Journal Pre-proof

Glyco-Nanoparticles: New drug delivery systems in cancer therapy

Haroon Khan, Hamid Reza Mirzaei, Atefeh Amiri, Esra Kupeli Akkol,
Syed Muhammad Ashhad Haleemi, Hamed Mirzaei

PII: S1044-579X(19)30400-6
DOI: https://doi.org/10.1016/j.semcancer.2019.12.004
Reference: YSCBI 1726

To appear in: Seminars in Cancer Biology

Received Date: 3 October 2019

Revised Date: 28 November 2019
Accepted Date: 2 December 2019

Please cite this article as: Khan H, Mirzaei HR, Amiri A, Kupeli Akkol E, Ashhad Haleemi SM,
Mirzaei H, Glyco-Nanoparticles: New drug delivery systems in cancer therapy, Seminars in
Cancer Biology (2019), doi: https://doi.org/10.1016/j.semcancer.2019.12.004

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© 2019 Published by Elsevier.

Glyco-Nanoparticles: New drug delivery systems in cancer therapy
a,*
Haroon Khan hkdr2006@gmail.com, Hamid Reza Mirzaeib, Atefeh Amiric, Esra Kupeli

Akkold, Syed Muhammad Ashhad Haleemi e, Hamed Mirzaei f,* h.mirzaei2002@gmail.com

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

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Sciences, Mashhad, Iran
d
Department of Pharmacognosy, Faculty of Pharmacy Gazi University 06330, Etiler/Ankara,

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Turkey
e
Department of Pharmacy, University of Peshawar, 21200 Pakistan
f -p
Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic

Sciences, Kashan University of Medical Sciences, Kashan, Iran

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* Corresponding Authors

Haroon Khan. Department of Pharmacy, Abdul Wali Khan University, Mardan, 23200,
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Pakistan. Email address: & haroonkhan@awkum.edu.pk

Hamed Mirzaei. Research Center for Biochemistry and Nutrition in Metabolic Diseases,
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Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran. Tel: +98-

31-55540022; Fax: +98-31-55540022; E-mail addresses: & Mirzaei-h@kaums.ac.ir

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Abstract

Cancer is known as one of the most common diseases that are associated with high mobility

and mortality in the world. Despite several efforts, current cancer treatment modalities often

are highly toxic and lack efficacy and specificity. However, the application of

nanotechnology has led to the development of effective nanosized drug 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

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different drug delivery systems, carbohydrate-functionalized nanomaterials, specially based

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on their multi-valent binding capacities and desirable bio-compatibility, have attracted

considerable attention as an excellent candidate for controlled release of therapeutic agents.

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In addition, these carbohydrate functionalized nano-carriers are more compatible with

construction of the intracellular delivery platforms like the carbohydrate-modified metal NPs,
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quantum dots, and magnetic nano-materials. In this review, we discuss recent research in the
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field of multifunctional glycol-nanoparticles (GNPs) intended for cancer

drug delivery applications.

Keywords: Glyco-nanoparticles, Cancer, Drug delivery system

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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

tissues 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 efficient therapeutic tools for recognizing the attributes of the healthy

cells and cancer cells in the clinical contexts, and concurrently target the cancerous tissues.

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Notably, clinics need intelligent, sensible, and particular nano-carrier systems for the targeted

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delivery of the chemotherapeutic agents [3-8]. Some studies have addressed a number of

nano-carrier which could employed as effective delivery systems such as the polymeric NPs,
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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
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ingredients of the living organisms. There is sufficient knowledge of the structures,
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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
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study showed that carbohydrate appeared basically conjugated to the lipids and proteins (i.e.,

glycoprotein, glycolipid, & proteoglycan) in the glycocalyx. Indeed, it acts as a

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glycoconjugate, which develops its biological functions. We know that such complex
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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-

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nanotechnology is one of the strategies to tailor the sugar bio-functional gold nano-clusters

(glycol-nanoparticles or GNPs) in a convenient and flexible manner [17-19]. Actually, GNPs

present a glycocalix-like surface with multi-valent carbohydrate representation and globular

form [18]. The GNPs have a series 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.

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2. Nanotherapeutics: A new way for treatment

Nano-therapeutics is one of the current applications of nanotechnology with a great effect on

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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 according to the
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predictions of Richard P. Feynman [28]. According to the studies, a nano-meter is 1 millionth
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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
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diverse nanotechnological strategies such as nano-biosensors and biological instruments [21].

