Seminars in Cancer Biology 69 (2021) 24–42

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Seminars in Cancer Biology

journal homepage: www.elsevier.com/locate/semcancer

Review

Glyco-nanoparticles: New drug delivery systems in cancer therapy

Haroon Khan a, *, Hamid Reza Mirzaei b, Atefeh Amiri c, Esra Kupeli Akkol d,
Syed Muhammad Ashhad Halimi e, Hamed Mirzaei f, *
a
Department of Pharmacy, Abdul Wali Khan University, Mardan, 23200, Pakistan
b
Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran. Iran
c
Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
d
Department of Pharmacognosy, Faculty of Pharmacy, Gazi University, 06330, Etiler, Ankara, Turkey
e
Department of Pharmacy, University of Peshawar, 21200, Pakistan
f
Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran

A R T I C L E I N F O A B S T R A C T

Keywords: Cancer is known as one of the most common diseases that are associated with high mobility and mortality in the
Glyco-nanoparticles world. Despite several efforts, current cancer treatment modalities often are highly toxic and lack efficacy and
Cancer specificity. However, the application of nanotechnology has led to the development of effective nanosized drug
Drug delivery system
delivery systems which are highly selective for tumors and allow a slow release of active anticancer agents.
Different Nanoparticles (NPs) such as the silicon-based nano-materials, polymers, liposomes and metal NPs have
been designed to deliver anti-cancer drugs to tumor sites. Among different drug delivery systems, carbohydrate-
functionalized nanomaterials, specially based on their multi-valent binding capacities and desirable bio-
compatibility, have attracted considerable attention as an excellent candidate for controlled release of thera­
peutic agents. In addition, these carbohydrate functionalized nano-carriers are more compatible with con­
struction of the intracellular delivery platforms like the carbohydrate-modified metal NPs, quantum dots, and
magnetic nano-materials. In this review, we discuss recent research in the field of multifunctional glycol-
nanoparticles (GNPs) intended for cancer drug delivery applications.

1. Introduction
It is commonly accepted that cancer is an important public health
problem with a high mortality throughout the world [1]. In spite of the
broad used of common chemotherapeutic agents for treating cancer,
these agents have some shortcomings, including inadequate tumor tis­
sues recognition leading to damage to the healthy tissues and low
bio-compatibility caused by their hydrophobicity, which results in the
aggregation [2,3]. Hence, researchers should necessarily provide effi­
cient therapeutic tools for recognizing the attributes of the healthy cells
and cancer cells in the clinical contexts, and concurrently target the
cancerous tissues. Notably, clinics need intelligent, sensible, and
particular nano-carrier systems for the targeted delivery of the chemo­
therapeutic agents [3–8]. Some studies have addressed a number of
nano-carrier which could employed as effective delivery systems such as
the polymeric NPs, dendrimers micelles, and liposomes, for optimizing
the treatment regimens for cancer [9–14].
According to research, carbohydrate, nucleic acid, and protein are
among the prominent ingredients of the living organisms. There is suf­
ficient knowledge of the structures, interactions, and functions of the
nucleic acid and protein. Nevertheless, there is not enough knowledge
about the contribution of carbohydrate to the cells. In fact, a dense
coating of carbohydrate, known as glycocalyx, covers the the surface of
mammalian cells [15]. Another study showed that carbohydrate
appeared basically conjugated to the lipids and proteins (i.e., glyco­
protein, glycolipid, & proteoglycan) in the glycocalyx. Indeed, it acts as
a glycoconjugate, which develops its biological functions. We know that
such complex oligosaccharides play a role in controlling several normal
and pathological procedures [16]. However, multivalent ligands
compensate for the excessive low affinities of the carbohydrates to the
biological objects. Therefore, we designed a novel integrated strategy
called glyco-nanotechnology strategy 4 for examining and interfering in
the carbohydrate to protein-mediated and carbohydrate to carbohydrate
interactions. It is notable that glycol-nanotechnology is one of the
strategies to tailor the sugar bio-functional gold nano-clusters (glyco­
l-nanoparticles or GNPs) in a convenient and flexible manner [17–19].

* Corresponding authors.
E-mail addresses: haroonkhan@awkum.edu.pk (H. Khan), Mirzaei-h@kaums.ac.ir (H. Mirzaei).

https://doi.org/10.1016/j.semcancer.2019.12.004
Received 3 October 2019; Received in revised form 28 November 2019; Accepted 2 December 2019
Available online 20 December 2019
1044-579X/© 2019 Elsevier Ltd. All rights reserved.
H. Khan et al.
Actually, GNPs present a glycocalix-like surface with multi-valent car­
bohydrate representation and globular form [18]. The GNPs have a se­
ries of benefits in comparison to the formerly procured colloids that are
simplified procurement and treatment, exceptional little core dimension
and narrow distribution size, control over the ligand numbers and NPs
sizes, water solubility, higher storage stability with no flocculation,
singular physical features, and lack of cyto-toxicity [20]. Herein, we
summarize the GNPs used in treatment of cancer.
2. Nanotherapeutics: a new way for treatment
Nano-therapeutics is one of the current applications of nanotech­
nology with a great effect on the medical fields [21–26].
Nano-technology is the source of nano-drug [27]. Nanomedicine is a
relatively developing area of science which dates back to 1959 accord­
ing to the predictions of Richard P. Feynman [28]. According to the
studies, a nano-meter is 1 millionth part of a milli-meter, and the term
nano refers to the dwarf [29]. Therefore, nanotechnology addresses
examination, control, and modifications of the molecular and/or atomic
structures in a range from 1 to 100 nm in size. It should be noted that the
nano-drug branch is using diverse nanotechnological strategies such as
nano-biosensors and biological instruments [21]. Notably, the quantum
impacts the nano level affect the chemical, biological, optical physical,
and mechanical features that allow the experts in the field to utilize the
advantages of these phenomena [30]. Moreover, nano drug involves
novel notions and uses of the molecular nano technology in order to
design the nano-machines termed nano-robots. In addition, basic
working power of the nano-structures is provided by biological
macro-molecules and structures or xenobiotic chemical medicines.
However, the most important reality of the nano-materials refers to their
size that is the same as numerous biological macro-molecules that fa­
cilitates the application of the nano-materials in-vivo and in-vitro.
Therefore, multiple diagnostic kits, analytical devices, physio-therapy
uses, and drug delivery systems have been presented so far by amal­
gamating the nano-technology with the biological materials. Thus, as a
branch of medicine, nano-therapeutic reserves numerous studies and
advancements. In spite of the traditional techniques of medicine, ac­
cording to the new method, the medicine would bind on NPs that
empower it for acting with higher efficiency and accuracy and fewer
consequences. As demonstrated by researchers, nano-therapeutics offers
novel opportunities for enhancing safe and efficient traditional treat­
ments [31]. For this reason, diverse international and domestic orga­
nizations and pharmaceutical firms have investment on this area for
generating novel in-vivo imaging methods, gene treatment, and drug
delivery systems. It should be mentioned that the sale rate of the
nano-drug has been $16 just in nanotechnology. Given that the
nano-medicine products are expected to obtain 350.8 billion dollars by
2025 which this suggests its considerable impacts on the universal
economies [21]. Presently, those involved in the healthcare industries
are attempting to achieve greater productivity, accessibility, and ther­
apeutic quality at less expenditure. Of course, one of the challenges for
the healthcare experts has been the permanent and severe neurological
dysfunctions like cancer, HIV or AIDS, diabetes, and heart diseases. One
of the other challenges is the infectious illnesses, in which traditional
anti-microbial factors applied for their healing enhance reverse conse­
quences and higher resistance to the drugs. However, targeted speci­
ficity is a key barrier to achieve the treatment efficacy [21]. It has been
approved that NPs are reasonable and motivating means to deliver the
medicines in a controlled and targeted manner. In addition, nano-drugs
contribute significantly to resolving these as nanotechnology based
formulations would improve the pharmaco-kinetic traits,
bio-availability, and medicine targeting in multiple dysfunctions [21].
Some researchers believe that nano-drug can prevent and treat illnesses,
and also enjoys potent utilizations in diagnosing, monitoring treating,
discovering drugs, performing surgical operation, and doing gene de­
livery through molecular information of the human systems [32,33].
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Seminars in Cancer Biology 69 (2021) 24–42
Based on the aforesaid discussion, nanotechnology would have a lot of
usages in the health care management (Fig. 1). Over the last twenty
years, FDA confirmed multiple nano-medicines to treat cancer, diabetes,
hepatitis, autoimmune diseases, cardio-vascular illnesses, neurological
diseases, the increased cholesterol, Parkinson’s, and specific infectious
illnesses (Tables 1, 2) [34]. Hundreds of nano-carrier-based products
have been recently provided at different phases of pre-clinical and
clinical developments [35]. Hence, it seems that developing nano-based
therapies open new horizons in the medical field.
3. Advantage of nano-technology for cancer
It is notable that biological processes such as the procedures essential
for life and the ones, which result in the cancer, take place at the nano-
scale. Actually, the human’s body consists of multiple biological nano-
machines [49]. In fact, nanotechnology offers opportunities for study­
ing and manipulating the macro-molecules in the real time and over the
initial phases of cancer development [50]. Nanotechnology is able to
detect rapidly and sensitively the cancer-associated molecules that en­
ables the scientists for detecting molecular modifications even when
they take place just in a small percentage of cells [49,51–53]. Moreover,
it enjoys potentials for generating thoroughly new and strongly efficient
treatment factors. Eventually, using the nano-scale materials for cancer
results from their capability to be easily functionalized and readily
adjusted; their capability for delivering and functioning as diagnostic
and therapeutic agents; and their capability for passively accumulating
at the tumor area in order to have active targeting to the cancer cells and
delivering through the conventional biological obstacles in the body like
the blood-brain barrier (BBB) or pancreas dense stromal tissue, which
largely modulates delivering the bio-molecules to create our central
nervous system [49]. In the below, we highlighted different advantages
which are associated with nano-based therapies in the treatment of
cancer.
3.1. Passive tumor accumulation
According to recent studies, an efficient cancer medicine delivery
must gain strong accumulation in the environment around a tumor and
not any adverse effects on the surrounding normal cells [54]. It has been
found that passive localization of numerous medicines and medicine
carriers because of the respective extra-vasation via enhanced perme­
ability and retention (EPR) effect that is a leaky vasculature, has an
extremely good performance for tumors [55,56]. With the rapid growth
of the tumor mass, a network of the blood vessels should be expanded
rapidly for accommodating the needs of the tumor cells for oxygen and
nutrients [54]. It should be noted that such an abnormal and weakly
modulated vessel formations, i.e. angiogenesis, would lead to the ves­
sel’s walls with big pores. It has been indicated that the leaky vessels
would permit the comparatively great NPs for extravasating into the
tumor masses. Since the rapid developing tumor mass lacks a functional
lymphatic system, clearing such NPs would be limited and additionally
improves the accumulation. Using the EPR effect, the NPs greater than
8 nm may passively select the cancer cells via free passage across the
great pores and attain greater intra-tumoral accumulation (Fig. 2) [57].
Most recent nano-medicines for treating the solid tumor rely on the EPR
effect for ensuring higher medicine accumulations and improvement of
the therapeutic efficiency. In fact, in the case of the absence of the tar­
geting cell kinds, which express the targeting interest ligand, this drug
delivery system would be named the passive targeting [54]. Prior to
reaching the adjacency of the tumor site for the passive targeting to
occur, the EPR effect needs the drug delivery systems to have a lengthy
circulation for allowing adequate levels of drugs to the target areas. For
designing nano-medicines, which are able to stay in the blood longer, we
can mask such nano-medicines via modification of the surface with
using different polymeric materials such as poly-ethylene glycol (PEG).
Actually, PEG is frequently employed for making the water-insoluble
H. Khan et al. Seminars in Cancer Biology 69 (2021) 24–42

