems
(SNEDDS). Expert Opinion on Drug Delivery, 14(11), 1325e1340. https://doi.org/10.1080/
17425247.2016.1218462
Rinaldi, F., Del Favero, E., Rondelli, V., Pieretti, S., Bogni, A., Ponti, J., Rossi, F., Di Marzio, L.,
Paolino, D., Marianecci, C., & Carafa, M. (2017). pH-sensitive niosomes: Effects on cytotoxicity and
on inflammation and pain in murine models. Journal of Enzyme Inhibition and Medicinal Chemistry,
32(1), 538e546. https://doi.org/10.1080/14756366.2016.1268607
Robbins, G. P., Saunders, R. L., Haun, J. B., Rawson, J., Therien, M. J., & Hammer, D. A. (2010). Tunable
leuko-polymersomes that adhere specifically to inflammatory markers. Langmuir, 26(17), 14089e14096.
https://doi.org/10.1021/la1017032
Rojanarat, W., Changsan, N., Tawithong, E., Pinsuwan, S., Chan, H.-K., & Srichana, T. (2011). Isoniazid
proliposome powders for inhalationdpreparation, characterization and cell culture studies. International
Journal of Molecular Sciences, 12(7), 4414e4434. https://doi.org/10.3390/ijms12074414
Rubel, M. H. K., & Hossain, M. K. (2022). Crystal structures and properties of nanomagnetic materials. In
R. K. Gupta, S. R. Mishra, & T. A. Nguyen (Eds.), Fundamentals of Low Dimensional Magnets. CRC Press,
Taylor & Francis Group. https://doi.org/10.1201/9781003197492-10
Sadler, K., & Tam, J. P. (2002). Peptide dendrimers: Applications and synthesis. Reviews in Molecular
Biotechnology, 90(3e4), 195e229. https://doi.org/10.1016/S1389-0352(01)00061-7
Sahin, N. O. (2007). Niosomes as nanocarrier systems. In Nanomaterials and nanosystems for biomedical
applications (pp. 67e81). Springer Netherlands. https://doi.org/10.1007/978-1-4020-6289-6_4
Sanchez, L., Yi, Y., & Yu, Y. (2017). Effect of partial PEGylation on particle uptake by macrophages.
Nanoscale, 9(1), 288e297. https://doi.org/10.1039/C6NR07353K
Sandhya, P., Poornima, P., & Bhikshapathi, D. V. R. N. (2020). Self nanoemulsifying drug delivery system
of Sorafenib tosylate: Development and in vivo studies. Pharmaceutical Nanotechnology, 8(6), 471e484.
https://doi.org/10.2174/2211738508666201016151406
Santo, I. E., Pedro, A. S., Fialho, R., & Cabral-Albuquerque, E. (2013). Characteristics of lipid micro- and
nanoparticles based on supercritical formation for potential pharmaceutical application. Nanoscale
Research Letters, 8(1), 386. https://doi.org/10.1186/1556-276X-8-386
Smart drug delivery nanostructured systems for cancer therapy 37
Seo, Y. G., Kim, D. H., Ramasamy, T., Kim, J. H., Marasini, N., Oh, Y.-K., Kim, D.-W., Kim, J. K.,
Yong, C. S., Kim, J. O., & Choi, H.-G. (2013). Development of docetaxel-loaded solid self-
nanoemulsifying drug delivery system (SNEDDS) for enhanced chemotherapeutic effect. International
Journal of Pharmaceutics, 452(1e2), 412e420. https://doi.org/10.1016/j.ijpharm.2013.05.034
Shahiwala, A., & Misra, A. (2002). Studies in topical application of niosomally entrapped nimesulide. Journal
of Pharmacy and Pharmaceutical Sciences, 5(3), 220e225.
Singh, S., Pandey, V. K., Tewari, R. P., & Agarwal, V. (2011). Nanoparticle based drug delivery system:
Advantages and applications. Indian Journal of Science and Technology, 4(3), 177e180.