Notably, the quantum impacts the nano level affect the chemical, biological, optical physical,
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and mechanical features that allow the experts in the field to utilize the advantages of these
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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

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that facilitates 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 amalgamating 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, according 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 treatments [31]. For this reason, diverse

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international and domestic organizations and pharmaceutical firms have investment on this

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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
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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].
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Presently, those involved in the healthcare industries are attempting to achieve greater
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productivity, accessibility, and therapeutic 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
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challenges is the infectious illnesses, in which traditional anti-microbial factors applied for

their healing enhance reverse consequences and higher resistance to the drugs. However,
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targeted specificity is a key barrier to achieve the treatment efficacy [21]. It has been
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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

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diagnosing, monitoring treating, discovering drugs, performing surgical operation, and doing

gene delivery through molecular information of the human systems [32, 33]. Based on the

aforesaid discussion, nanotechnology would have a lot of usages in the health care

management (Figure 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

(Table 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

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developing nano-based therapies open new horizons in the medical field.

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Figure 1. Various Nano-therapeutics in Healthcare.

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 Table 1. Selected nano-materials in cancer therapy

Type of Nano-material Cancer Outcome Reference

Nano-capsules Colon Enhancement of therapeutic efficiency of drug [36]

Lipid nano-capsules Melanoma, Improve anticancer potential of drug, Effective in [37, 38]
Ovarian cancer lung cancer therapy

Polyamidoamine Hepatic cancer Enhance treatment of hepatic cancer [39]

dendrimers
Modified solid lipid Cervical cancer Synergistic anticancer effect on cervical cancer [40]
nanoparticles

Hyaluronan solid Ovarian cancer Improve paclitaxel targeting [38]

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nanoemulsions

Cyclodextrin-nanosponges Prostate cancer Improve delivery of the drug [41]

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Conjugated Dendrimers Pancreatic cancer Improve efficacy of drug [42]

GNPs GBM -p
Anti-cancer effects [43]
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Chitosan based NPs Liver cancer Improve efficacy of drug [44]

Mesoporous nano-silica - Improve efficacy of drug [45]

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MCM-41
Nano-Fe3O4/CA Breast cancer Induce apoptosis [46]
Nano-magnetic pancreatic Improve efficacy of drug, and anti-cancer effects [47]
formulation malignancy
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Nano-graphene oxide breast cancer Improve efficacy of drug, and anti-cancer effects [48]
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Table 2. FDA-approved nano-medicines

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Year of Disease Drug Component Nanoparticle benefits

approval
2000 Iron deficiency in Venofer® Iron sucrose Permits improved dose
chronic kidney disease
2003 Menopausal therapy Estrasorb™ Micellar Controlled delivery of
Estradiol therapeutic
2005 Breast cancer Abraxane®/ABI- Albumin-bound Enhanced solubility;
007 paclitaxelnanopa Enhanced delivery to
rticles tumor bioavailability;

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 Increased release

2007 Anemia associated with Mircera® or Chemically Elevated aptamers

chronic kidney disease Methoxy synthesized stability as a result of
PEGepoetin erythrocyteinduc PEGylation
ing
agent
2008 Imaging agent Feridex®/Endorem SPION-dex Superparamagnetic
® character

2008 multiple myeloma Doxil®/Caelyx™ Liposomal Elevated delivery to

(Janssen) doxorubicin tumor site; lowered
systemic toxicity which
arises from side-effects

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2008 Crohn’s disease Cimzia® Antibody Improve efficacy of drug
conjugate

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2009 Rheumatoid arthritis Cimzia® Antibody Improve efficacy of drug
conjugate

2009 Imaging agent GastroMARK™;

umirem®
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SPION-silicone Super paramagnetic
character
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2009 Deficiency anemia iron Feraheme™ SPION Magnetite suspension
deficiency in chronic withpolyglucose contributes to prolonged
kidney disease sorbitolcarboxy steady release and
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methylether decreases dose numbers

2009 Schizophrenia Invega® Paliperidone Improve efficacy of drug
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2009 Bone substitute EquivaBone® Hydroxyapatite Mimics bone structure

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2010 Chronic gout Krystexxa PEGylated PEGylated

porcine-like porcine-like uricase
uricase
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2012 Non-small-cell lung Abraxane®/ABI- Albumin-bound Improve efficacy of drug

carcinoma 007 paclitaxel NPs

2012 Acute Lymphoblastic Marqibo® Liposomal Improve efficacy of drug

Leukemia Vincristine

2013 Pancreatic cancer Abraxane®/ABI- Albumin-bound Improve efficacy of drug

007 paclitaxel
nanoparticles

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2013 Psoriatic Arthritis Cimzia® Antibody Improve efficacy of drug
conjugate

2013 Ankylosing Spondylitis Cimzia® Antibody Improve efficacy of drug

conjugate

2014 Malignant hypothermia Ryanodex® Dantrolene Improve efficacy of drug

sodium
2014 Multple Sclerosis Plegridy® PEGylated IFN Improve efficacy of drug
beta-1a
2015 Hemophilia Adynovate Polymer-protein Improve efficacy of drug
conjugate
2015 Pancreatic Cancer Onivyde® Liposomal Improve efficacy of drug
Irinotecan

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3. Advantage of Nano-Technology for Cancer

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It is notable that biological processes such as the procedures essential for life and the ones,
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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