Fig. 1. Various Nano-therapeutics in Healthcare.

more rapid uptakes of the NPs with a negative charge, the

Table 1
nano-medicines containing a positive or neutral charge would be esti­
Selected nano-materials in cancer therapy.
mated to possess a more prolonged plasma half-life [58]. Using the EPR
Type of Nano- Cancer Outcome Reference effect for the passive tumor targeting drug delivery would have its’ own
material
problems and issues. Even though the EPR effect would be one of the
Nano-capsules Colon Enhancement of [36] specific phenomena in solid tumors, the greater tumor mass and central
therapeutic efficiency of area of the metastasis would not show the EPR effect due to an extreme
drug
Lipid nano-capsules Melanoma, Improve anticancer [37,38]
hypoxic condition. Therefore, some techniques are employed in clinical
Ovarian cancer potential of drug, Effective settings for artificially enhancing the EPR effect: gradual angiotensin II
in lung cancer therapy infusion for increasing the systolic blood pressure, topical utilization of
Polyamidoamine Hepatic cancer Enhance treatment of [39] the NO-releasing factors for expanding the blood and photo-dynamic
dendrimers hepatic cancer
treatment or hyperthermia-mediated vascular per-meabilization in the
Modified solid lipid Cervical cancer Synergistic anticancer [40]
nanoparticles effect on cervical cancer solid tumors [58]. It should be noted that the passive accumulation via
Hyaluronan solid Ovarian cancer Improve paclitaxel [38] the EPR impact is very important reasonable drug delivery system for
nanoemulsions targeting solid tumors therapy. Nonetheless, the sizes or the molecular weights of
Cyclodextrin- Prostate cancer Improve delivery of the [41] NPs is not just a determining factor of the EPR effect, but also another
nanosponges drug
Conjugated Pancreatic Improve efficacy of drug [42]
factor, including the surface charge, bio-compatibility, and in vivo sur­
Dendrimers cancer veillance system for macro-molecules must be considered when devel­
GNPs GBM Anti-cancer effects [43] oping a nano-medicine for effective passive tumor accumulation [57].
Chitosan based NPs Liver cancer Improve efficacy of drug [44]
Mesoporous nano- – Improve efficacy of drug [45]
silica MCM-41 3.2. Active tumor targeting
Nano-Fe3O4/CA Breast cancer Induce apoptosis [46]
Nano-magnetic pancreatic Improve efficacy of drug, [47]
formulation malignancy and anti-cancer effects
It is usually accepted that the EPR effect that is used as a particle
Nano-graphene breast cancer Improve efficacy of drug, [48] "passive tumor targeting" scheme has control over the particles in the
oxide and anti-cancer effects tumor area. Nevertheless, the EPR effect would not result in higher
uptakes of NPs into the cells, but it is necessary to internalize the NPs or
drugs cell for a number of the therapeutic modalities depending on the
NPs in order to be water-soluble in several preclinical study laboratories.
medicine activations into the cell nucleus or cytosol [60]. In a similar
The PEG-coated liposomal doxorubicin (Doxil) would be applied in the
way, delivering the nucleic acids (siRNA, DNA, & miRNA) in the genetic
clinics for the breast cancer holding passive tumor accumulations. Since
treatments would require the escape of such molecules from the endo­
the in vivo surveillance platforms for macro-molecules (e.g., scavenger
some; therefore, these can achieve favorable sub-cellular compartments.
receptors in the reticuloendothelial system) are apparently indicated
Additionally, the EPR is heterogeneous and its strength is variable

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H. Khan et al. Seminars in Cancer Biology 69 (2021) 24–42

Table 2
FDA-approved nano-medicines.
Year of Disease Drug Component Nanoparticle benefits
approval

2000 Iron deficiency in chronic kidney Venofer® Iron sucrose Permits improved dose
disease
2003 Menopausal therapy Estrasorb™ Micellar Estradiol Controlled delivery of therapeutic
2005 Breast cancer Abraxane®/ABI-007 Albumin-bound paclitaxelnanoparticles Enhanced solubility; Enhanced delivery
to
tumor bioavailability; Increased release
2007 Anemia associated with Mircera® or Methoxy Chemically synthesized Elevated aptamers stability as a result of
chronic kidney disease PEGepoetin erythrocyteinducing PEGylation
agent
2008 Imaging agent Feridex®/Endorem® SPION-dex Superparamagnetic character
2008 multiple myeloma Doxil®/Caelyx™ (Janssen) Liposomal doxorubicin Elevated delivery to tumor site; lowered
systemic toxicity which arises from side-
effects
2008 Crohn’s disease Cimzia® Antibody conjugate Improve efficacy of drug
2009 Rheumatoid arthritis Cimzia® Antibody conjugate Improve efficacy of drug
2009 Imaging agent GastroMARK™; umirem® SPION-silicone Super paramagnetic character
2009 Deficiency anemia iron deficiency in Feraheme™ SPION withpolyglucose Magnetite suspension contributes to
chronic sorbitolcarboxymethylether prolonged
kidney disease steady release and decreases dose
numbers
2009 Schizophrenia Invega® Paliperidone Improve efficacy of drug
2009 Bone substitute EquivaBone® Hydroxyapatite Mimics bone structure
2010 Chronic gout Krystexxa PEGylated PEGylated
porcine-like uricase porcine-like uricase
2012 Non-small-cell lung carcinoma Abraxane®/ABI-007 Albumin-bound paclitaxel NPs Improve efficacy of drug
2012 Acute Lymphoblastic Marqibo® Liposomal Vincristine Improve efficacy of drug
Leukemia
2013 Pancreatic cancer Abraxane®/ABI-007 Albumin-bound paclitaxel nanoparticles Improve efficacy of drug
2013 Psoriatic Arthritis Cimzia® Antibody conjugate Improve efficacy of drug
2013 Ankylosing Spondylitis Cimzia® Antibody conjugate Improve efficacy of drug
2014 Malignant hypothermia Ryanodex® Dantrolene sodium Improve efficacy of drug
2014 Multple Sclerosis Plegridy® PEGylated IFN Improve efficacy of drug
beta-1a
2015 Hemophilia Adynovate Polymer-protein conjugate Improve efficacy of drug
2015 Pancreatic Cancer Onivyde® Liposomal Irinotecan Improve efficacy of drug

amongst various tumors and or patients. Thus, the active targeting
would be regarded as a crucial trait for the next generation NPs drugs
(Fig. 2) [60]. It should be noted that this would empower specific mo­
dalities of treatments which could not be achieved with the EPR and
enhance the therapeutic efficacy that may be done through the EPR, but
with lower acceptable impacts [61]. Based on the results, it is possible to
attain NPs’ active targeting to the tumor cell, micro-environment or
vasculature and the directed delivery to intra-cellular compartments by
changing the NPs surface with fewer molecules, anti-bodies, affi-bodies,
peptides and aptamers [61]. Moreover, the EPR effects is a path for NPs’
extravasating from the circulation to tumor microenvironment via using
leaky vasculature tumors. Then, the therapeutic agents which are car­
ried by NPs could be released in an extra-cellular matrix and diffuse
across the tumor tissues [62]. Afterwards, the NPs would transfer a
variety of surface ligands which are associated with the active targeting
of the NPs to the target cells or tissues. However, it is estimated that the
active targeting enhances the accumulations of NPs or medicines in the
tumor and promotes their prospective cell uptake via the
receptor-induced endocytosis. In addition, particles engineered for
vascular targeting would combine the ligands binding to the endothelial
cell-surface receptors [62]. According to the predictions, vascular tar­
geting provides synergistic approach that uses the targeting of the
vascular tissue and cells into the illed tissues. It should be mentioned
that a majority of the nanotechnology-based approaches that have been
confirmed to be used clinically or have been in the developed clinical
trials rely e on the EPR effects. Therefore, the next generation
nano-therapies would apply the targeting for enabling and enhancing
the intra-cellular uptakes, intra-cellular trafficking, and penetrating the
physiological obstacles that obstruct the medicine accessibility to a
number of tumors [62].
3.3. Transport across the tissue obstacles
NPs or nano-medicine delivery would be impeded by tissue obstacles
prior to the medicine and reach the tumor region [63]. It has been
revealed that there are a variety of tissue barriers for obtaining an
effective transfer of the NPs to the tumor microenvironment such as
biological obstacles, tumor endothelium obstacles, and the functional
obstacles. It should be mentioned that the biological obstacles are the
physical constructs or cell formations restricting the NPs motions.
Moreover, the functional obstacles may have an effect on the transfer of
the intact NPs or nano-medicine within the tumor masses, higher
interstitial fluid pressure, and acidic environments. Thus, designing NPs
and approaches for resolving such obstacles would be of high impor­
tance for improving the cancer therapeutic efficiency [64].
According to the studies, the tumor micro-environment (TME) is one
of the dynamic systems consisting of irregular vasculature, fibro-blasts,
and immune cells so that each of them has been placed in an extra-
cellular matrix (ECM). In fact, TME creates the two biological and
functional obstacles to the nano-medicine delivery in treating cancers
[65]. Notably, the abnormal vasculature and increased level of the cell
density would affect on the interstitial fluid pressure into tumor
microenvironment. Consequently, this pressure gradient would be un­
desirable for freely diffusing the NPs and would be frequently a limita­
tion for greater EPR effects. It should be noted that as the numbers of the
tumor masses reaches 106 cells, the metabolic strains would ensue.
Many times, the cells in the core of such a growing cluster have a dis­
tance of 100–200 u m from the nutrient source; that is, 200um would be
a limiting distance for the oxygen diffusion. Therefore, in the core of
tumors, tumor cells have a hypoxic condition and could be lived at the
2.5–10 mmHg concentrations of pO2 [65]. In fact, the anoxic metabolic
pathways may kick in and produce lactic acid. NPs would have

