International Journal of

Molecular Sciences

Review
Prevention of Deficit in Neuropsychiatric Disorders
through Monitoring of Arsenic and Its Derivatives as
Well as Through Bioinformatics and Cheminformatics
Speranta Avram 1, *, Ana Maria Udrea 2 , Adina Negrea 3, *, Mihaela Ciopec 3, *,
Narcis Duteanu 3, * , Carmen Postolache 1 , Corina Duda-Seiman 4 , Daniel Duda-Seiman 5, * and
Sergey Shaposhnikov 6
1 Faculty of Biology, University of Bucharest, Splaiul Independentei 91-95, 050095 Bucharest, Romania;
carmen_postolache83@yahoo.com
2 National Institute for Laser Plasma and Radiation Physics, Atomistilor Street 409, 077125 Magurele,
Romania; m.a.u.anamaria@gmail.com
3 Politehnica University of Timisoara, Faculty of Industrial Chemistry and Environmental Engineering,
Piata Victoriei, 2, 300006 Timisoara, Romania
4 Faculty of Chemistry, Biology, Geography, West University of Timis, oara, I.H.Pestalozzi 16, 300115 Timisoara,
Romania; cori_mam@yahoo.com
5 University of Medicine and Pharmacy "Victor Babes, Timişoara, Eftimie Murgu Square 2,
300041 Timisoara, Romania
6 Norgenotech AS, Gaustadalleen 21, 0349 Oslo, Norway; sas@norgenotech.no
* Correspondence: speranta.avram@gmail.com (S.A.); adina.negrea@upt.ro (A.N.);
mihaela.ciopec@upt.ro (M.C.); narcis.duteanu@upt.ro (N.D.); dannymduda@gmail.com (D.D.-S.)




Received: 23 February 2019; Accepted: 9 April 2019; Published: 12 April 2019


Abstract: Neuropsychiatric disorders are induced by various risk factors, including direct exposure
to environmental chemicals. Arsenic exposure induces neurodegeneration and severe psychiatric
disorders, but the molecular mechanisms by which brain damage is induced are not yet elucidated.
Our aim is to better understand the molecular mechanisms of arsenic toxicity in the brain and to
elucidate possible ways to prevent arsenic neurotoxicity, by reviewing significant experimental,
bioinformatics, and cheminformatics studies. Brain damage induced by arsenic exposure is discussed
taking in account: the correlation between neuropsychiatric disorders and the presence of arsenic and
its derivatives in the brain; possible molecular mechanisms by which arsenic induces disturbances
of cognitive and behavioral human functions; and arsenic influence during psychiatric treatments.
Additionally, we present bioinformatics and cheminformatics tools used for studying brain toxicity of
arsenic and its derivatives, new nanoparticles used as arsenic delivery systems into the human body,
and experimental ways to prevent arsenic contamination by its removal from water. The main aim of
the present paper is to correlate bioinformatics, cheminformatics, and experimental information on
the molecular mechanism of cerebral damage induced by exposure to arsenic, and to elucidate more
efficient methods used to reduce its toxicity in real groundwater.

Keywords: arsenic; brain; bioinformatics; cheminformatics; nanoparticles

1. Arsenic Exposure Induces the Neuropsychiatric Disorders—General Aspects

Increased exposure of humans to higher levels of metals represents a serious concern for public
health and, from these metals, lead (Pb), arsenic (As), and manganese (Mn) are considered biomarkers
and are studied and proposed for detection because of their severe adverse health effects. It is important
to note that, generally, from the literature to date, people are exposed to one, as opposed to all of the
metals: this limits the real-life exposure scenarios [1].

Int. J. Mol. Sci. 2019, 20, 1804; doi:10.3390/ijms20081804 www.mdpi.com/journal/ijms