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studying and manipulating the macro-molecules in the real time and over the initial phases of
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cancer development [50]. Nanotechnology is able to detect rapidly and sensitively the cancer-

associated molecules that enables the scientists for detecting molecular modifications even

when they take place just in a small percentage of cells [49, 51-53]. Moreover, it enjoys
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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
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functionalized and readily adjusted; their capability for delivering and functioning as
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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

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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

permeability and retention (EPR) effect that is a leaky vasculature, has an extremely good

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performance for tumors [55, 56]. With the rapid growth of the tumor mass, a network of the

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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
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vessel formations, i.e. angiogenesis, would lead to the vessel’s walls with big pores. It has

been indicated that the leaky vessels would permit the comparatively great NPs for
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extravasating into the tumor masses. Since the rapid developing tumor mass lacks a
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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
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accumulation (Figure 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
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therapeutic efficiency. In fact, in the case of the absence of the targeting cell kinds, which
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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

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surface with using different polymeric materials such as poly-ethylene glycol (PEG).

Actually, PEG is frequently employed for making the water-insoluble NPs in order to be

water-soluble in several preclinical study laboratories. The PEG-coated liposomal

doxorubicin (Doxil) would be applied in the clinics for the breast cancer holding passive

tumor accumulations. Since the in vivo surveillance platforms for macro-molecules (e.g.,

scavenger receptors in the reticuloendothelial system) are apparently indicated more rapid

uptakes of the NPs with a negative charge, the nano-medicines containing a positive or

neutral charge would be estimated to possess a more prolonged plasma half-life [58]. Using

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the EPR effect for the passive tumor targeting drug delivery would have its' own problems

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and issues. Even though the EPR effect would be one of the specific phenomena in solid

tumors, the greater tumor mass and central area of the metastasis would not show the EPR
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effect due to an extreme hypoxic condition. Therefore, some techniques are employed in

clinical settings for artificially enhancing the EPR effect: gradual angiotensin II infusion for
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increasing the systolic blood pressure, topical utilization of the NO-releasing factors for
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expanding the blood and photo-dynamic treatment or hyperthermia-mediated vascular per-

meabilization in the solid tumors [58]. It should be noted that the passive accumulation via

the EPR impact is very important reasonable drug delivery system for solid tumors therapy.
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Nonetheless, the sizes or the molecular weights of NPs is not just a determining factor of the

EPR effect, but also another factor, including the surface charge, bio-compatibility, and in
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vivo surveillance system for macro-molecules must be considered when developing a nano-
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medicine for effective passive tumor accumulation [57].

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Figure 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
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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).
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(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
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surface contributes to their interactions with the receptors present on the tumor cell resulting

in the greater accumulations and preferential cellular uptakes across the receptor-mediated

endocytosis (b).

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 3.2. Active Tumor Targeting

It is usually accepted that the EPR effect that is used as a particle "passive tumor targeting"

scheme has control over the particles in the 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 medicine activations

into the cell nucleus or cytosol [60]. In a similar way, delivering the nucleic acids (siRNA,

DNA, & miRNA) in the genetic treatments would require the escape of such molecules from

the endosome; therefore, these can achieve favorable sub-cellular compartments.

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Additionally, the EPR is heterogeneous and its strength is variable amongst various tumors

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and or patients. Thus, the active targeting would be regarded as a crucial trait for the next

generation NPs drugs (Figure 2)[60]. It should be noted that this would empower specific
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modalities 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
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[61]. Based on the results, it is possible to attain NPs' active targeting to the tumor cell,
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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
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to tumor microenvironment via using leaky vasculature tumors. Then, the therapeutic agents

which are carried by NPs could be released in an extra-cellular matrix and diffuse across the
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tumor tissues [62]. Afterwards, the NPs would transfer a variety of surface ligands which are
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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 targeting

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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

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NPs or nano-medicine delivery would be impeded by tissue obstacles prior to the medicine

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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
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biological obstacles, tumor endothelium obstacles, and the functional obstacles. It should be

mentioned that the biological obstacles are the physical constructs or cell formations
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restricting the NPs motions. Moreover, the functional obstacles may have an effect on the
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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 importance for improving the cancer therapeutic efficiency [64].
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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
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been placed in an extra-cellular matrix (ECM). In fact, TME creates the two biological and
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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

undesirable for freely diffusing the NPs and would be frequently a limitation for greater EPR

effects. It should be noted that as the numbers of the tumor masses reaches 106 cells, the

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metabolic strains would ensue. Many times, the cells in the core of such a growing cluster

have a distance of 100 to 200 um 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 to 10 mmHg concentrations of pO2 [65]. In

fact, the anoxic metabolic pathways may kick in and produce lactic acid. NPs would have

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

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would expand quickly in the aggressive cancer as a result of fast growth of the stromal cells.