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H. Khan et al. Seminars in Cancer Biology 69 (2021) 24–42

Fig. 2. Passive vs. active targeting approaches for anti-cancer drug delivering systems (Top). Through enhancing the retention effects as well as permeability, the NPs
would diffuse via the leaky vasculature and aggregate in the tumor tissue. Therefore, it is possible to release the medicine in extra-cellular matrix and consequently
diffuse across the tissues (a). (Down) Considering the active targeting, when the particles have been extravasated in the tumor tissues, targeting ligands existence
(such as carbohydrate and anti-body on the NP surface contributes to their interactions with the receptors present on the tumor cell resulting in the greater ac­
cumulations and preferential cellular uptakes across the receptor-mediated endocytosis (b).

instability in the acidic environment. Thus, the medicine delivery to the
target tumor cells could not be anticipated. In addition, the tumor ECM
would provide a nutrient for the stromal and cancer cells. Actually, it
would be a set of the fibrous proteins and poly-saccharides that would
expand quickly in the aggressive cancer as a result of fast growth of the
stromal cells. Cancer stroma is known as a cancer with abnormal and
weakly functioning vasculature, modified extra-cellular matrix, rapid
growth of the fibroblasts and infiltration of the macrophages. Therefore,
both tumor-stroma interactions would increase the pancreatic tumor cell
invasions and metastasis; however, the tumor stroma and TME would
provide an undesirable environment for delivering the drugs and other
kinds of the cancer therapies [66].
Since the EPR effect is one of the clinically related phenomena for
permeation of the nano-carriers tumor, some approaches have been
designed for addressing the tumor endothelium barriers [67]. Notably,
the approaches for declining the interstitial fluid pressures for
improvement of the tumor permeation are the ECM-targeting pharma­
cological interventions for normalizing the vasculature into the TME,
hypertonic solutions for shrinking the hyperthermia, ECM cells,
high-intensity focused ultrasound (HIFU), or radiofrequency (RF) for
enhancing the nanomedicine transfers and accumulations. Moreover,
such approaches diminish the hypoxic conditions in the greater tumor
masses [67]. Even though the tumor masses and TME provide a severe
and an acidic environment for nano-based delivery system stabilization,
the designing of pH-responsive nano-carrier could be useful. Multiple
procedures that have been presented earlier would be applied for
addressing the tumor stroma barriers [67].
One of the other formidable tissue barriers for the medicines and NPs
delivery is the BBB [68]. It should be noted that BBB is one of the
physical barriers in the central nervous system for preventing detri­
mental materials from entering the brain. In fact, it contains the
endothelial cells sealed in the continual tight junction surrounding the
capillaries. Indeed, the astrocytes cover outside the layer of the epithe­
lial cells, which additionally play a role in the selectiveness of the pas­
sage of materials. However, since the BBB keeps detrimental materials
from the brain, it constrains the drugs delivery for the brain illnesses like
the brain tumors and other neurological illnesses. Notably, a lot of
studies have been done for resolving the BBB to deliver drugs. Moreover,
multivalent property of the NPs would make the nano-carriers inter­
esting for developing the BBB-crossing delivering approaches. In addi­
tion, a hopeful NP design has transferrin receptor-targeting moiety for
facilitating such NPs transfer through BBB [68].
4. Nanoparticles and Cancer therapy
Based on the research, traditional cancer chemotherapy possesses
the cancer treatment factors, which distribute non-specifically in the
humans bodies. Therefore, such medicines would have an effect on the
cancerous and normal cells. Such nonspecific distribution of the medi­
cines would limit the drug dosage into the cancer cells while creating
very high toxicity to the normal cells, tissues, and parts of the body, so
that it causes different reverse consequences such as hair loss, weakness,
and organ dysfunctions, which result in lower quality of life for patients
with cancer [69]. Some researchers believe that NPs have been signifi­
cantly considered during the past ten years, because they would have a
lot of advantages for drug delivery for overcoming the restrictions in
traditional chemotherapy [60,70]. In fact, NPs may be formed in
different sizes ranging between 1 and 1000 nm. Moreover, they may
consist of different substances such as the polymers (bio-degradable
polymeric NPs and dendrimers), lipids, (the solid-lipid NPs and lipo­
somes), in-organic substances (metal NPs and quantum dots), and bio­
logical substances (the viral NPs and albumin NPs). Additionally, they