Int. J. Mol. Sci. 2019, 20, 1804 2 of 18

Currently, arsenic is considered the most ubiquitous environmental pollutant and due to this,
subsequently, the U.S. Environmental Protection Agency and Agency for Toxic Substances and Disease
Registry [2] mention arsenic on the U.S. Priority List of Hazardous Substances [3].
The presence of arsenic in the environment has become a major problem for the world, especially
in Bangladesh, India, China, and Japan [4,5]. Bangladesh and some Indian provinces, such as
Bengal, are the most affected regions of the world in which more than 100 million people drink water
contaminated with arsenic, and 21% of reported deaths are associated with arsenic poisoning [3].
Many types of minerals existing naturally in the Earth’s crust are responsible for arsenic release in
water [6]. While the arsenic concentration in natural water is very low, in some areas it is sufficiently
high (between 100–500 mg L−1 ) to be necessary to trigger alarms [7,8]. Many industries release
arsenic-contaminated waters without adequate treatment, and in various regions the antropic source
represents a major source for a higher concentration of arsenic and its derivatives in groundwater [4].
For this reason, the removal of arsenic from water is an important and urgent preoccupation
around the world and, at present, many techniques have been developed for removing arsenic
(e.g., precipitation, filtration, solvent extraction, bioremediation, and widely used-absorption) [9].
Recently, many types of absorbents have been developed [9–11]. Techniques based on reverse osmosis
and electrodialysis [10] are generally expensive and have a low efficiency if not performed in advance
to oxidize As(III) to As(V), but are more efficient in removing As(V) [11].
A systematic review regarding the pollutant effects of chemicals, such as bisphenol A, polycyclic
aromatic hydrocarbons (PAHs), polyfluoroalkyl chemicals, and metals on the nervous system was
published by Avram et al. [12]. It was mentioned that the presence of pollutants is associated with the
presence of several severe psychiatric disorders, such as ADHD [13,14], autism [15], schizophrenia [16],
anxiety [17], and depression [18]. It was mentioned that human arsenic exposure may induce
genotoxicity and cancer and is harmful for the liver, skin, kidneys, and the central nervous system.
Arsenic exposure is known as a risk factor for developing Alzheimer’s and Parkinson’s diseases [19],
but also the presence of arsenic could affect the whole body.
Recent publications discussed the chemical complexity of arsenic due to its multitude of compounds
and reported arsenic toxicities and oxidation states in inducing neurodegeneration or others psychiatric
disorders. Sub-chronic arsenic exposure is linked to neurodegeneration, which represents the main
cause of cognitive disturbances, relevant for many neuropsychiatric disorders. Unfortunately, there
are limited data regarding the effects of sub-chronic exposure to arsenic-contaminated drinking water
on neuropsychiatric disorders and its mechanisms are able to induce a low activity in the prefrontal
cortex [20].
Chia-Yu Chang et al. [21] mentioned that sub-chronic exposure to arsenic from drinking water
(10 mg L−1 As2 O3 ) represents a key factor in induced anxiety-like symptoms on normal mice
for four weeks and intensified the depression symptoms in depressive mice after eight weeks.
The symptomatology of depressive behavior was evaluated with a tail suspension test (TST) and
forced swimming test (FST) on normal and depressive chemically-induced models, with and without
arsenic-contaminated water [21]. The study results showed that, during eight weeks, the mice
with chemically-induced depression, by drinking arsenic-contaminated water, presented statistically
significant worse performances in both tests compared to other test groups [20].
Another important result from this study suggested that arsenic exposure has a high impact
in neurodegeneration in the prefrontal cortex by reducing the number of proliferating cell nuclear
antigens (PCNAs). It was mentioned that the number of PCNA-positive cells was (i) in normal
mice, 32.5 ± 2.9; (ii) in normal mice with arsenic exposure, 16.5 ± 1.4; (iii) in the chemically-induced
depression lot, 12 ± 2.6; and (iv) in the lot of mice with chemically-induced depression and arsenic
exposure, 3.6 ± 2.05. Behavioral patterns of depression and anxiety involved the inhibition of serotonin
receptor 5-HT subtype 1A. Chang et al. [21] showed that after eight weeks of arsenic exposure only
the group of mice with chemically-induced depression and exposed to arsenic showed the decreased
levels of the 5-HT subtype 1A receptor [20].
Int. J. Mol. Sci. 2019, 20, 1804 3 of 18

Denise Hill’s study [22] was concerned about the effect of common environmental toxicants
including mercury (Hg), lead (Pb), manganese (Mn), arsenic (As), and cadmium (Cd) on autism
spectrum disorders. Recent information has mentioned that prenatal manganese and lead exposure
represents a serious cause of adverse neurobehavioral development in progeny. In their work,
the authors analyzed in utero exposure to these toxicants, during the neuronal developmental stage.
It was mentioned that the exposure to the brain of these metals leads to behavioral abnormalities and
these changes are persistent in adult life [22].
Dickerson et al. [23] indicated that in districts with high concentrations of mercury and arsenic
in the air, the rate of autism spectrum disorders are increased. The study was performed using data
from five locations of Autism and Developmental Disabilities Monitoring (ADDM) during 2000–2008.
The results showed that the incidence of pathologies from autism spectrum disorders is linked with
the proximity of industrial areas with reported emissions of arsenic, lead, and mercury in the air [23].
Another study published in 2016 by Rodrigues et al. [24] mentioned that: (i) drinking
arsenic-contaminated water is connected with decreased cognitive scores for children from Pabna
(Bangladesh); and (ii) the high concentration of lead in blood was also associated with a decrease of
cognitive scores using the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) [25].
This study was performed on 524 children exposed to lead- and arsenic-contaminated water in pre- and
perinatal life. The study results do not confirm an association between arsenic levels in blood and
motor and language scores [24]. We selected from this work a suggestive table (Table 1) in which
are presented the results revealed by the multivariate model between As, Mn, and Pb exposures and
BSID-III scores at 20–40 months.