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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
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macrophages. Therefore, both tumor-stroma interactions would increase the pancreatic tumor

cell invasions and metastasis; however, the tumor stroma and TME would provide an
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undesirable environment for delivering the drugs and other kinds of the cancer therapies [66].
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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
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improvement of the tumor permeation are the ECM-targeting pharmacological interventions

for normalizing the vasculature into the TME, hypertonic solutions for shrinking the
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hyperthermia, ECM cells, high-intensity focused ultrasound (HIFU), or radiofrequency (RF)

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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

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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 detrimental 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 epithelial cells, which additionally play a role in the

selectiveness of the passage of materials. However, since the BBB keeps detrimental

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materials from the brain, it constrains the drugs delivery for the brain illnesses like the brain

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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-
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carriers interesting for developing the BBB-crossing delivering approaches. In addition, a

hopeful NP design has transferrin receptor-targeting moiety for facilitating such NPs transfer
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through BBB [68].
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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
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would have an effect on the cancerous and normal cells. Such nonspecific distribution of the

medicines would limit the drug dosage into the cancer cells while creating very high toxicity
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to the normal cells, tissues, and parts of the body, so that it causes different reverse
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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

significantly 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,

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they may consist of different substances such as the polymers (bio-degradable polymeric NPs

and dendrimers), lipids, (the solid-lipid NPs and liposomes), in-organic substances (metal

NPs and quantum dots), and biological substances (the viral NPs and albumin NPs).

Additionally, they 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

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delivery have been confirmed and/or are recently being developed as a result of their

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numerous benefits [60]. Benefits of NPs are the higher solubility of the hydrophobic

medicines, more lengthy circulation time, lower nonspecific uptakes, prevention of

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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
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chemotherapeutic factors in treating cancers would be accompanied by several benefits for
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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
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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-

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sensitive delivery system of drugs possibly delivers and releases the medicines into more
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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

ultrasound waves, magnetic fields, and so forth in order to use the combined therapies,

including the chemotherapy and hyperthermia. Notably, the NPs targeting to the tumors

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through the cancer-specific properties and moieties declined the impacts of the compositions,

sizes, and molecular masses of the NPs on their efficiency [73]. Moreover, 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 strategies 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

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the medicines released from the targeted NPs to be inefficient. It should be noted that the

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combined treatments such as using the targeted NPs to deliver the chemo-therapeutics and

gene therapeutics are probably delivered efficiently and particularly targeted to cancer cells
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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-
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functional targeted NPs. Moreover, the targeted NPs for treating the cancer, as the other
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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
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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
ur

number of substances applied for making the NPs like aspoly(lactic-co-glycolic acid)(PLGA)
Jo

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 utilization for the iterated therapies [75]. In fact, the newly

18
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

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

of
release profiles, distribution in the body, circulation, and costs. As an example, researchers

ro
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
-p
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
re
the proper substances and particles size is one of the other significant aspects in the targeted
lP

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
na

of the efficient targeted NPs results from the absence of information of distributing and

localizing the targeted NPs following the oral administrations or injections [77]. As an
ur

instance, the majority of the studies conducted have not explored the NPs’ targeting efficacy
Jo

in real time in-vivo. Therefore, there are insufficient data on the accurate bio-distribution and

consequent treatment impacts. Hence, eradication of cancer (malignant) 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

19
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

procurement 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

of
to the carbohydrates because of their utilization in the biomimetic purposes that contribute

ro
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
-p
[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

re
carbohydrate molecules with certain functionalities that is called glycocluster effect [85, 86].
lP

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
na

would assist the additional increase of their specific recognition features on the multi-valent

scaffolds in glycoscience. However, glycol-polymers are the synthetic macro-molecules

ur

containing sugar moiety and high potentials to mimic oligosaccharides [87-89]. Based on the
Jo

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,

20
including ligands, phospholipids, lipids, deoxyribonucleic acid plasmids, 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 nano-

carriers has been procured in various kinds such the vesicles, micelles, 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

of
kinds of glycol NPs such as metallic, semi-conductor glycol-quantum dots, magnetic, and

ro
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

-p
re
It is commonly agreed that the fluorescent semi-conductor nano-crystals (also called quantum
lP

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

mechanical features of the substances have considerable differences from the bulk solid
na

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
ur

solubility in various types of biological systems. In fact, different protection procedures must
Jo

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

21
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 glutaraldehyde 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.

of
However, Sun et al. showed coupling the commercially available QD-streptavidin with a

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biotin end-terminated lactose glycol-polymer. Actually, the Ricinus communis agglutinin

(RCA120)-immobilized agarose beads approved for the fluorescent staining by Confocal

-p
microscopy because of glycopolymer–lectin interactions [98]. For example, Chen et al.

showed an approach that directed the functionalization of ZnS:Mn2+ and ZnS QDs containing
re
chitosan. Researchers attained QDs functionalized by chitosan with a mean size of 4.5 nm
lP

when a mix of Zn(Ac)2, Mn(Ac)2, chitosan, and Na2S2O3 aqueous solution was irradiated

with a 1.1 × 1015 Bq 60

Co γ-ray source at the atmospheric pressure and room temperature

[99]. Finally, Surolia et al. could reveal that melibiose-QDs selectively bind to soybean
na

agglutinin (SBA) and have been particulaly de-agglutinated through α-galactose [100].