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H. Khan et al.
can be adapted for concurrently carrying the medicines and imaging
probes and developed for specifically targeting the diseased tissues
molecules [60]. As it is known, the NPs for the delivery of anticancer
agents reached the 1st clinical trial in the mid-1980s. In fact, the 1st NPs,
such as liposomal with encapsulated doxorubicin (DOX) entered the
pharmaceutical markets in 1995. Ever since, multiple novel NPs for
cancer medicine delivery have been confirmed and/or are recently being
developed as a result of their numerous benefits [60]. Benefits of NPs are
the higher solubility of the hydrophobic medicines, more lengthy cir­
culation time, lower nonspecific uptakes, prevention of unfavorable
off-target and consequences, greater intra-cellular permeation, and
more specific cancer-targeting. Some studies showed that the utilization
of the targeted NPs for delivering chemotherapeutic factors in treating
cancers would be accompanied by several benefits for improving the
medicine or gene delivery and overcoming multiple issues related to
traditional chemotherapy [71,72]. As an instance, NPs through the
passive targeting or active targeting, would promote intra-cellular
concentrations of the genes and therapeutic agents in the tumor cells
while stopping toxicity in the normal cells. Moreover, the functionalized
NPs may be developed as the temperature-sensitive or pH-sensitive
carriers. Furthermore, the pH-sensitive delivery system of drugs
possibly delivers and releases the medicines into more acidic
micro-environment of the tumor cells and/or elements in the cancer
cells. Researchers showed that temperature-sensitive systems are
capable of carrying and releasing medicines with modifications in the
temperature locally in a tumor area supplied by resources like the ul­
trasound waves, magnetic fields, and so forth in order to use the com­
bined therapies, including the chemotherapy and hyperthermia.
Notably, the NPs targeting to the tumors through the cancer-specific
properties and moieties declined the impacts of the compositions,
sizes, and molecular masses of the NPs on their efficiency [73]. More­
over, the targeted NPs are able to make additional modifications or
functionalization for reducing toxicity. As an instance, modification of
NPs surface chemistry could decline their toxicity and immuno-toxicity
[74]. Even though the targeted NPs are considered as one of the stra­
tegies for overcoming the absence of the traditional chemotherapy
specificity, probable hazards and challenges related to the new approach
would be followed. However, a number of the cancer cell types would
enhance the medicine resistance to the medicine therapy period and
render the medicines released from the targeted NPs to be inefficient. It
should be noted that the combined treatments such as using the targeted
NPs to deliver the chemo-therapeutics and gene therapeutics are prob­
ably delivered efficiently and particularly targeted to cancer cells and
tissues for overcoming the drug resistance and stopping the tumor
development. One of the other strategies for overcoming this medicine
resistance is the development of the multi-functional targeted NPs.
Moreover, the targeted NPs for treating the cancer, as the other novel
technologies, would be followed by numerous challenges and issues.
One of the challenges of the targeted NPs is the probable alteration in the
solubility, stability, and pharmaco-kinetic features of the medicines
carried by the NPs. Nonetheless, researchers did not highly examine
such issues. In addition, shelf life, accumulation, leakage, and toxicity of
the substances employed for making NPs are the other restrictions for
their utilization. A number of substances applied for making the NPs like
aspoly(lactic-co-glycolic acid)(PLGA) are of lower toxicity; however,
they degrade rapidly and would not circulate in the tissues long enough
for the prolonged medicine and gene delivery. In other words, additional
substances like the carbon nano-tubes and quantum dots would have
higher durability, and could preserve in the body for weeks, months, or
even years; this makes them potentially poisonous and limits their uti­
lization for the iterated therapies [75]. In fact, the newly developed
substances for making the targeted NPs like silicon and silica, such as the
solid, porous, and hollow silicon NPs, have been designed but their
application for delivering the drug to the cancer patients has been taken
off gradually as a result of the probable health hazards related to the
introduction of novel substances in the humans bodies. It should be
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Seminars in Cancer Biology 69 (2021) 24–42
noted that development of the novel substances, selection of the proper
substances for all specific treatments, and other parameters should be
optimally chosen for designing more acceptable targeted NPs [76]. As
reported by researchers, the above parameters are the NPs’ dimension,
from, sedimentation, the medicine encapsulation efficiency, favorable
medicine release profiles, distribution in the body, circulation, and
costs. As an example, researchers demonstrated about the particles size
that the clearance rate of very little NPs could be high, and the majority
of the NPs could finish in the liver and spleen and result in infeasible and
inefficient utilization of the targeted NPs [76]. Put differently, greater
NPs are possibly too large for going across the little capillaries for
delivering the drug [76]. Therefore, selection of the proper substances
and particles size is one of the other significant aspects in the targeted
NPs for cancer therapy. Although researchers performed a lot of studies
for developing novel targeted NPs, just a few of them are used clinically,
such as the Abraxane®, Doxil®, and MyocetTM that are confirmed by
the FDA. One of the main accounts for gradual progression of the effi­
cient targeted NPs results from the absence of information of distrib­
uting and localizing the targeted NPs following the oral administrations
or injections [77]. As an instance, the majority of the studies conducted
have not explored the NPs’ targeting efficacy in real time in-vivo.
Therefore, there are insufficient data on the accurate bio-distribution
and consequent treatment impacts. Hence, eradication of cancer (ma­
lignant) cells in the body and control over the therapeutic impacts on the
cells in real time would be one of the other challenges that should be
eliminated for developing effective targeted NPs [78].
5. Glyco-nanoparticles
Researchers extensively dealt with integrating nanotechnology with
carbohydrates over the past ten years. In fact, advancements in the
glycol-nanotechnology resulted in creating diverse bio-active glycol-
nanostructures for different health associated utilizations like the drug
delivery, bio-materials, gene therapies, pathogen detection, suppressors
of toxins, and lectin-based bio-sensors [79–82]. Researchers indicated
that the NPs functionalized with the carbohydrates would provide a
largely multi-valent technique of interactions with lectins and pro­
curement of the increased local ligands level on small surfaces. In fact,
researchers extremely paid attention to inserting their biological traits
into the nano-structured substances to the carbohydrates because of
their utilization in the biomimetic purposes that contribute crucially to
the biorecognition procedures at molecular levels and functionally to
the living systems [83]. Indeed, their significant performance is to be
used as the recognition markers [84]. Even though there is a weak
binding between the carbohydrates and lectins, it is possible to enhance
it largely through the multivalent impact of densely packaged carbo­
hydrate molecules with certain functionalities that is called glycocluster
effect [85,86]. It should be mentioned that glycol NPs as the
carbohydrate-based systems would work similarly for mimicking the
behaviors of the naturally available glycocalyx. Hence, making and
engineering the highly innovative glycol NPs with certain
physio-chemical features would assist the additional increase of their
specific recognition features on the multi-valent scaffolds in glyco­
science. However, glycol-polymers are the synthetic macro-molecules
containing sugar moiety and high potentials to mimic oligosaccharides
[87–89]. Based on the results, oligosaccharides contribute crucially to
multiple biological procedures like signal transmission, inter-cellular
recognition, and fertilization [90–92]. Other studies have developed
the self-assembled nano-products functionalized with the different type
of oligosaccharides for studying and evaluating the
protein-carbohydrate and carbohydrate–carbohydrate interactions
[93]. Actually, conjugating glycol-polymers with bio-molecules,
including ligands, phospholipids, lipids, deoxyribonucleic acid plas­
mids, oligopeptides, and proteins has been done for yielding a big family
of the neo-glycoconjugates with the intended features to make the
self-assembled GNPs [94]. In addition, the glycol-polymer as
H. Khan et al.
nano-carriers has been procured in various kinds such the vesicles, mi­
celles, NPs, and nano-fibers in order to deliver the bio-active molecules
like the folic acid, biotin–avidin, antibody, and DNA sequences. Based
on the new advancements in the conventional synthetic techniques of
the complicated glycol-conjugates, at present, it is feasible to provide
novel polyvalent systems that offer multi-valent carbohydrate–receptor
interactions [94]. In fact, multiple kinds of glycol NPs such as metallic,
semi-conductor glycol-quantum dots, magnetic, and self-assembled
glycol NPs are found [94].In the below, we highlighted different kinds
of GNPs as well as their application in cancer treatment.
6. Types of glyco-nanoparticles
6.1. Glyco-quantum dots
It is commonly agreed that the fluorescent semi-conductor nano-
crystals (also called quantum dots (QDs)) have been greatly considered
over the past ten years as a result of their specific size-dependent optical
features [95]. It should be noted that quantum electronic and mechan­
ical features of the substances have considerable differences from the
bulk solid features. In spite of the possible use of the optical imaging, the
GNPs containing semi-conductor nano-crystals, the early hydrophobic
QDs indicated higher cytotoxicity and weaker solubility in various types
of biological systems. In fact, different protection procedures must be
conducted for conjugating with antibodies, proteins, and DNA for
conferring the water solubility and stability. Moreover, the glyco-QDs
have been applied as a label for in vivo imaging concurrently. Notably,
Fang et al. initially used the glyco-QDs as in vitro bio-labels [96]. In
addition, optical features of the mannose-encapsulated CdSe/ZnS core
and shell QDs have been specified by the confocal microscope imaging
for staining the living cells. Based on the outputs extracted, in spite of
the prevalence of the mannose-QDs over the whole sperm body, the
sperm heads have a high concentration of the GlcNAc-QDs because of
diverse distributions of mannose receptor and GlcNAc on the sperm
surfaces. A study applied the chitosan-QD (CS-QD) hybrid nano-spheres
to bio-image and bio-label [97]. It is notable that a non-solvent-assisted
counterion complexation technique has been used to prepare the hybrid
nanospheres where CS aqueous solution used for adding the glutaral­
dehyde aqueous solution to QDs. The above two research indicated that
QD proper systems may display powerful fluorescence emissions and
longer stability as compared to other imaging systems. However, Sun
et al. showed coupling the commercially available QD-streptavidin with
a biotin end-terminated lactose glycol-polymer. Actually, the Ricinus
communis agglutinin (RCA120)-immobilized agarose beads approved for
the fluorescent staining by Confocal microscopy because of
Fig. 3. Accumulation of the sugar-QDs via Con A tetramer.
30
Seminars in Cancer Biology 69 (2021) 24–42
glycopolymer–lectin interactions [98]. For example, Chen et al. showed
an approach that directed the functionalization of ZnS:Mn2+ and ZnS
QDs containing chitosan. Researchers attained QDs functionalized by
chitosan with a mean size of 4.5 nm when a mix of Zn(Ac)2, Mn(Ac)2,
chitosan, and Na2S2O3 aqueous solution was irradiated with a 1.1 × 1015
Bq 60Co γ-ray source at the atmospheric pressure and room temperature
[99]. Finally, Surolia et al. could reveal that melibiose-QDs selectively
bind to soybean agglutinin (SBA) and have been particulaly
de-agglutinated through α-galactose [100]. Furthermore, binding abil­
ities of the maltotriose-QDs with Con A have been analyzed by con­
trolling the light diffused at 600 nm (Fig. 3).
6.1.1. Metal glyco-nanoparticles
Researchers reported that magnetic NPs (MNPs), which may be
manipulated through an exterior magnetic field, was followed by novel
opportunities such as improving quality of the MRI, site-specific drug
deliveries, hyper-thermic treatments for tumor cells, and current studies
attention to the manipulation of the cell membranes. In addition, they
are so potent that they can be employed for clinical diagnoses and
treatments as a result of their specific physical traits. However, the
magnetic cores like the cobalt ferrites, iron oxide, manganese, and nickel
may be functionalized with proper glycol-conjugates. Overall, co-
precipitation, thermal decomposition, and microemulsion have been
considered as the most widely applied techniques of the preparation of
the magnetic NPs. For example, Kasteren et al. utilized the cross-linked
iron oxide (CLIO) amine-functionalized dextran-coated NPs as a ground
to combine several copies of sialyl LewisX [102]. Moreover, metal oxide
surfaces may be readily altered by chloro-, alkoxy-, and
aminoalkyl-silanes for additional coupling of the bio-molecules. In fact,
the silica-coated magnetite NPs functionalized with the α-d-mannosides
have been attained by a triazole (Huisgen-type reaction) or an amide
(peptidic coupling) link. In addition, terminal alkynyl or carboxy func­
tional groups entered the silica oxide-coated magnetite and azidopropyl-
or aminopropyl-armed α-d-mannosides have been applied for uniform
orientation of carbohydrates at the surface of the NPs. It has been found
that the binding efficiency with mannose-MGNPs has been greater than
the other magnetic functionalized particles containing lectins [103].
Pieters and colleagues have recently revealed that magnetic NPs con­
jugated to the mono-valent galabiose conjugates and tetravalent
galabiose-linked dendrimers through the biotin–streptavidin coupling
are probably employed for detection of Streptococcus suis [104]. The
magnetic NPs coated with the mono-valent galabiose conjugates had
greater interactions in comparison to the tetra-valent particles. It should
be noted that Davis group utilized the iron oxide NPs (IONPs) for
functionalization of the 3 distinct glycol-polymers (α-D-mannose,
H. Khan et al.
α-D-glucose and β-D-glucose bearing glycol-polymers) by grafting to the
IONPs [105]. One of the studies in the field showed the
photo-chemically-induced coupling of the unmodified
mono-saccharides over the actuated spindle-type hematite and spherical
magnetite NPs [106]. Initially, 4-azido-2,3,5,6-tetra-fluorobenzamido
derivatives functionalized the iron oxide NPs by sonication and termi­
nal phosphate groups have been coupled to the metal oxide surface of
the NPs that generate the Fe–O–P structures. In the next stage, coupling
the D-mannose has been done to the functionalized NPs via
photochemically-induced CH with no chemical derivatization of car­
bohydrates (Fig. 4). It has been found that the synthesized mannose
conjugated magnetic NPs had higher recognition abilities toward the
Con A. However, one of the newly designed strategies produced
glycol-polymer modified magnetic NPs via incorporating the polymer
grafting from strategy with glycosylation through the click chemistry
[107,108]. In other words, the poly(N-carboxyanhydrides) has been
synthesized with ring-opening polymerization in the presence of 3-ami­
nopropyl-triethoxysilane (APTS)-functionalized magnetic NPs which
could lead to providing clickable alkyne groups. Notably,
azide-functionalized galactose has been bound to such NPs for making
the glycol-MNPs through the Huisgen click reaction.
6.2. Polymeric glycol-nanoparticles
Research showed that synthetic paths which were very new and
significant prompted the polymer chemists to preparation of the poly­
meric glycol NPs with distinct chemical functional groups and diverse
morphologies. Such polymeric glycol NPs are hopeful for creating
diverse bio-active glycol-polymer structures for different health associ­
ated utilizations like the drug delivery, bio-materials, biotechnology,
and nanotechnology, and gene treatments. For example, Chen et al.
presented an approach for synthesizing the self-assembled porphyr­
in–glycopolymer conjugates by incorporating the Reversible Addi­
tion− Fragmentation chain Transfer (RAFT) polymerization and one-pot
conjugation reaction as one of the one-pots of multireactions [109].
Such porphyrin–PMAG conjugates had self-assembly behaviors for
forming the micelles in the water as a result of the hydrophobic
porphyrin in the middle and hydrophilic glycopolymer at the two ends.
It should be mentioned that Con A has been used to test the binding
abilities of the synthesized glycol NPs. Results indicated the anticancer
Fig. 4. Functionalizing the hematite NPs with 1 accompanied by coupling the D-mannose and consequent binding with Con A.
31
Seminars in Cancer Biology 69 (2021) 24–42
effects for the cancer cells (K562) and higher and more specific binding
abilities with Con A. Additionally, in vitro examination demonstrated
that the glycol-micelles are able to kill cancer cells under light irradia­
tion and in the light treatment length-dependent approach. Hence, this
study is of high importance to develop the utilizations for the cancer
imaging and treatments [109].
Reineke et al. synthesized the cationic poly(methacrylamido­
trehalose) (poly(trehalose)) through the RAFT polymerization [110].
They made the nano-complexes of the cationic polymers with siRNA for
developing the delivery system as an effective targeting system to GBM
cells. Reineke et al. also published the other flexible strategies for syn­
thesizing the glycol-polymers via the condensation polymerization of
the esterified carbohydrates and diamines. Such glycopolymers created
a nano-complex containing nucleic acid and have been applied to deliver
the genes [111,112]. For example, Zhou et al. used glycopolymers
grafted onto poly(l-lysine) (PLL) as gene delivery system [113].
Although PLL possesses considerable condensations potential with
plasmid DNA because of the hydrophilic amino groups with positive
charge in water, it would not be generally selected as one of the gene
delivery vectors due to higher cytotoxicity and lower transfection effi­
cacy. Nonetheless, the PLL has been modified by the saccharide-with
polymers for reducing cytotoxicity and increasing transfection efficacy
of the PLL. Indeed, glycopolymer modified PLL had less cytotoxicity in
comparison to the PLL based on the MTT assays in HepG2 and NIH3T3
cell lines. Outputs indicated that a lower substitution degree on the PLL
is able to enhance the pDNA condensation capacities. Such a situation
resulted in the higher usefulness of PLL for delivering the genes with
greater biological features [113].
PLGA is known as a bio-degradable polymer with the highest rate of
success utilization because its hydrolysis results in the metabolite
monomers, glycolic acid and lactic acid. Based on the research, since the
above 2 monomers are as endogenous molecules and could be readily
metabolized through Krebs cycle in the body. There is a relationship
between the minimum systemic toxicity and PLGA utilization for the
drug delivery or bio-material uses [114]. It confirmed the PLGA could be
employed as proper drug delivery systems for human. Various polymers
are found in the markets with various molecular weights and co-polymer
compounds. However, degradation time is variable from numerous
months to multiple years that depends on the copolymer ratios and
molecular weights [115,116]. Of course, the monomers ratio applied
H. Khan et al.
would identify the PLGA types. As an instance, the PLGA 50:50 would
identify a copolymer whose composition equals 50 % glycolic acid and
50 % lactic acid. Moreover, poly(lactic acid) (PLA) has been utilized to a
lower extent in comparison to the PLGA because of the decreased
degradation rates.
As shown in the Figure, PLGA-NPs are internalized in the cells
partially via the fluid phase pinocytosis as well as the clathrin-mediated
endocytosis. Furthermore, the PLGA-NPs could escape the endo-
lysosomes and enter the cytoplasm (Fig. 5). Such a condition would
facilitate the NPs interaction with the vesicular membranes that results
in the temporal and localized de-stabilization of the membranes leading
to escaping the NPs into the cytosol [117]. In fact, researchers approved
the PLGA NPs capacities as the drug delivery systems for a lot of treat­
ment factors such as chemotherapy, antibiotic, antiseptic,
anti-inflammatory and antioxidant medicines, and proteins, and may be
desirable for tumor- and or DNA-targeting [118,119].
7. Glyco-nanoparticles and cancer therapy
It is commonly accepted that one of the most severe medical issues
resulting in mortality throughout the world is cancer. In spite of the
broad utilization of the traditional chemo-therapeutic agents for treating
cancer, they suffer from a number of shortcomings like improper
recognition of tumor tissues leading to damages to the healthy tissues
and lower bio-compatibility as a result of their hydrophobicity, which
result in aggregation. Hence, it is highly necessary for the clinics to have
an efficient treatment instrument for recognizing the features of the
healthy and cancer cells, and concurrently select the cancerous tissues.
Intelligent, sensible, and particular nano-carrier platforms for the tar­
geted delivery of the anti-cancer agents could be necessary for the
clinical utilization. Some researchers examined various nano-carrier-
based medicine delivery systems containing the polymeric NPs, lipo­
somes, micelles, and dendrimers for optimizing the treatment regimens
for cancer [9–11,13,121,122]. Co-polymers with the hydrophilic and
hydrophobic chains would self-assemble into developed NPs with
diverse morphology; for example, dimension, shapes, compositions,
structures, and so on have been significantly considered as the result of
Fig. 5. A schema of nanoparticle internalization in the cells.
32
Seminars in Cancer Biology 69 (2021) 24–42
the respective flexibility in the control of chemical, physiological, and
biological characteristics [123]. According to some studies, researchers
applied the core-shell structured and self-assembled block copolymer
NPs for medicines, proteins, gene deliveries, and the imaging factors
[124–128]. The majority of the synthesized NPs are single-functional.
Therefore, these NPs would be inadequate in a complicated physiolog­
ical context. This suggests the requirement for developing innovative
multi-functional NPs [123]. Commonly, we have crucial documents for
indicating that easy, effective, and stable ligands critically contribute to
the active selection of the cancer cells. However, the function of the
effective medicine releases for the targeted cancer cells via utilization of
the nano-carriers may be influenced by a number of the factors,
including stimuli-responsive medicine releases, tumor-targeting capa­
bility, cellular internalizations, medicine loading levels, and circulation
times. Actually, many examinations have tried to using of specific li­
gands that have a direct relationship to the cancer cellular uptakes of the
nano-carriers for reducing injuries in the normal tissues [123]. Anyway,
the nano-carriers extracted from self- assembly of the amphiphilic block
co-polymers offer wide possibilities [129]. Although they have been
synthesized via the controlled polymerization methods, the experts in
the field have discovered the glycopolymers for over 50 years so that
their significance has been increased for becoming a helpful means in
the drug delivery utilizations due to the respective recognition features
[130,131]. Moreover, glycopolymers enjoy a key potent for increasing
their specificity via interaction with the cell surfaces and proteins in the
physiologic events. In addition, the crosstalk between
carbohydrate-binding proteins and carbohydrates would be fully weak
in the biological procedures, though it could be improved via applica­
tion of the multi-meric carbohydrate molecules called cluster glycoside
effect [131,132]. Taken together, it seems that glycol-nanoparticles
could employed as potential delivery system for targeting different
anti-cancer-agents. Table 3 illustrates various glycol-nanoparticles
which are applied in cancer therapy.
7.1. Inorganic glycol-nanoparticles
Notably, the gold glycol-nanoparticles (GNPs) have been considered
H. Khan et al. Seminars in Cancer Biology 69 (2021) 24–42