Table 1. Models of metals exposure and BSID-III scores regarding cognitive and fine motor activities
collected from children living in Sirajdikhan and Pabna, Bangladesh, adapted after [24].
Cognitive Score Fine Motor Score
Sirajdikhan, n = 239 Children Pabna, n = 286 Children Sirajdikhan, n = 239 Children Pabna, n = 285 Children
Exposures Statistical Values
β (SE) p-Value β (SE) p-Value β (SE) p-Value β (SE) p-Value
Water and Arsenic −0.002 (0.02) 0.93 −0.06 (0.03) 0.05 −0.05 (0.03) 0.09 0.02 (0.03) 0.48
Water and
0.02 (0.02) 0.35 −0.06 (0.07) 0.33 −0.04 (0.03) 0.21 0.85 (0.39) 0.03
Manganese (Mn)
Water and
- - - - - - −0.08 (0.03) 0.02
Manganese (Mn2)
Blood and Lead
−0.17 (0.09) 0.05 0.02 (0.12) 0.87 0.07 (0.11) 0.50 −0.07 (0.11) 0.50
metal (Pb)

Katherine von Stackelberg et al. [26] reviewed the effects of prenatal and perinatal exposure to
lead, arsenic, cadmium, and manganese and their subsequent effects on neurodevelopment. In this
review it was mentioned that the high concentration of arsenic and lead in blood or urine was linked
with autism behavior and cognition changes [26]. Stackelber’s work [27] mentioned that the long-time
exposure at arsenic induced in the human body: ”(i) autism by down-regulating the CAT gene (catalase
gene) which is involved in immune system response to oxidative stress; (ii) intellectual disabilities and
autism by down-regulating of BDNF (brain-derived neurotrophic factor); (iii) various learning disorders
which are linked by up–regulation of MAPK1 and MAPK3 (mitogen activated protein-kinases);
(iv) up–regulates IL1B (mediator of inflammatory response)—linked to learning disorders; (v) increases
the level of serotonin and decreasing norephinephrine associated with apoptosis or apoptotic markers
in astrocytes”. It was also mentioned by Chou et al. [28] that arsenite down-regulates the expression of
brain-derived neurotrophic factor, one of the critical factors involved in memory and learning from
neuroblastoma SH-SY5Y cells.
Int. J. Mol. Sci. 2019, 20, 1804 4 of 18

2. Possible Molecular Mechanisms of Arsenic-Induced Disturbance of Cognitive

Human Functions
There are mentioned few possible mechanisms by which arsenic and other metals are able to
induce neuropsychiatric disorders. It was mentioned that arsenic has the ability to easily cross the
blood brain barrier, affecting basal ganglia, the hippocampus, and cortex [1].
It was reported that few chemicals could inhibit the acetylcholine esterase causing neurotoxicity
by accumulation of acetylcholine in the synaptic cleft, thus being at the root of overstimulation of
nicotinic and muscarinic receptors. Lipid peroxidation caused by oxidative stress may alter the
enzyme’s activity [29–31]. More so, acetylcholine and dopamine functions are affected by the presence
of arsenic [32–34].
There are several studies [24,35–37] which reported that arsenic exposure could disturb attention
and memory processes. The inorganic form of arsenic, known as sodium arsenite, is linked to impairing
memory and learning in pregnant dams and future offspring [38]. The effects of sodium arsenite were
studied on spatial memory and it was shown that a daily dose of 15 mg kg−1 greatly affected the
performance in the Y maze test and Morris water maze task [39]. The impaired learning and memory
performance noticed in rats exposed to arsenic may be explained by decreased expression of mRNA
glutamate receptor [40]. It was reported that arsenic metabolites permeated the blood brain barrier
and are accumulated in the hippocampus creating cytotoxicity. Additionally, the arsenic exposure
decreased expression of 2A subunit belonging to N-methyl-d-aspartate receptor gene, from the rat
hippocampus alongside with phosphorylated-Ca2+ /calmodulin-independent protein kinase II alpha
and postsynaptic density protein 95 [41]. More so, the protein expression of synaptic GTP-ase which is
a negative regulator of mitogen-activated protein kinases had an increase in activity [42].
Few studies presented the ability of arsenic to modify the structure of hippocampal neurons by
inducing the pathological alterations of endothelial cells and neurons [41,43].
Recently, Bao-Fei Sun et al. [44] published a paper regarding the arsenic effect in memory, by tested
the negative effects of arsenic exposure of mice in their long-term memory and in their ability for object
recognition. Different doses of arsenic (e.g., 0, 1, 3, and 10 mg kg−1 ) were administered on a daily
basis for 12 weeks [44]. The study results revealed that: (i) the doses decreased the mice body weights,
while increasing the toxicant level in the brain; (ii) the object recognition test was disrupted by 3 mg
and 10 mg doses but not by a 1 mg test set; and (iii) swimming had the ability to prevent the long-term
memory impairment of the 3 mg group but not the 10 mg mice. In this study it was mentioned that
arsenic exposure did not influence the total CREB expression. The swimming exercises prevented
object recognition ability deterioration, which could be mediated by CREB and BDNF from the dorsal
hippocampus. They concluded that the swimming exercises can exert the effect of removal arsenic and
may activate some protection-based process.
Ramos-Chávez et al. [45] mentioned that the arsenic exposure has been linked with learning
disabilities, memory impairment and lower intelligence coefficient. Authors’ utilized CD1 mouse
models for tested the effects of gestational arsenic exposure, which leaded to many molecular events,
such as unruly cysteine/glutamate transport, oxidative damage, and negative effects on learning and
memory. Studies results showed that: ”(i) exposure to arsenic during gestation would be responsible
for increasing oxidative stress thus up-regulating xCT (a component of the xc − amino-acid transporter),
(ii) 20 mg L−1 of arsenic failed to cause clear signs of toxicity in during gestation or before mating in
CD1 mouse, (iii) day 90 males which were exposed during gestation while continuing to ingest water
with arsenic showed memory deficits and an increase of expression in xCT and minor down-regulation
of N-methyl-d-aspartate receptor subunit NR2B, but not subunit NR2A, suggesting a problem in
synaptic efficiency, (iv) their results clearly indicate that gestational exposure to inorganic arsenic
negatively impacts hippocampal N-methyl-d-aspartate (NMDA) receptor subunits expression” [45].
Kyaw Htet Aung et al. [46] mentioned that arsenic compounds are capable of inducing alterations
in morphology and neuronal cell death, especially neurite outgrowth and the cyostekeleton of neurons.
Arsenic exposure is responsible for alteration of the expression of nuclear factor cells, the decrease
Int. J. Mol. Sci. 2019, 20, 1804 5 of 18