Furthermore, binding abilities of the maltotriose-QDs with Con A have been analyzed by
ur

controlling the light diffused at 600 nm (Figure 3).

Jo

22
 of
Figure 3. Accumulation of the sugar-QDs via Con A tetramer.

ro
Metal glyco-nanoparticles

Researchers reported that magnetic NPs (MNPs), which may be manipulated through an
-p
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
re
studies attention to the manipulation of the cell membranes. In addition, they are so potent
lP

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,

na

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
ur

cross-linked iron oxide (CLIO) amine-functionalized dextran-coated NPs as a ground to

Jo

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 functional groups entered the silica oxide-coated

23
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 conjugated 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

of
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, α-d-glucose and β-d-

ro
glucose bearing glycol-polymers) by grafting to the IONPs [105]. One of the studies in the
-p
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-
re
2,3,5,6-tetra-fluorobenzamido derivatives functionalized the iron oxide NPs by sonication
lP

and terminal 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

na

carbohydrates (Figure 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
ur

designed strategies produced glycol-polymer modified magnetic NPs via incorporating the
Jo

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-aminopropyl-triethoxysilane (APTS)-functionalized

magnetic NPs which could lead to providing clickable alkyne groups. Notably, azide-

24
functionalized galactose has been bound to such NPs for making the glycol-MNPs through

the Huisgen click reaction.

of
ro
-p
re
Figure 4. Functionalizing the hematite NPs with 1 accompanied by coupling the d-mannose
lP

and consequent binding with Con A.

6.2. Polymeric glycol-nanoparticles

Research showed that synthetic paths which were very new and significant prompted the
na

polymer chemists to preparation of the polymeric glycol NPs with distinct chemical

functional groups and diverse morphologies. Such polymeric glycol NPs are hopeful for
ur

creating diverse bio-active glycol-polymer structures for different health associated

Jo

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 porphyrin–glycopolymer conjugates by incorporating the Reversible

Addition−Fragmentation chain Transfer (RAFT) polymerization and one-pot conjugation

reaction as one of the one-pots of multireactions [109]. Such porphyrin–PMAG conjugates

25
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 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 irradiation 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].

of
Reineke et al. synthesized the cationic poly(methacrylamidotrehalose) (poly(trehalose))

ro
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
-p
GBM cells. Reineke et al. also published the other flexible strategies for synthesizing the

glycol-polymers via the condensation polymerization of the esterified carbohydrates and

re
diamines. Such glycopolymers created a nano-complex containing nucleic acid and have been
lP

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
na

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 efficacy. Nonetheless, the
ur

PLL has been modified by the saccharide-with polymers for reducing cytotoxicity and
Jo

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].

26
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

of
multiple years that depends on the copolymer ratios and molecular weights [115, 116]. Of

ro
course, the monomers ratio applied would identify the PLGA types. As an instance, the

PLGA 50:50 would identify a copolymer whose composition equals 50% glycolic acid and
-p
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.

re
As shown in the Figure, PLGA-NPs are internalized in the cells partially via the fluid phase
lP

pinocytosis as well as the clathrin-mediated endocytosis. Furthermore, the PLGA-NPs could

escape the endo-lysosomes and enter the cytoplasm (Figure 5). Such a condition would

facilitate the NPs interaction with the vesicular membranes that results in the temporal and
na

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
ur

for a lot of treatment factors such as chemotherapy, antibiotic, antiseptic, anti-inflammatory

Jo

and antioxidant medicines, and proteins, and may be desirable for tumor- and or DNA-

targeting [118, 119].

27
 of
ro
-p
Figure 5. A schema of nanoparticle internalization in the cells.
re
7. Glyco-nanoparticles and cancer therapy

It is commonly accepted that one of the most severe medical issues resulting in mortality
lP

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
na

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

ur

highly necessary for the clinics to have an efficient treatment instrument for recognizing the
Jo

features of the healthy and cancer cells, and concurrently select the cancerous tissues.

Intelligent, sensible, and particular nano-carrier platforms for the targeted 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,

liposomes, micelles, and dendrimers for optimizing the treatment regimens for cancer [9-11,

28
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 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 physiological context. This suggests the

of
requirement for developing innovative multi-functional NPs [123]. Commonly, we have

ro
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
-p
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

re
capability, cellular internalizations, medicine loading levels, and circulation times. Actually,
lP

many examinations have tried to using of specific ligands 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-
na

polymers offer wide possibilities [129]. Although they have been synthesized via the

controlled polymerization methods, the experts in the field have discovered the
ur

glycopolymers for over 50 years so that their significance has been increased for becoming a
Jo

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 application of the multi-meric

29
 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.