Table 3
Selected glycol-nanoparticles which are used in cancer therapy. A variety of GNPs such as magnetic, and gold NPs enable to carry different anti-cancer agents.
Cancer Nanoparticle Drug Model Type of cell line Ref

Human tumors β‑Cyclodextrin-Bearing Gold Glyco-nanoparticles Methotrexate In vitro – [133]

Melanoma cancer Gold glycol-nanoparticles In vivo B16OVA, A37, Mel JuSo, B16.F10, MeWo, [134]
In vitro SKMel24, CHO
Prostate cancer Gold nanoparticles + NaBH4+Either thio-glucose or In vitro DU-145 [135]
sodium citrate
adenocarcinoma Gold glyconanoparticles + glucose + biotin + siRNA In vivo in CMT/167 [136]
vitro
Leukemia cancer Gold nanoparticles+ in vitro THP-1, MCF-7 [137]
thio-PEG + thio-glucose+
Glycopolymer-Stabilized Gold Nanoparticles [138]
Breast cancer Metformin Loaded gold glycol-nanoparticles Metformin In vitro MCF-7 [139]
Neuroblastoma Glycol-polymer-coated gold nanoparticles DOX In vitro SH-SY5Y [140]
Prostate cancer Galacto-glycogen nanoparticles – In vitro PC3 [141]
Hepatocellular Magnetic iron oxide nanoparticles + polydopamine + Hypericin In vitro HepG2, MCF-7 [142]
carcinoma Hypericin +
Lac
Breast cancer Iron oxide nanoparticles + polydopamine + glucose – In vitro MDA-MB-231, MCF-10A, 4T1 [143]
oxidase In vivo
Multiple cancers Magnetic glyco-nanoparticle – In vitro TA3-ST TA3-HA, MCF-7, B16-F1, B16-F10, SKOV- [144]
3, HT29, A549, A498, 184B5
Lung cancer Fluorescein isothiocyanate- (FITC)-doped mesoporous DOX In vitro A549, PCC [145]
silica
Nanoparticles
Hepatocarcinoma Galactose-based glycopolymer-drug conjugates DOX In vitro HepG2, COS7 [146]
nanoparticle
Breast cancer Glucose-conjugated chitosan DOX In vitro 4T1 [147]
Nanoparticles