of nuclear factor transport to axonal outgrowth, as well as increasing perikaryal nuclear factor
expression [46]. Aung’s team noticed that the exposure to sodium arsenite caused a significant increase
in the gene expression of nuclear factor -L and nuclear factor -M proteins in neural cells while the neurite
outgrowth suppression was also marked. This study strongly suggests that arsenic-induced neurite
suppression leaded to nuclear factor dynamic alteration. They also observed that the microtubule gene
expression, and also protein Tau, were significantly decreased due to exposure to sodium arsenite [46].
A recent study performed by Yachen Wang et al. [47] tested if arsenic exposure induced apoptosis
in the hippocampus. The authors utilized 64 mice divided into four groups. Group 1 was the control
group, thus receiving only water. For Groups 2–4 they were orally given arsenic trioxide (As2 O3 ) at
concentrations of 1, 2, and 4 ppm. The treatment lasted for 60 days. The results observed apoptosis
and abnormal histopathological changes found in the hippocampus of mice who were exposed to
arsenic [47]. The hippocampal expression of Bcl-2(B-cell lymphoma 2) gene and its protein were
significantly lower than the control group’s results (p < 0.05). The expression ratio of Bax (BCL2
Associated X)/Bcl-2 and the expression of Bax gene and its protein were far higher in the arsenic
groups compared to the control group. Even the activity of caspase-3 in the hippocampus was higher
in the groups exposed to arsenic than control. This study concludes that sub-chronic dosages of
arsenic disturbs the normal Bax/Bcl-2 pathways and is responsible for apoptosis in mice hippocampus.
Arsenic-induced neurotoxicity may be partially explained by the induced apoptotic effect in the
hippocampus [47].
Katharine E. Caldwell’s study [48] reported a possible molecular pathway of arsenic in the
nervous system represented by the glucocorticoid system, which has an important role in many
cellular functions including learning, memory, and mood disorders. From this study it was postulated
that the disturbance of the glucocorticoid receptor (GR) pathway in the fetal brain and placenta are
critical. Two critical periods represented by embryos, 14 and 18 days, were evaluated and the study
was focused on 11β-hydroxysteroid dehydrogenases (11β-HSD), which exert a key function in the
synthesis of glucocorticoid. They have identified that at the E14 time checkpoint arsenic exposure
decreased in a significant manner the expression of enzyme 11β-HSD1, while the 11β-HSD2 enzyme
level was increased. The changes continued into the E18 checkpoint, but mRNA levels stopped being
altered significantly. In the arsenic-exposed condition, GR placental levels were decreased at E18.
Sonia Ronchetti et al. [49] mentioned that arsenic can affect the anterior pituitary gland and uterus.
The authors studied if low doses of in vivo administration through drinking water would display
xenoestreogenic effects in the uterus and anterior pituitary gland of ovariectomized rats. Arsenic
significantly affects the anterior pituitary by exerting strong xenoestreogenic effects [49].

3. Perturbance of Neuropsychiatric Treatments during Arsenic Exposure

Arsenic exposure, particularly the chronic type, can lead to poisoning with manifestations
presenting in multiple organ systems. It is very important to prove that the nervous system damages
induced by arsenic are reversible.
However, acute psychosis is not a commonly described manifestation of arsenic exposure.
Wu et al. [50] published in their work a study about acute psychosis induced by arsenic exposure.
According to Wu et al. patients presented a severe symptomatology which includes obsessive
compulsive symptoms, psychosis, and hallucinations. By treating such patients with a combination
of antipsychotic and antidepressant drugs a significant improvement in obsessive-compulsive and
acute psychosis symptoms was observed. Based on the research results the authors conclude that
following arsenic poisoning patients can develop several atypical symptoms, including acute psychosis.
The treatment of patient was represented by combinatorial therapies with antidepressants and
neuroleptics but is not clear the molecular mechanism by which these drugs are able to combat
psychosis symptoms.
A very interesting paper was published by Christina R. Tyler et al. [51] about the reduced perinatal
symptoms of depression during fetal exposure of arsenic during fluoxetine treatment. In their study
Int. J. Mol. Sci. 2019, 20, 1804 6 of 18