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 Ref

line
Human tumors β‑Cyclodextrin-Bearing Methotrexate In vitro - [133]

of
Gold Glyco-nanoparticles

ro
Melanoma cancer Gold glycol-nanoparticles In vivo B16OVA, A37, [134]
In vitro Mel JuSo,
B16.F10,
-p MeWo,
SKMel24, CHO
re
lP

Prostate cancer Gold nanoparticles In vitro DU-145 [135]

+NaBH4+Either thio-
glucose or sodium citrate
na

adenocarcinoma Gold glyconanoparticles In vivo CMT/167 [136]

+glucose+biotin+siRNA in vitro
ur

THP-1, MCF-7 [137]

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Leukemia cancer Gold nanoparticles+ in vitro

thio-PEG + thio-glucose+

30
 Glycopolymer-Stabilized [138]
Gold Nanoparticles

Breast cancer Metformin Loaded gold Metformin In vitro MCF-7 [139]

glycol-nanoparticles
Neuroblastoma Glycol-polymer-coated DOX In vitro SH-SY5Y [140]
gold nanoparticles

Prostate cancer Galacto-glycogen - In vitro PC3 [141]

of
nanoparticles

ro
Hepatocellular Hypericin HepG2, MCF-7 [142]
carcinoma Magnetic iron oxide
nanoparticles +
polydopamine +
Hypericin +
-p
In vitro

Lac
re
Breast cancer Iron oxide nanoparticles + - In vitro MDA-MB-231, [143]
polydopamine + glucose In vivo MCF-10A, 4T1
oxidase
lP

Multiple cancers Magnetic glyco- - In vitro TA3-ST TA3- [144]

nanoparticle HA, MCF-7,
B16-F1, B16-
na

F10, SKOV-3,
HT29, A549,
A498, 184B5
ur
Jo

Lung cancer Fluorescein isothiocyanate- DOX In vitro A549, PCC [145]

(FITC)-doped mesoporous
silica
Nanoparticles

31
Hepatocarcinoma Galactose-based DOX In vitro HepG2, COS7 [146]
glycopolymer-drug
conjugates nanoparticle

Breast cancer Glucose-conjugated DOX In vitro 4T1 [147]

chitosan
Nanoparticles

7.1. Inorganic glycol-nanoparticles

of
Notably, the gold glycol-nanoparticles (GNPs) have been considered significantly as a result

ro
of the respective organized properties as the water-soluble carbohydrate-functionalized nano-

clusters with the excellent capacity for chemical glycobiology, bio-medicine, diagnostics, and
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clinical utilizations. Over the past decade, de la Fuente et al. published a leading integrated

glycol-nanotechnology method. The researchers examined and assessed the carbohydrate and
re
carbohydrate–protein interactions according to the utilization of such NPs. They also applied
lP

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
na

colorimetric assays [152].

For example, Conde et al. assessed the anti-cancer effects of the siRNAGlycoNPs
ur

(AuNP@PEG@Glucose@siRNA) as compared to the PEGylated GlycoNPs

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(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 responses.

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

32
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

of
(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–

ro
Hy–MNP composite NPs (PHMs) by adding Michael or Schiff base reaction under alkaline conditions

[156]. The resulting constructed Hy-entrapped glycol-nanoparticles (expressed as Lac-PHMs) possess

-p
such e features as very good stability and dispersibility in the aqueous environment, fair targeting

capability for the ASGP-R-overexpressing tumor cells, and insignificant cytotoxicity in the absence of
re
light, and a good function in the PDT. Researchers also presented an approach to deliver Hy that is
lP

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].
na

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)
ur

indicated very good stability, water dispersibility, and selectiveness for the asialoglycoprotein

receptors overexpressing HepG2 cells. Moreover, the atomic adsorption spectroscopy

Jo

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].

33
Some researchers claimed that engineering the multi-valent glycol-nanoparticles for effective

selection of the carbohydrate binding proteins 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

of
synthetic systems provided with the carbohydrate ligands in a multi-valent form has been

ro
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,
-p
they increase probable binding with the recognition receptors such as lectins [161].

Due to the carbohydrate-lectin interactions, the glycol-nanomaterials could probably

re
intervene in several cellular activities such as cell to cell communications, immune responses,
lP

and bacterial and viral infections [162, 163]. Particularly, the multi-valent 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
na

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,
ur

has been functionalized with lactose and attained by copper(I)-catalyzed alkyne-azide

Jo

cycloaddition chemistry 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-galactoside-specific lectin which has been seen by dynamic light

scattering, optical wave guide lightmode spectroscopy, and quartz crystal micro-balance

34
measurement. With regard to the results, GG NPs had multivalent bindings to the PNA with

an affinity constant of 3.4x105 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 observations 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 between the prostate cancer cells. Such findings

of
revealed an approach to engineer a biosourced polysaccharide with the surface moieties,

ro
which indicate influential multi-valent interactions with lectins and the targeted interactions

with the prostate cancer cells [164].