significantly as a result of the respective organized properties as the
water-soluble carbohydrate-functionalized nano-clusters with the
excellent capacity for chemical glycobiology, bio-medicine, diagnostics,
and clinical utilizations. Over the past decade, de la Fuente et al. pub­
lished a leading integrated glycol-nanotechnology method. The re­
searchers examined and assessed the carbohydrate and
carbohydrate–protein interactions according to the utilization of such
NPs. They also applied the NPs as the potent means in the anti-adhesive
treatment for cell to cell adhesion examinations and for preventing the
pathogen invasion [148–151]. However, small carbohydrates like
glucose may be bound to the gold NPs (AuNPs) and applied for sensitive
colorimetric assays [152].
For example, Conde et al. assessed the anti-cancer effects of the
siRNAGlycoNPs (AuNP@PEG@Glucose@siRNA) as compared to the
PEGylated GlycoNPs (AuNP@PEG@Glucose) both in vitro and in vivo
[153]. In fact, siRNA GlycoNPs are associated with the expression of the
pro-apoptotic proteins (i.e., caspases 3 and 9 and Fas/CD95) in a
dosage-dependent way that is not dependent on the inflammatory re­
sponses. In addition, the targeting of siRNA GlycoNPs could target
expressing the c-Myc gene in animal modelthat is one of the essential
regulators of the cell rapid growth and apoptosis through in-vivo RNAi
in the tumor tissues that results in about 80 % decline in the tumor size
with no related inflammation.
Research indicates that photo-dynamic treatment is one of the safe,
non-invasive modalities to treat cancer, where photosensitizer (PS) is
one of the essential components [154]. In general, hypericin (Hy) is one
of the promising l PSs, but its clinical utilization is considerably
restricted by its weak hydrophilicity [155]. For example, Shao et al.
provided an easy and new approach for designing a nano-carrier to
deliver Hy. In fact, Hy has been initially entrapped into the
poly-dopamine (PDA) film via the dopamine polymerization procedure
on the surface of the magnetic iron oxide nanoparticles (MNPs) [156].
Therefore, there may be a specific interaction between lactose and
asialoglycoprotein receptors (ASGP-R) that has been conjugated to the
surface of the PDA of the as-constructed PDA–Hy–MNP composite NPs
(PHMs) by adding Michael or Schiff base reaction under alkaline con­
ditions [156]. The resulting constructed Hy-entrapped glyco­
l-nanoparticles (expressed as Lac-PHMs) possess such e features as very
good stability and dispersibility in the aqueous environment, fair tar­
geting capability for the ASGP-R-overexpressing tumor cells, and
insignificant cytotoxicity in the absence of light, and a good function in
the PDT. Researchers also presented an approach to deliver Hy that is
highly flexible and can be readily expanded so that Hy can be replaced
with other hydrophobic PSs; however, it can conjugate the targeting
moiety and the scaffold for performing various performances [142].
Researchers used the spectrophotometry analyses and showed that
the amount of Hy in the PHMs was 72 μmol g-1 PHMs. In fact, the
developed Hy-entrapped glycol NPs (Lac-PHM) indicated very good
stability, water dispersibility, and selectiveness for the asialoglycopro­
tein receptors overexpressing HepG2 cells. Moreover, the atomic
adsorption spectroscopy analyses demonstrated that the amounts of the
Lac-PHMs taken in the HepG2 cells has been 2.1-fold greater than that of
the triethylene glycol-modified PHMs. In addition, the outputs of the
intra-cellular reactive oxygen specimens production, detection, cyto-
toxicity examination, and apoptosis determination revealed that the
Lac-PHMs had a good photo-dynamic impact on the HepG2 cells [142].
Some researchers claimed that engineering the multi-valent glycol-
nanoparticles for effective selection of the carbohydrate binding pro­
teins in the mammalian cells was significantly favored for molecular
recognition examinations as well as treatment utilizations. In fact, the
multi-valent receptor ligand presentation in the biological systems is one
of the strategies used for compensating the poor and lower affinity
binding between the proteins and carbohydrates [157]. Due to such a
multi-valency, general binding of a multi-functional ligand may be
considerably more powerful than a combined distinct binding events of
the single ligands [158]. According to the studies, the biologically
inspired engineering of the synthetic systems provided with the carbo­
hydrate ligands in a multi-valent form has been extremely investigated
over the past ten years [159,160]. Indeed, the GNPs function as a
multi-valent scaffold that could carry several copies of the carbohydrate
ligands. Therefore, they increase probable binding with the recognition
receptors such as lectins [161].
Due to the carbohydrate-lectin interactions, the glycol-
nanomaterials could probably intervene in several cellular activities
such as cell to cell communications, immune responses, and bacterial
and viral infections [162,163]. Particularly, the multi-valent

33
H. Khan et al.
carbohydrate binding proteins, which have a mediatory role in the
malignant cellular activities, are attractive molecular targets. For
example, Besford et al. used the glycogen NPs as a biosourced
glyco-scaffold to engineer the multivalent glycol-nanoparticles [164].
Actually, the glycogen NPs that is one of the naturally occurring
greatly-branched glucose polymers, has been functionalized with lactose
and attained by copper(I)-catalyzed alkyne-azide cycloaddition chem­
istry for the targeted interactions with lectins ex-situ and on the prostate
cancer cells. Therefore, lactosylated glycogen consisting of the terminal
β-galactoside moieties has been called galacto-glycogen (GG). It has a
strong interaction with the peanut agglutinin (PNA) that is a β-gal­
actoside-specific lectin which has been seen by dynamic light scattering,
optical wave guide lightmode spectroscopy, and quartz crystal
micro-balance measurement. With regard to the results, GG NPs had
multivalent bindings to the PNA with an affinity constant of 3.4 × 105
M− 1, and the GG-PNA complex could not be displaced by lactose. This
condition demonstrates a competitive binding of GG to the lectin. Such
GG NPs have been experimented in terms of the relationships with the
cell membranes of prostate cancer in-vitro, in which the particles had
higher affinity for the membrane, which has been confirmed by obser­
vations from the flow cytometry and confocal microscopy. The above
finding could be related to the results from particular extra-cellular
galectin-1 targeting. Moreover, the GG NPs cause accumulation be­
tween the prostate cancer cells. Such findings revealed an approach to
engineer a biosourced polysaccharide with the surface moieties, which
indicate influential multi-valent interactions with lectins and the tar­
geted interactions with the prostate cancer cells [164].
As we know, the hepatic galactose/N-acetylglucosamine receptor
called asialoglycoprotein receptor (ASGPR) is particularly subjected
significantly to the hepatoma cells surfaces [165,166]. For this reason,
the ASGPR has been employed as one of the autoantigens for achieving
the targeted hepatopathy therapies by specifically recognizing the
galactose [167]. In addition, the tumor micro-environment like hypoxia,
acidity, higher glutathione (GSH), and over-expressed enzymes, inspired
the reasonable development of the intelligent NPs for responding to
diverse physic-chemical and biochemical stimuli [168–172]. To achieve
the above-mentioned objective, the authors presented the cleavable
linkages like the pH-sensitive bonds (i.e., boronate ester & “Schiff” base)
and redox-responsive linkages (i.e., disulfide & Se–Se bonds] for making
the NPs. This would distinguish the carcinoma cells from the normal
ones and regulate the medicine release processes. It also exactly satisfies
the mechanisms of diverse factors, including the extra-cellular and
intra-cellular releases [173–176]. Hence, for realizing a valid and
effective NP-induced HCC therapy, the stable loading of the hydropho­
bic factors in the blood circulation with no leakages, selective transports,
and drugs release into the hepatoma cells is required. For example, Wu
et al. designed a crucial cross-linking glycol-polymerdrug conjugates
(GPDs) NPs with certain dual-responsive traits for attaining the selective
transfer and program release of anti-cancer drugs to treat HCC [177]. It
should be noted that Wu et al. addressed certain recognition between
galactose and ASGPR, and the cluster glycoside impact that may effi­
ciently cause the carbohydrate ligand to improve the affinity for their
protein receptors [178,179]. They utilized galactose for building the
glycopolymer for achieving the higher ASGPR-induced hepatoma
cellular binding and internalizations [177]. Indeed, a disulfide bond has
been proposed for the side-chain of glycopolymer through a dynamically
covalent boronate ester between the galactose moiety and
phenyl-boronic acid that shows the pH-modulated traits. Then, the hy­
drophobic model anti-cancer medicine DOX has been conjugated with
glycol-polymer for forming diverse amphiphilic conjugates by a
self-eliminating disulfide bond [180]. The above procedure can ensure
the traceless releases of DOX that keeps the original chemical structures
and pharmacological actions of DOX. Additionally, hydrophobic core of
the self-assembly GPD NPs has been internally cross-linked by a disulfide
bond for stabilizing the architecture and avoiding the drug permeation
in a physiological environment. Notably, GSH levels in the cancer cells’
34
Seminars in Cancer Biology 69 (2021) 24–42
cytosol are much greater than the ones in the normal cells or
extra-cellular fluids [181]. Finally, via incorporation of the two
redox-responsive and pH sensitive features into the GPD NPs, DOX may
be precisely and systematically released from the NPs in the hepatoma
cells’ cytoplasm that are reductive and acidic.
According to the studies, the cancer cells can be reproduced with
higher speed and prolonged living compared to the normal cells as they
apply certain proteins and glucose for supporting their continual growth
[182]. However, their capability of covalently conjugating with diverse
bio-molecules through the thiol groups is an interesting features of GNPs
[183]. In fact, the GNPs capped with proper functional bio-molecules
may increase their uptakes through the cancer cells but not enclosing
the normal cells; for example, macrophage and endothelial cell, and thus
has been considered for detecting and treating tumors [184–187].
Actually, glucose is one of the major sources of the metabolic energies
for the cells. Therefore, the cancer cells consume considerably higher
glucose than the normal cells. In particular, greater numbers of the
glucose molecules are internalized by GLUT receptors found on the
cancer cell surfaces [188,189]. Hence, some researchers believe that
glucose tagging is one of the efficient ways for facilitating the GNPs
introduction into the cells. in vitro and in vivo examinations showed that
the pegylated glucose coated GNPs (or Glu-GNPs) with a diameter of
20 nm would have higher efficiency in selecting the solid cancer such as
the prostate, breast, ovarian, and liver cancers [186,190]. Moreover,
images indicated that Glu-GNPs enteres the cancer cell more than the
surrounding normal cell in the animal examinations [176,191]. Even
though treatment efficiency of the Glu-GNPs against the naked GNPs has
been significantly considered by researchers, multiple studies have
considered the NPs uptake in the bound-growing cells (e.g., MCF-7 and
HeLa cells) and solid tumors. Researchers applied the suspension cells,
specifically THP-1 cells, for modelling the metastatic cells and cancer
stem cells [192]. They assessed the Glu-GNPs cellular uptake and made a
comparison between it and the uptake of the bound cells, specifically the
MCF-7 cells. Based on the outputs, Glu-GNPs had a greater effect on the
THP-1 cells as compared to the MCF-7 cells. Moreover, average gold
concentrations in all THP-1 cells could be up to ~35 % higher than the
MCF-7 cells. Additionally, one to two hour starvation would be opti­
mum, and differential targeting impacts would be lost in a case of the
cells starvation more than three hours. Of course, X-ray outputs showed
that 9 Gy was an optimum irradiation dose. In fact, the Glu-GNPs plus
X-rays could obtain more reasonable cancer killing impacts (at least 20
% more) in comparison with the GNPs plus X-rays or X-rays itself. The
above findings can contribute to more acceptable cancer therapies of the
cancer metastasis as well as cancer stem cells [192].
7.2. Polymeric glycol-nanoparticles
It is widely accepted that the mammary glands healthy cells is
described by presenting the surface of the branched, O-linked core 2
glycans with higher amounts of N-acetyl-D-glucosamine (GlcNAc).
Nonetheless, proteins presented on breast tumors surface provide basi­
cally linear, truncated core 1 mucin-type glycans like α-N-acetyl-D-
galactosamine (αGalNAc, the Tnantigenglycan) with complete or near
the complete lack of the core 2 residues [193]. Notably, such differences
would be selected as one of the strategies for the cancer immuno-therapy
[194]. Correspondingly, multi-valent glycol-conjugates have been pro­
cured where the mucin glycans have been provided on different scaf­
folds such as the peptides, dendrimers, lipo-peptides, and proteins
[195–198]. A number of such strategies have been designed as far as
clinical trials [199]. Nano-materials show a different ground to present
glycans8, which result in the higher synthetic controls and greater
densities compared to the recent protein scaffolds. Carbohydrates which
present AuNPs decorated with little molecule thiolated glycans have
been applied as the means for studying the
carbohydrate-to-carbohydrate interactions in anti-adhesive treatments
and as cancer vaccine and anti-HIV candidates [151,200–203].
H. Khan et al. Seminars in Cancer Biology 69 (2021) 24–42