authors, assessed the effects of fluoxetine, a strong antidepressant with a selective serotonin reuptake
inhibitor role, on adult animals exposed to arsenic during development. Perinatal arsenic exposure
induced depressive-like symptoms in a mild learned helplessness task and in the forced swim task after
acute exposure to 2,4,5-trimethylthiazoline (TMT). The results showed that: (i) the chronic fluoxetine
treatment prevented depression behaviours in case of arsenic-exposed; (ii) reduced the arsenic-induced
blunted stress responses; (iii) chronic fluoxetine treatment reversed deficits in adult hippocampal
neurogenesis after arsenic exposed. This study demonstrates that damage induced by perinatal arsenic
exposure is reversible with chronic fluoxetine treatment.
Additionally, it was proven that fluoxetine is a powerful antidepressant during neurogenesis in the
human adult hippocampus [52] by acting on serotonin receptor 5-TH1A and also the sigma1 receptor
(σ1R), but many molecular aspects of these processes are still unclear. Avram et al. [52] published a
review about possible antidepressants inducing enhanced effects on neurogenesis on 5-TH1A and also
the sigma1 receptor. Among these antidepressants, in our previous study we mentioned: escitalopram,
sertraline, paroxetine, or duloxetine. In our opinion if the chronic treatment with fluoxetine can reduce
the toxic effect of arsenic in the body, we suggest that future studies involve the chronic treatment with
antidepressants escitalopram, sertraline, and paroxetine, and antipsychotics, like piperazine, should be
very important for treatment during arsenic exposure.

4. Bioinformatics and Cheminformatics Tools Applied to Study Arsenic Toxicity in the Brain
In silico approaches of arsenic toxicity represent a new way to identify its neutralization in
the human body. Regarding this aim, the friendly bioinformatics (various databases, predictive
ADMET—absorption, distribution, metabolism excretion and toxicity) and cheminformatics
(quantitative chemical structure-biological activity relationship (QSAR), molecular docking,
high-throughput screening) tools were clearly recognized as very useful tools. QSAR is a very useful
tool in medical chemistry, allowing the investigation of the interactions between chemical compounds
(drugs, pro-drugs, various ligands, pollutants) and their macromolecular targets (e.g., enzymes,
membrane receptors) [53–55].
Basically, QSAR methods considered that the biological activity is induced by the molecular
structure and every change in molecular structure leads to a modification of these properties [56–61].
There are few differences among QSAR methods and these consisted in the way they describe
the structural properties of compounds and in the quantitative relationships found between these
properties and activities [21,62]. In QSAR, the molecular descriptors could be classified in: (i) atom
and bound counts, molecular weight, and the sum of atomic properties; (ii) molecular fragment
counts; (iii) topological descriptors; (iv) atomic coordinates or energy grid descriptors; and (v) the
combination of atomic coordinates and sampling of conformations. Additionally, QSAR methods
consider: (i) different types of probe atoms; (ii) different force fields; and (iii) different manners of
calculating the electronic interactions [53].
In QSAR methods, the appropriate selection of molecular descriptors assures the QSAR model’s
prediction power. Usually, the biological activity of compounds can be correlated with large sets of
molecular descriptors, such as: (i) steric (subdivided van der Waals surface and volume, subdivided
solvent accessible surface and volume); (ii) atom and bond counts (hydrophobic/polar, donor/acceptor
atoms, rigid and rotatable bonds); (iii) hydrophobicity and solubility; and (iv) electronic descriptors
(subdivided potential energy, molar refractivity, dipole moment, energies of frontier molecular
orbital) [63].
Presently, the predictive ADME-Tox (absorption, distribution, metabolism, and excretion toxicity)
for compounds are an important challenge. Among bioinformatics tools used in predictive ADME-Tox,
there are few databases (TOXNET, Drugbank, admetSAR, IDA2PM, etc.) [64–66] which are very useful
and freely accessible. There are also molecular simulation software packages (Discovery Studio,
Volsurf) [27,67] used to predict the toxicological and structural features of chemical compounds. Below,
we briefly present some of them.
Int. J. Mol. Sci. 2019, 20, 1804 7 of 18

The National Library of Medicine (NLM) portal provides reliable information on toxicology,
hazardous chemicals, environmental health, and toxic announcements [64]. TOXNET (Toxicology
Data Network), belonging to the NLM portal, is a free database system with information on toxicology,
environmental health, chemical nomenclature, poisoning, risk assessment and regulations, and
occupational safety and health. It is produced by the Specialized Information Services Division of the
US. From this database we selected a few useful links and, very importantly, the field covered by these
(Table 2).

Table 2. The databases able to be access TOXINET, and their covered fields [64].