-p
As we know, the hepatic galactose/N-acetylglucosamine receptor called asialoglycoprotein

receptor (ASGPR) is particularly subjected significantly to the hepatoma cells surfaces [165,
re
166]. For this reason, the ASGPR has been employed as one of the autoantigens for achieving
lP

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
na

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
ur

bonds (i.e., boronate ester & “Schiff” base) and redox-responsive linkages (i.e., disulfide &
Jo

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 hydrophobic factors in the blood circulation with no leakages, selective transports, and

35
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 efficiently 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-

of
chain of glycopolymer through a dynamically covalent boronate ester between the galactose

ro
moiety and phenyl-boronic acid that shows the pH-modulated traits. Then, the hydrophobic

model anti-cancer medicine DOX has been conjugated with glycol-polymer for forming
-p
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
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structures and pharmacological actions of DOX. Additionally, hydrophobic core of the self-
lP

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' cytosol are much greater than the ones in the normal cells or extra-
na

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
ur

in the hepatoma cells' cytoplasm that are reductive and acidic.

Jo

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

36
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-

of
GNPs) with a diameter of 20 nm would have higher efficiency in selecting the solid cancer

ro
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
-p
examinations [176, 191]. Even though treatment efficiency of the Glu-GNPs against the

naked GNPs has been significantly considered by researchers, multiple studies have
re
considered the NPs uptake in the bound-growing cells (e.g., MCF-7 and HeLa cells) and
lP

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,
na

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
ur

THP-1 cells could be up to ~35% higher than the MCF-7 cells. Additionally, one to two hour
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starvation would be optimum, 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-

37
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

basically 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

of
residues [193]. Notably, such differences would be selected as one of the strategies for the

ro
cancer immuno-therapy [194]. Correspondingly, multi-valent glycol-conjugates have been

procured where the mucin glycans have been provided on different scaffolds such as the
-p
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
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present glycans8, which result in the higher synthetic controls and greater densities compared
lP

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

na

candidates [151, 200-203].

Parry et al.'s study described designing and constructing the peptide-free multi-valent
ur

glycosylated nano-scale constructs as the potent synthetic cancer vaccines, which produce the
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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 polymerization. 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

38
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 requirement 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

of
functional groups to conjugate to several diagnostic factors; for example, radioisotopic,

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optical, or magnetic [206]. NPs carriers enjoy higher stability in the biological fluids. They

also have higher ability for avoiding the enzymatic metabolisms compared to additional
-p
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
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4 is a summary of them. The PLGA NPs with the docetaxel with the favorable dimension and
lP

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
na

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-
ur

loaded NPs [209, 210]. The study conducted by Cheng et al. demonstrated that diminishing
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the medicine-loading to 1% (w/w) diminished the particles accumulation and had docetaxel-

loaded PLGA NPs with narrower 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

39
behaviors may result from the fast degradation of polymer and decrease the ionic interactions

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 common cancer drugs like radiation therapies and chemo-therapy [212, 213].

It should be noted that hyperthermia results in the higher sensitivity 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,

of
Manchanda et al.'s research is important because of the multi-functional PLGA NPs synthesis

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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
-p
possess potent utilizations as the drug delivery systems for the incorporated the chemotherapy

and localized hyperthermia [214].

re
In a study, researchers procured the cisplatin NPs with the average dimension between 150
lP

and 160 nm and about 2% w/w cisplatin contents [215]. It has been shown that cisplatin-

loaded PLGA-monomethoxy (m)PEG NPs are efficient for hindering the tumor development

in the animal model of colon cancer which suffer serious combined immune deficiencies. It
na

should be noted that the mice given treatment with the cisplatin-loaded NPs have the greater

survival rates in comparison to the free cisplatin group [215]. Furthermore, the Cisplatin-
ur

loaded PLGA-mPEG NPs led to increasing of residence time of cisplatin in the systemic
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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.

Table 4. Selected poly lactic-co-glycolic acid (PLGA)-nanoparticles used in cancer therapy.

PLGA are able to carry different anti-cancer agent.

40
 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 DMAB-modified Docetaxel MCF-7, Caco-2 [220]
adenocarcinoma 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]

of
Breast cancer PLGA Vincristine MCF-7/ADR [224]
Verapamil

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Ovarian PLGA Hypericin NuTu-19 [225]
adenocarcinoma

Breast cancer PLGA Docetaxel MCF-7 TAX30 [226]

Ovarian
adenocarcinoma -
PLGA Curcumin
-p
A2780CP, MDA-MB-
231
[227]
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Breast cancer
Prostate cancer PLGA Curcumin LNCaP, PC3, DU-145 [228]

Breast cancer PLGA DOX MDA-MB-231 [229]

lP

Colon cancer PLGA-mPEG Cisplatin HT29 cells [230]