Parry et al.’s study described designing and constructing the peptide-
free multi-valent glycosylated nano-scale constructs as the potent syn­
thetic cancer vaccines, which produce the considerable titers of anti-
bodies that are selective for the abnormal mucin glycans [204]. A
poly-merizable version of Tn-antigen glycan has been procured and
transformed into the organized glycol-polymers through a RAFT poly­
merization. Afterwards, polymers have been combined with gold NPs
that yield the multi-copy multivalent nano-scale glycol-conjugates.
Immunological examinations showed that such nano-materials caused
influential and lengthy generation of antibody, which would be selective
to the Tn-antigen glycan and cross reactive towards the mucin proteins
presenting Tn. As revealed by the findings, the proof-of concept of an
easy and modular strategy towards the synthetic anti-cancer vaccines on
the basis of multi-valent glycosylated nano-materials with no require­
ment for a normal vaccine protein element [204].
PLGA NPs connected to the targeting ligands would be employed for
targeting the severe tumors with high affinities [205]. Moreover, the
PLGA NPs possess great surface areas and functional groups to conjugate
to several diagnostic factors; for example, radioisotopic, optical, or
magnetic [206]. NPs carriers enjoy higher stability in the biological
fluids. They also have higher ability for avoiding the enzymatic me­
tabolisms compared to additional colloidal carriers like the liposomes or
lipid vesicles [207]. Of course, a majority of the anti-cancer medicines
examined in the PLGA NPs procurements would be presented here.
Table 4 is a summary of them. The PLGA NPs with the docetaxel with the
favorable dimension and medicine-loading features appropriate for
intravenous injections may be procured without the use of the
Tween®80. For example, a study revealed that cellular cyto-toxicity of
NPs has been greater than free drugs. Moreover, docetaxel -loaded NPs
had acceptable levels of plasmas in-vivo as compared to the traditional
formulation of docetaxel (Taxotere®) [208]. Some researcher showed
the use of nano-precipitation procedure to create the docetaxel-loaded
NPs [209,210]. The study conducted by Cheng et al. demonstrated
that diminishing the medicine-loading to 1 % (w/w) diminished the
particles accumulation and had docetaxel-loaded PLGA NPs with nar­
rower size distribution [210].
Betancourt et al. formulated NPs via nano-precipitation of the acid-
ended PLGA for controlling DOX release in the pH-dependent way and
delivering great loads of active therapeutic agent to a breast cancer cell
line. It could be concluded that pH-dependent release behaviors may
result from the fast degradation of polymer and decrease the ionic in­
teractions between medicine and polymer at an acidic pH [211]. One of
the other approaches for improving efficiency and selectivity of the
cancer therapy is to employ hyperthermia when combining with com­
mon cancer drugs like radiation therapies and chemo-therapy [212,
213]. It should be noted that hyperthermia results in the higher sensi­
tivity of a number of cancer cells to the radiation. Moreover, it may
increase the effects of specific anti-cancer medicines and allow applying
lower chemotherapy dosages [212]. Indocyanine green is one of the
optical tracers, which is able to produce heat via absorption of
near-infrared light. In addition, Manchanda et al.’s research is important
because of the multi-functional PLGA NPs synthesis and combination of
the medicines with various physical features (indocyanine green that is
amphiphilic and DOX that is hydrophobic). Such indocyanine
green-DOX NPs would possess potent utilizations as the drug delivery
systems for the incorporated the chemotherapy and localized hyper­
thermia [214].
In a study, researchers procured the cisplatin NPs with the average
dimension between 150 and 160 nm and about 2 % w/w cisplatin
contents [215]. It has been shown that cisplatin-loaded PLGA-mono­
methoxy (m)PEG NPs are efficient for hindering the tumor development
in the animal model of colon cancer which suffer serious combined
immune deficiencies. It should be noted that the mice given treatment
with the cisplatin-loaded NPs have the greater survival rates in com­
parison to the free cisplatin group [215]. Furthermore, the
Cisplatin-loaded PLGA-mPEG NPs led to increasing of residence time of
cisplatin in the systemic circulation in animal model of prostate cancer
[216]. Taken together, these studies indicated that PLGA NPs have very
important properties which could be introduced it as powerful tools for
targeting different tumors with high affinity.
8. Glycoside-nanoparticles and cancer therapy
Researchers introduced a type of the synthetic glycosides as the
suppressors of adeno-carcinoma and glioma cell proliferations [236,
237]. Notably, glycosides are as a derivative of the N-acyl-D-glucos­
amine. Moreover, earlier findings showed that their activities would
enhance as the prolonged hydrocarbon chain has been present at the C-1
position of the glycoside moiety. Given that conjugating a sugar with an
oleyl chain would improve conjugate anti-tumoral activities [238].
However, this mechanism of the growth suppression would suggest
changes in the lipid metabolisms. Actually, results showed that the
glycoside-therapies led to significant alterations in the levels of glyco­
lsphingolipids with modulatory contributions to the tumor development

Table 4
Selected poly lactic-co-glycolic acid (PLGA)-nanoparticles used in cancer therapy. PLGA are able to carry different anti-cancer agent.
Cancer Polymer for nanoparticle Drug Cell line Reference
Preparation

Glioma PLGA Paclitaxel glioma C6 cells [217]

Colon carcinoma PLGA ethylene Paclitaxel HCT116 [218]
oxide fumarate
Colon cancer PLGA Paclitaxel HT-29 [219]
Breast -colorectal adenocarcinoma DMAB-modified Docetaxel MCF-7, Caco-2 [220]
PLGA-TPGS
Cervical cancer PLGA-d-a-TPGS Docetaxel HeLa [221]
Lymphoma PLGA Zinc (II) P388-D1 [222]
Phthalocyanine
Glioma PLGA Paclitaxel C6 rat glioma [223]
Breast cancer PLGA Vincristine MCF-7/ADR [224]
Verapamil
Ovarian adenocarcinoma PLGA Hypericin NuTu-19 [225]
Breast cancer PLGA Docetaxel MCF-7 TAX30 [226]
Ovarian adenocarcinoma -Breast cancer PLGA Curcumin A2780CP, MDA-MB-231 [227]
Prostate cancer PLGA Curcumin LNCaP, PC3, DU-145 [228]
Breast cancer PLGA DOX MDA-MB-231 [229]
Colon cancer PLGA-mPEG Cisplatin HT29 cells [230]
Prostate cancer PLGA-mPEG Cisplatin LNCaP [231]
Lung cancer PLGA Paclitaxel NCI-H69 (SCLC) [232,233]
Glioma PLGA Paclitaxel C6 glioma [234]
Cervical cancer PEGylated PLGA Paclitaxel HeLa [235]