Slingerland, M., Guchelaar, H.-J., & Gelderblom, H. (2012). Liposomal drug formulations in cancer therapy:
15 years along the road. Drug Discovery Today, 17(3e4), 160e166. https://doi.org/10.1016/
j.drudis.2011.09.015
Stojanov, K., Georgieva, J. V., Brinkhuis, R. P., van Hest, J. C., Rutjes, F. P., Dierckx, R. A. J. O., de
Vries, E. F. J., & Zuhorn, I. S. (2012). In vivo biodistribution of prion- and GM1-targeted polymer-
somes following intravenous administration in mice. Molecular Pharmaceutics, 9(6), 1620e1627.
https://doi.org/10.1021/mp200621v
Suhail, M., Rosenholm, J. M., Minhas, M. U., Badshah, S. F., Naeem, A., Khan, K. U., & Fahad, M. (2019).
Nanogels as drug-delivery systems: A comprehensive overview. Therapeutic Delivery, 10(11), 697e717.
https://doi.org/10.4155/tde-2019-0010
Taghipour-Sabzevar, V., Sharifi, T., Bagheri-Khoulenjani, S., Goodarzi, V., Kooshki, H., Halabian, R., &
Moosazadeh Moghaddam, M. (2020). Targeted delivery of a short antimicrobial peptide against CD44-
overexpressing tumor cells using hyaluronic acid-coated chitosan nanoparticles: An in vitro study. Journal
of Nanoparticle Research, 22(5), 99. https://doi.org/10.1007/s11051-020-04838-2
Taratula, O., Kuzmov, A., Shah, M., Garbuzenko, O. B., & Minko, T. (2013). Nanostructured lipid carriers
as multifunctional nanomedicine platform for pulmonary co-delivery of anticancer drugs and siRNA.
Journal of Controlled Release, 171(3), 349e357. https://doi.org/10.1016/j.jconrel.2013.04.018
Upponi, J. R., & Torchilin, V. P. (2014). Passive vs. Active targeting: An update of the EPR role in drug
delivery to tumors. In Nano-oncologicals (pp. 3e45). Springer. https://doi.org/10.1007/978-3-319-
08084-0_1
Usmani, A., Mishra, A., Arshad, M., & Jafri, A. (2019). Development and evaluation of doxorubicin self
nanoemulsifying drug delivery system with Nigella Sativa oil against human hepatocellular
carcinoma. Artificial Cells, Nanomedicine, and Biotechnology, 47(1), 933e944. https://doi.org/10.1080/
21691401.2019.1581791
Wagner, A., Vorauer-Uhl, K., Kreismayr, G., & Katinger, H. (2002). The crossflow injection technique: An
improvement of the ethanol injection method. Journal of Liposome Research, 12(3), 259e270. https://
doi.org/10.1081/LPR-120014761
Wang, X., Zhang, M., Zhang, L., Li, L., Li, S., Wang, C., Su, Z., Yuan, Y., & Pan, W. (2017). Designed
synthesis of lipid-coated polyacrylic acid/calcium phosphate nanoparticles as dual pH-responsive drug-
delivery vehicles for cancer chemotherapy. ChemistrydA European Journal, 23(27), 6586e6595. https://
doi.org/10.1002/chem.201700060
Weissig, V. (2017). Liposomes came first: The early history of liposomology.https://doi.org/10.1007/978-1-4939-
6591-5_1
Wisniewska-Becker, A., & Gruszecki, W. I. (2013). Biomembrane models. In Drug-biomembrane interaction
studies (pp. 47e95). Elsevier. https://doi.org/10.1533/9781908818348.47
Xu, W., Ling, P., & Zhang, T. (2013). Polymeric micelles, a promising drug delivery system to enhance
bioavailability of poorly water-soluble drugs. Journal of Drug Delivery,1e15. https://doi.org/10.1155/