Prostate cancer PLGA-mPEG Cisplatin LNCaP [231]

na

Lung cancer PLGA Paclitaxel NCI-H69 (SCLC) [232, 233]

Glioma PLGA Paclitaxel C6 glioma [234]

ur

Cervical cancer PEGylated PLGA Paclitaxel HeLa [235]

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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-glucosamine. Moreover, earlier findings showed that their activities would

enhance as the prolonged hydrocarbon chain has been present at the C-1 position of the
41
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 glycolsphingolipids with modulatory

contributions to the tumor development 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,

of
a number of them have been exposed to the enzymatic degradation that declined their

ro
biological stabilities [243]. In fact, using the intra-tumoral injections of the medicines

distributed in a dimethyl sulfoxide (DMSO)/H2O mixture has been feasible with the Bovine
-p
Serum Albumin (BSA) as a carrier. However, just 1 enzyme-resistant thioglycoside

derivative experienced considerable suppressive activities of the tumor growth with highly
re
recurrent dosages [244]. It could be found that IONP-based drug delivery systems possibly
lP

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

na

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

ur

[245]. Overall, each solution requires a pre-available hydrophilic coating with functional
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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 surface 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

42
regard to the physic-chemical features (i.e., the size or dimension, the size distribution,

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 stabilization 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

of
via hydrophobic interactions, whereas hydrophilic sugar would be dispersed on the micelle

ro
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
-p
coating would require further experiments for studying the drug delivery system viability. For

the first stage, researchers should test if bio-active coatings would meet the requirements of
re
the resultant hydrophilic matrix for in vivo application of the probes or not; that is, prevention
lP

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 compounds.
na

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
ur

between the micelle anti-mitotic activities and activities of the relative free glycosides.
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Overall, glycoside-coated IONP micelles formulation of the above glycosides had their own

antitumor impacts; just in 1 case, it exhibited an uncommon therapeutic improvement.

Eventually, micelles showed optimum relaxometric features for their application as the T2-

weighed MRI contrast agents. Their outputs suggested that the bio-active hydrophilic nano-

formulations are the theranostic agents with synergistic features achieved from 2 entities that

43
individually would not be prepared 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.

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

of
advantages of the colloidal gold is its application as one of sources of radiation for brachy-

ro
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
-p
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

re
provide the ground for several systems presented in this research. Although any AuNP
lP

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 Nanospectra, is the
na

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
ur

stated by researchers, silica core is utilized as a dielectric core, gold shell provides thermal
Jo

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 induction of irreparable

44
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 clinical trials (Table I). 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

of
examining the AuroLase® to treat the primary and or metastatic lung tumors, in which the

ro
airway has been blocked. AuroLase® is one of the examples of the in-organic NPs, which

has been regularly studies and approved efficiency in ablating the tumor at the pre-clinical
-p
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
re
avoiding several consequences related to more common tumor treatments such as
lP

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 treatment. Therefore, it would
na

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

ur

and imaging and some other commercial utilization [257, 258]. However, it has specific
Jo

biological and technical challenges prior to the clinical approvals. 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.

45
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 systemic 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 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

of
chemotherapy utilization for this disease or relapse within six months after adjuvant

ro
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
-p
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
re
limits dosing Taxol [260]. Moreover, it enjoys features such as the albumin pharmaco-
lP

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
na

proteins for anabolic procedures [260]. Apparently, albumin would help endothelial

transcytosis of the protein bound and unbound plasma constituents by attaching to a cell
ur

surface receptor (gp60). Consequently, the Gp60 would bind to the caveolin-1 with
Jo

consequent creation 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

46
therefore makes easy the intra-tumoral accumulation of the albumin-bound medicines.

Finally and at the Phase III of the research, Abraxane led to greater tumor response rate, a

more acceptable 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.

of
10. Conclusion

ro
It has been known that recent therapeutic options for diverse cancers are surgical operation,

hormone therapies, radiation, and chemotherapy. Even though the above traditional
-p
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
re
problems in the drug delivery, particularly to the tumor site. Despite of the conventional drug
lP

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 permeation into the cellular membrane, and
na

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 encapsulation
ur

of different medicines. However, current progressions in the polymeric nano-medicines

Jo

include the targeting of the polymer-based NPs, polyplexes, micelles, polymersomes,

dendrimers, medicines/proteins 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 visualizations. Of course, one of the goals of the synthetic

47
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 interacting with the carbohydrate binding proteins.

Nonetheless, one of the challenges to do this would be the controlling of the spatial and

topological requirements for such systems. GNPs are the sugar-coated gold, iron oxide or

semi-conductor NPs with certain thiol-ending glycosides 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

of
molecules; for example, luminescent probe, peptide, and magnetic chelate, onto a similar

ro
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-
-p
valent glyco-scaffold appropriate to do research of the carbohydrate mediated interactions

and utilizations in molecular imaging and therapies.

re
lP
na
ur
Jo

48
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