ChemIDplus Chemical names, formulas, structures

CCRIS Carcinogenicity, mutagenicity
CPDB Cancer testing
CTD Toxicogenomics information
GENE-TOX Mutagenicity test data
IRIS Human health risk assessment
ITER Risk information
TOXLINE Toxicology journal literature
DART Reproductive toxicology journal literature
Haz-Map Occupational health
HSDB Health effects, toxicity, regulations
TOXMAP Interactive U.S. maps of chemical releases

Another important bioinformatics database is DrugBank [65]. DrugBank is a wide-range database

that contains information on drugs and drug targets. As a bioinformatics and cheminformatics source,
DrugBank collects detailed information regarding drug features (i.e., chemical, pharmacological, and
pharmaceutical) with comprehensive drug target information (i.e., sequence, structure, and pathway).
The database contains over 8000 drug entries including chemicals and additionally, 4270 non-redundant
protein (i.e., drug target/enzyme/transporter/carrier) sequences are linked to these drug entries [68].
We search arsenic and its derivatives in DrugBank and we mentioned that there is just
one arsenic derivative, namely arsenic trioxide, a very important compound in tumor treatment
(Table 3). We mentioned that the important experimental ADMET features of arsenic trioxide are not
elucidated yet.

Table 3. Structural, functional, and pharmacokinetic data of arsenic trioxide extracted from the
DrugBank database [65].

ID arsenic Trioxide DB01169

Chemical Formula As2 O3
SMILES O=[As]O[As]=O
“For induction of remission and consolidation in patients with acute promyelocytic leukemia (APL), and whose APL is
Therapeutic Indication
characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression”
“Arsenic Trioxide is indicated for induction of remission and consolidation in patients with acute promyelocytic
Pharmacodynamics
leukemia (APL) who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy.”
Absorption Not available
Volume of Distribution Not available
Protein Binding 75% bound
Route of Elimination Trivalent arsenic is mostly methylated in humans and excreted in urine
Half Life Not Available
Clearance Not Available
Toxicity “Symptoms of overdose include convulsions, muscle weakness and confusion”

Based on our expertise in bioinformatics and cheminformatics, here we accessed the bioinformatics
tools Accelerys Discovery Studio (DS) [27] and the online ADME-Tox database [69], in order to predict
the few ADME-Tox features of arsenic and its derivative arsenic trioxide (Table 4).
Int. J. Mol. Sci. 2018, 19, x 8 of 18

Based
Int. J. Mol. on 20,
Sci. 2019, our1804
expertise
in bioinformatics and cheminformatics, here we accessed8 ofthe 18
bioinformatics tools Accelerys Discovery Studio (DS) [27] and the online ADME-Tox database [69],
in order to predict the few ADME-Tox features of arsenic and its derivative arsenic trioxide (Table
4). Table 4. Predictive ADME-Tox (absorption, distribution, metabolism, and excretion and toxicity)
features of arsenic trioxide and arsenic [27,69].
Table Trioxide
Arsenic 4. Predictive ADME-Tox (absorption, distribution, metabolism, and excretion and toxicity)
features ADME-Tox
of arsenic trioxide and arsenic [27,69]. Features Unit

Arsenic Trioxide
Absorption
Water solubility (log S) 0.84 (log mol/L)

ADME-Tox Featuresabsorption
Intestinal Unit 100%
Water solubility
Volume (log S)(human)
of distribution 0.84 (log mol/L )log (L/Kg)
−0.48
Absorption
IntestinalBarrier
Blood-brain absorption
Permeability (BBB) 100% −0.361(log BB)
Distribution Volume of distribution
Central Nervous (human) (CNS)
System permeability −0.48 log (L/Kg)
−2.70 (log PS)
Blood-brain
FractionBarrier Permeability
of plasma(BBB) −0.361(log BB) 75%
Distribution unbounded proteins
Metabolism
Central Nervous System permeability (CNS)
CYP2D6 substrate/inhibitor
−2.70 (log PS)
NO
Fraction unbounded of plasma proteins 75%
Excretion Total clearance 1.064 (log mL/min/kg)
Metabolism CYP2D6 substrate/inhibitor NO
AMES (mutagenic feature) NO
Excretion Total clearance 1.064 (log ml/min/kg)
Hepatotoxicity
AMES (mutagenic feature) NO NO
Toxicity
Hepatotoxicity
Skin permeability NO NO
Toxicity Skin
Max. permeability
tolerated dose (human) NO1.125 (log mg/kg/day)
Max. tolerated dose (human)
Oral rat acute toxicity (LD50) 1.125 (log mg/kg/day)
2.331 (mol/kg)
Arsenic Oral rat acute toxicity (LD50) 2.331 (mol/kg)
Arsenic Blood-brain Barrier Permeability (BBB) 0.003 (log BB)
Distribution
Blood-brain BarrierSystem
Permeability (BBB)(CNS) 0.003 (log BB)
Distribution Central Nervous permeability −2.30 (log PS)
Central Nervous System permeability (CNS) −2.30 (log PS)
AMES (mutagenic mutagenic) NO
AMES (mutagenic mutagenic) NO
Hepatotoxicity NO
Hepatotoxicity NO
Toxicity Skin permeability NO
Toxicity Skin permeability NO
Max. tolerated dose (human) 1.18 (log mg/kg/day)
Max. tolerated dose (human) 1.18 (log mg/kg/day)
Oral rat acute
Oral toxicity
rat acute (LD50)
toxicity (LD50) 2.21(mol/kg)2.21(mol/kg)