35
H. Khan et al.
and play a role in the paths of the cell mortality or rapid growth
[239–241]. Nevertheless, initial in-vivo tests with the most acceptable
candidates have been accompanied by moderate outputs [242]. Due to
their lengthy alkyl chain, compositions have been weakly soluble in the
aqueous physiological media. Moreover, a number of them have been
exposed to the enzymatic degradation that declined their biological
stabilities [243]. In fact, using the intra-tumoral injections of the med­
icines distributed in a dimethyl sulfoxide (DMSO)/H2O mixture has been
feasible with the Bovine Serum Albumin (BSA) as a carrier. However,
just 1 enzyme-resistant thioglycoside derivative experienced consider­
able suppressive activities of the tumor growth with highly recurrent
dosages [244]. It could be found that IONP-based drug delivery systems
possibly affect the stabilization and selection of the bio-active glycosides
to the tumor site and result in the greater treatment activities.
As stated by researchers, treatment agents in a majority of the IONP
medicne delivery systems would have a covalent binding or electro-
static adsorption over the IONP surface, distributed into a polymer
matrix, or encapsulated within the amphiphilic nano-structures [245].
Overall, each solution requires a pre-available hydrophilic coating with
functional moiety over IONP scaffold. In order to create a simplified
procedure, the technique on the basis of co-precipitation yielding
aqueous IONP would be prioritized because of possible additional sur­
face tailoring, even though the NP achieved via the technique would
have lower qualities [246]. In addition, more stages would be needed to
integrate the medicines [247]. Indeed, thermal degradation technique
would provide the most reasonable solution with regard to the
physic-chemical features (i.e., the size or dimension, the size distribu­
tion, crystallinity and reproducibility) of the iron oxide cores; however,
it would yield IONP just stable in the organic solvent. As a result, a
further stage would be necessary for aqueously stabilizer the NP prior to
the medicine integration [248].
A study conducted by Groult et al. dealt with possible direct stabi­
lization of the oleic acid-coated iron oxide NPs (OA-IONP) procured by
thermally degrading via micellation with bio-active glycosides
mentioned earlier [249]. It should be noted that hydrophobic alkyl
glycoside tails in such colloidal structures would enclose aliphatic chain
of OA-coated IONP via hydrophobic interactions, whereas hydrophilic
sugar would be dispersed on the micelle outer surface and improves the
water-dispersibility via creating a coverage of the hydrophobic layer.
Such a configuration, in which the treatment cargo works as a micellar
coating would require further experiments for studying the drug de­
livery system viability. For the first stage, researchers should test if
bio-active coatings would meet the requirements of the resultant hy­
drophilic matrix for in vivo application of the probes or not; that is,
prevention of the opsonization, improvement of the colloidal stability,
bio-compatibility, and proper relaxometric features for imaging uses.
Afterwards, it should be monitored if antitumor activities would be
maintained into the micellar formulations of such therapeutic com­
pounds. Next, glycoside-coated IONP micelles have been experimented
as MRI contrast agents and anti-mitotics on the glioma and lung cancer
cell lines. Then, a comparison has been made between the micelle
anti-mitotic activities and activities of the relative free glycosides.
Overall, glycoside-coated IONP micelles formulation of the above gly­
cosides had their own antitumor impacts; just in 1 case, it exhibited an
uncommon therapeutic improvement. Eventually, micelles showed op­
timum relaxometric features for their application as the T2-weighed
MRI contrast agents. Their outputs suggested that the bio-active hy­
drophilic nano-formulations are the theranostic agents with synergistic
features achieved from 2 entities that individually would not be pre­
pared for in vivo utilizations, and reinforce possible use of the
bio-molecules as both medicines for treatment and a coating for
OA-IONP micellar stabilization [249]. It seems that glycoside-NPs could
be employed as new delivery system for targeting various anti-cancer
agents. In this regard, more studies for approving it as a proper drug
delivery system in the treatment of cancer are needed.
36
Seminars in Cancer Biology 69 (2021) 24–42
9. Clinical status
There is evidence of the history of the colloidal gold utilization for
enjoying its health advantages for many centuries [250]. One of the
earliest approved successes of the health advantages of the colloidal gold
is its application as one of sources of radiation for brachy-therapy and
arthritis treatment [251]. Surely, such a success has enhanced the
attention to the use of the gold and further noble metals for health care
uses. For example, a number of AuNPs, including Aurimune that is a
tumor necrosis factor-bound AuNP, finished the major clinical trials
(NCT00356980 & NCT00436410 from www.clinicaltrials.gov) so that
they provide the ground for several systems presented in this research.
Although any AuNP products have been not clinically confirmed, each of
them holds light adsorption features of AuNPs and is examined in terms
of diverse treatment utilizations ranging from the healing solid tumors
to acne. For instance, AuroLase® that has been provided by Nano­
spectra, is the silica-gold nano-shells coated with (poly)ethylene glycol
(PEG) developed for thermal ablation of the solid tumors after triggering
with a near-infrared energy source [250]. As stated by researchers, silica
core is utilized as a dielectric core, gold shell provides thermal ablation
capability after intense adsorption of the near-infrared NIR light, and
PEG layer causes general particle stability. Researchers published the
above technology more than 10 years ago [252]. Their major results that
is a foundation for AuroLase® indicated that AuroLase® might be used
inducing photo-thermal cell mortality in-vitro after triggering with a
NIR energy source and increasing the solid tumor temperature for in­
duction of irreparable thermal damages to the tumors in the mice after
intra-tumoral injections [252]. Some studies indicated the use of
AuroLase® for a follow-up for treating the thermal ablation of the brain
and prostate cancers so that prostate cancer exhibited potentials for total
thermal ablation of the solid tumors after an organized injection of
AuNPs [253,254]. Then, AuroLase® introduced into 2 individual clin­
ical trials (Table 1). The first clinical trial has been updated in September
2014 (NCT00848042). Reports showed that it could be completed to
treat the patients suffering from refractory and or recurrent tumors for
the head and neck cancers (www.clinicaltrials.gov). The other clinical
trial that is recently active but not recruiting is examining the Auro­
Lase® to treat the primary and or metastatic lung tumors, in which the
airway has been blocked. AuroLase® is one of the examples of the
in-organic NPs, which has been regularly studies and approved effi­
ciency in ablating the tumor at the pre-clinical phase and is currently
being explored in the clinics. AuroLase® has several benefits for treating
tumors. It should be mentioned that AuroLase® is capable of treating
tumors and avoiding several consequences related to more common
tumor treatments such as chemotherapy via a localized tumor treatment
that would selectively treat the tumor and restrict damages to the
healthy tissues [255,256]. In addition, AuroLase® would provide the
ground for exploring an obvious limitation in the recent tumor treat­
ment. Therefore, it would be a means for providing a treatment, which
could not be currently feasible. Notably, AuroLase at pre-clinical phase
would be examined as a supplementary treatment for radiation and
imaging and some other commercial utilization [257,258]. However, it
has specific biological and technical challenges prior to the clinical ap­
provals. For example, it should be proved that the system is able to be
administered intra-venously, and the target tumors can utilize the
enhanced permeation and retention (EPR) effects as one of the active
targeting moieties. Researchers approved that EPR effect can assist in
the tumor aggregation of NPs in the pre-clinical animal examinations;
however, it has lower validity in the clinical settings. Therefore,
dependence on the EPR’s targeting effect would be accompanied by
challenges for AuroLase® [259]. Moreover, as the AuroLase® is one of
the local therapies developed for treating the solid tumors at the tumor
site, it would be hard to translate the technology for treating the sys­
temic malignancies. For this reason, many polymeric NPs undergo
pre-clinical stage of advancement; however, they possess potentials for
the targeted drug delivery of the anti-cancer medicines as a result the
H. Khan et al.
convenience, by which the ligands are able to bind. Furthermore, the
albumin-bound NPs of paclitaxel (Abraxane) had successful utilization
for delivering paclitaxel to treat the breast cancer after a fail in of
various combined chemotherapy utilization for this disease or relapse
within six months after adjuvant chemotherapy. Thus Abraxane is
associated with different advantages. For example, albumin could be as
non-toxic agent and immune system completely tolerates it, because
albumin is a plasma protein which has 66 kDa molecular weight. In
addition, its application would eliminate the needs for poison solvent
(Cremophor EL poly-oxyethylated castor oil); that is, it limits dosing
Taxol [260]. Moreover, it enjoys features such as the albumin
pharmaco-kinetics, particularly its prolonged half-life that would be
specifically interesting for designing the medicine carriers for passive
targeting. Researchers indicated that Abraxane targets cancer the tissues
due to higher metabolic demands and active transports of the plasma
proteins for anabolic procedures [260]. Apparently, albumin would help
endothelial transcytosis of the protein bound and unbound plasma
constituents by attaching to a cell surface receptor (gp60). Conse­
quently, the Gp60 would bind to the caveolin-1 with consequent crea­
tion of the transcytolic vesicles. Furthermore, Abraxane might be
transferred into the tumor via the secreted protein acidic that is rich in
cysteine (SPARC) or osteonectin, which binds albumin due to a sequence
homology with gp60. It should be noted that the SPARC, as caveolin-1,
would be frequently expressed in a number cancer such as the breast,
lung, and prostate, which explains why albumin accumulates in a
number tumors and therefore makes easy the intra-tumoral accumula­
tion of the albumin-bound medicines. Finally and at the Phase III of the
research, Abraxane led to greater tumor response rate, a more accept­
able safety profile, and greater survival in comparison to the common
paclitaxel in the patients taking the 2nd phase of chemotherapy [261]. A
few nanoparticle-based therapies are approved by FDA for cancer
therapy. There are not any glycol-nanoparticles-based therapies in the
clinical in the treatment of various diseases such as cancer. Hence, it
seems that clinical studies could release these NPs as new and effective
cancer therapies.
10. Conclusion
It has been known that recent therapeutic options for diverse cancers
are surgical operation, hormone therapies, radiation, and chemo­
therapy. Even though the above traditional alternatives enhanced the
patients’ survival rate, they still suffer from different constraints. In fact,
targeting the pharmaceutical is one of the quickly emerging strategies
for overcoming problems in the drug delivery, particularly to the tumor
site. Despite of the conventional drug delivery systems, NPs-based
compounds gain higher accumulation in the tumor site through the
respective active or passive mechanisms. It should be noted that the
nano-sized carriers support lengthier circulation time, simple perme­
ation into the cellular membrane, and effective site-specific targeting as
a result of their exclusive features such the little sizes, larger surface to
volume ratios, adjustable surface chemistry, and capability of encapsu­
lation of different medicines. However, current progressions in the
polymeric nano-medicines include the targeting of the polymer-based
NPs, polyplexes, micelles, polymersomes, dendrimers, medicines/pro­
teins conjugates, and the lipid hybrid systems to the tumor pathological
site. As NPs have various functional moieties, they enhance functions
with regard to the target capability, circulation durability, greater intra-
cellular permeation, stimuli sensitivity, and carrier mediated visualiza­
tions. Of course, one of the goals of the synthetic chemists when the
multi-valent nature of the carbohydrate mediated interaction has been
discovered is a long search for constructing multi-valent carbohydrate
systems with accurate geometries, which are largely effective in inter­
acting with the carbohydrate binding proteins. Nonetheless, one of the
challenges to do this would be the controlling of the spatial and topo­
logical requirements for such systems. GNPs are the sugar-coated gold,
iron oxide or semi-conductor NPs with certain thiol-ending glycosides
37
Seminars in Cancer Biology 69 (2021) 24–42
combining multi-valent presentation of carbohydrates (glycol-clusters)
with specific chemicophysical features of the nanosized metallic core.
Notably, feasible binding of various kinds of carbohydrates and other
molecules; for example, luminescent probe, peptide, and magnetic
chelate, onto a similar gold nanoparticle in a controlled manner (multi-
functional GNPs) and modification of the core for obtaining GNPs with
magnetic or fluorescence features would make such a multi-valent
glyco-scaffold appropriate to do research of the carbohydrate medi­
ated interactions and utilizations in molecular imaging and therapies.
Funding source
None.
Declaration of Competing Interest
None.
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