2013/340315
Yang, Q., Liu, D., Liu, M., Ji, Q., Mei, Q., Cheng, Y., & Zhou, S. (2021). Bone-targeted calcium
phosphate-polymer hybrid nanoparticle Co-deliver zoledronate and docetaxel to treat bone metastasis
of prostate cancer. Journal of Pharmaceutical Sciences, 110(2), 876e887. https://doi.org/10.1016/
j.xphs.2020.11.005
Yan, W., Leung, S. S., & To, K. K. (2020). Updates on the use of liposomes for active tumor targeting in
cancer therapy. Nanomedicine, 15(3), 303e318. https://doi.org/10.2217/nnm-2019-0308
Ying, X., Wen, H., Lu, W.-L., Du, J., Guo, J., Tian, W., Men, Y., Zhang, Y., Li, R.-J., Yang, T.-Y.,
Shang, D.-W., Lou, J.-N., Zhang, L.-R., & Zhang, Q. (2010). Dual-targeting daunorubicin liposomes
improve the therapeutic efficacy of brain glioma in animals. Journal of Controlled Release, 141(2),
183e192. https://doi.org/10.1016/j.jconrel.2009.09.020
38 New Trends in Smart Nanostructured Biomaterials in Health Sciences
Yin, Y., Hu, B., Yuan, X., Cai, L., Gao, H., & Yang, Q. (2020). Nanogel: A versatile nano-delivery system
for biomedical applications. Pharmaceutics, 12(3), 290. https://doi.org/10.3390/pharmaceutics12030290
Zeng, F., Xu, D., Zhan, C., Liang, C., Zhao, W., Zhang, J., Feng, H., & Ma, X. (2018). Surfactant-free
synthesis of graphene oxide coated silver nanoparticles for SERS biosensing and intracellular drug
delivery. ACS Applied Nano Materials, 1(6), 2748e2753. https://doi.org/10.1021/acsanm.8b00444
Zhang, J., Xiao, X., Zhu, J., Gao, Z., Lai, X., Zhu, X., & Mao, G. (2018). Lactoferrin- and RGD-
comodified, temozolomide and vincristine-coloaded nanostructured lipid carriers for gliomatosis cerebri
combination therapy. International Journal of Nanomedicine, 13, 3039e3051. https://doi.org/10.2147/
IJN.S161163
Zhao, L., Li, N., Wang, K., Shi, C., Zhang, L., & Luan, Y. (2014). A review of polypeptide-based
polymersomes. Biomaterials, 35(4), 1284e1301. https://doi.org/10.1016/j.biomaterials.2013.10.063
Zhao, C., Song, X., Liu, Y., Fu, Y., Ye, L., Wang, N., Wang, F., Li, L., Mohammadniaei, M., Zhang, M.,
Zhang, Q., & Liu, J. (2020). Synthesis of graphene quantum dots and their applications in drug delivery.
Journal of Nanobiotechnology, 18(1), 142. https://doi.org/10.1186/s12951-020-00698-z
Zhi, D., Yang, T., Yang, J., Fu, S., & Zhang, S. (2020). Targeting strategies for superparamagnetic iron oxide
nanoparticles in cancer therapy. Acta Biomaterialia, 102,13e34. https://doi.org/10.1016/j.act-
bio.2019.11.027. November 2019.
Zielinska, A., Carreiro, F., Oliveira, A. M., Neves, A., Pires, B., Venkatesh, D. N., Durazzo, A.,
Lucarini, M., Eder, P., Silva, A. M., Santini, A., & Souto, E. B. (2020). Polymeric nanoparticles: Pro-
duction, characterization, toxicology and ecotoxicology. Molecules, 25(16), 3731. https://doi.org/
10.3390/molecules25163731
Zununi Vahed, S., Salehi, R., Davaran, S., & Sharifi, S. (2017). Liposome-based drug co-delivery systems in
cancer cells. Materials Science and Engineering: C, 71, 1327e1341. https://doi.org/10.1016/
j.msec.2016.11.073
Smart drug delivery nanostructured systems for cancer therapy 39