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Internet theWe
[70]. Internet
search[70]. We searchcomplex
the molecular the molecular complex
of arsenic and weof arsenic and we
found PDB found
code 5DAK,PDB code
posted
5DAK,
by posted
Parker et al. by
[71]Parker
about ettheal.crystal
[71] about the crystal
structure of human structure of human
glutathione glutathione
transferase transferase
pi complexes withpi
a
complexes with a metalloid in the absence
metalloid in the absence of glutathione (Figure 1). of glutathione (Figure 1).

Figure 1.
Figure 1. Crystal
Crystal structure
structure of
of human
human glutathione
glutathione transferase
transferase pi
pi complexed
complexed with
with aa metalloid
metalloid in
in the
the
absence ofofglutathione,
absence glutathione,
PDBPDB ID: 5DAK:
ID: 5DAK: molecule:
molecule: glutathione
glutathione S-transferase
S-transferase P B),
P (chain: A, (chain: A, B),
heteroatoms
heteroatoms
CSO CSO (S-hydroxycysteine),
(S-hydroxycysteine), MES (2-(n-morpholino)-ethanesulfonic
MES (2-(n-morpholino)-ethanesulfonic acid) and As acid) and As (arsenic).
(arsenic).
Int. J. Mol. Sci. 2019, 20, 1804 9 of 18

In 2014, Canaval et al. [72] published a study about hybrid ab initio quantum mechanics and
molecular mechanical simulations applied to investigate the hydrolysis process of arsenic(III), ultimately
leading to arsenous acid (H3 AsO3 ). In this study are discussed: (i) the geometrical properties of H-bonds
involved in each of the three protons transfer; and (ii) subsequent proton bounding reactions. For results
interpretation Laguerre tessellation analysis has been employed in order to estimate the molecular
volume of H3 AsO3 . As novelty of this study, the authors performed Fourier transform infrared
(FT-IR) spectroscopy measurements, which have been compared to power simulation spectra. The
study results, represented by simulation findings, as well as results from computational spectroscopic
calculations utilizing the PT2-VSCF methodology, fitting the experimental FT-IR data well.
Another interesting paper regarding the critical molecular descriptors involved in arsenic toxicity
was published by Roy et al. [73]. In this study the following were considered as critical molecular
descriptors: atomic number (Z) and electrophilicity index (omega) in order to explain toxicity of
various alkali and arsenic ions. The results studied were mentioned as critical molecular descriptors
of toxicity: (i) the global electrophilicity (omega), (ii) number of non-hydrogenic atoms (N (NH));
(iii) philicity (omega); and (iv) the atomic charge (Q) on the arsenic. Additionally, by applying the
regression models from the training sets, the toxicity of some unknown arsenic derivatives is predicted.
A helpful use of arsenic was mentioned by Zhang et al. [74]. In this paper it was mentioned that
arsenic trioxide presented a great clinical success in the treatment of acute promyelocytic leukemia
(APL). In this paper the authors reported that “a “one-pot” method to develop arsenic-based nanodrugs
by in situ coating the as-prepared arsenic nanocomplexes with porous silicashells”. Here it was
mentioned that, in accord with these unique features, the nanodrugs are able to strongly inhibit the
growth of solid tumors. These effects are very important; in addition, these principal effects happened
without adverse side effects. The authors, based on their results, suggested that the arsenic-based
nanodrugs generated by this facile synthetic route may be a powerful and alternative strategy for solid
tumor therapy.
A very interesting paper was published by Wei Kheng Teoh et al. [75], in order to establish the
description of Thiomonas delicata arsenite oxidase identified in Escherichia coli by using bioinformatics
and cheminformatics. This study represents the first characterization of arsenite oxidase found in
Thiomonas genus. It was mentioned that arsenite oxidase presents a real potential to be used for
biosensors and bioremediation applications in acidic environments. For the performed homology
model of arsenite oxidase from T. delicate, the authors used a SWISS-MODEL workspace, and used as
template the arsenite oxidase crystal structure isolated from A. faecalis (PDB: 1G8K chains A and B).
The structural superimposition and graphical representation of the structure model was prepared in
UCSF CHIMERA software.
The homology results showed that: (i) the reliability of the model was supported by its high
sequence identity of 64% and with QMEAN4 score of −2.16; (ii) a homology comparison of the
model and template showed a high similarity in overall fold and active site residues; and (iii)
electrostatic charges on both enzymes revealed that the surfaces of arsenite oxidase in T. delicata are
rich with positively-charged residues, while arsenite oxidase in A. faecalis has more negatively-charged
surface residues.
An interesting study was performed by Tsai et al. [76] in order to employ molecular
dynamics for elucidation of structural/dynamic features of arsenic in a lipid bilayer. In this
study, it was considered that the cell membranes are composed mainly of phospholipids which
are, in turn, composed of five major chemical elements: carbon, hydrogen, nitrogen, oxygen,
and phosphorus. Tsai et al. studied the arsenated-lipid bilayer interactions by simulating the
arsenic-lipid interaction, 1-palmitoyl-2-oleoyl-sn-glycero-3-arsenocholine (POAC) and arsenic-lipid
1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, (POPC). The structural and dynamical properties
of these two complexes was mentioned, with emphasis on the differences among them. The results
studied reveal that: POAC lipid bilayers present different structural and dynamical features from those
of native POPC lipid bilayers; (ii) “compact structure of POAC lipid bilayers is due to the fact that more
Int. J. Mol. Sci. 2019, 20, 1804 10 of 18

inter-lipid salt bridges are formed with arsenate-choline compared to the phosphate-choline of POPC
lipid bilayers”; and (iii) POAC and POPC lipid bilayers would have different biological implications.
Molecular dynamic protocols were used in CHARMM-GUI, developed by Jo et al. [77]. The initial
configurations of the POAC and POPC systems were prepared. Water molecules were modeled using
the TIP3 model [78,79].
Another study performed by Altaf Hussain Pandith et al. [80] reveal the importance of two
molecular descriptors in the toxicity of aliphatic compounds from Tetrahymena pyriformis. A series of
important molecular descriptors, such as: orbital energy (LUMO energy, HOMO energy), ionization
energy, chemical potential, electron affinity, electronegativity, philicity, and electrophilicity of a series of
aliphatic compounds are calculated. In this study were involved a large series of molecules, such as: (i)
polyaromatic hydrocarbons (e.g., polychlorinated biphenyls (PCBs)), polychlorinated dibenzofurans
(PCDFs), polychlorinated dibenzo-p-dioxins (PCDDs), and chlorophenols (CP), as well as arsenic
derivatives. A wide number of QSAR models were presented and the statistic parameters R2 correlation,
Fisher F, and unexplained variance RSS, recorded significant values.
The results studied revealed that:

(i) For various chemical structures the critical molecular features for structure toxicity is different;
(ii) The chemical structure constructed based on the electrophilicity index (ω) and log P (R2 adj =
0.965 for acceptors, 0.888 for donors) is better than the model based on eLUMO and log P (R2 =
0.963 for acceptors, 0.842 for donors); and
(iii) The QSAR model can improve molecules’ toxicity predictability, and can be developed by taking
into account the electrophilic property in addition to molecule hydrophobicity.

Recently, Hui Dong et al. [81] reported new small molecules as possible inhibitors of human As(III)
S-adenosylmethionine methyltransferase (AS3MT) by molecular docking. It was mentioned that, in
humans, arsenic is primarily metabolized by the enzyme As(III) SAM methyltransferase (hAS3MT),
a member of the large superfamily of SAM methyltransferases (SAM MTs) [82–84] knowing that
methylation is important for human biochemical processes (Table 5).

Table 5. Comparison of binding properties of 10 small molecule inhibitors to AS3MT calculated using
Autodock Vina33 [81].

hAS3MT Binding Catachol O-Methyltransferase Catachol O-Methyltransferase

Compound hAS3MT Kd (µM)
Affinity (kcal/mol) (COMT) Binding Affinity (kcal/mol) COMT Kd (µM)
TPI-1 −7.3 4.5 −4.3 704
TPI-2 −8.4 0.7 −5.6 79
TPI-3 −9.3 0.2 −4.6 424
TPI-4 −8.0 1.3 −3.6 229
TPI-5 −9.4 0.1 −1.4 9410
TPI-6 −7.2 5.3 −4.7 358
TPI-7 −8.5 0.6 −5.0 216
TPI-8 −9.2 0.2 −2.2 2440
TPI-9 −8.8 0.5 −0.7 306,800
TPI-10 −9.0 0.3 −5.5 93

Considering it, the biochemical events are: “AS3MT biotransforms of inorganic arsenic (As(III))
into trivalent methylated species methylarsenite (MAs(III)) and dimethylarsenite (DMAs(III)) using
SAM as the methyl donor”. The major aim of this study was to report new hAS3MT ligands, able to
modulate enzyme activity. In this study authors identified 10 compounds that inhibit hAS3MT with
IC50 values varies from 30 µM to 50 µM. None of them inhibit the binding of either As(III) or MAs(III),
and they do not inhibit catachol o-methyltransferase (COMT), a nonarsenic SAM MT. In silico methods,
namely molecular docking, were used in this study. By using the PDB database, CmArsM (4FS8) and
COMT (3BWM) structures were prepared for docking analysis, adding Gasteiger charges.
The study results revealed that all 10 ligands inhibited As(III) methylation, but only five inhibit
MAs(III) methylation, indicating differences in their mechanism of action. The authors proposed that
 Int. J. Mol. Sci. 2018, 19, x 11 of 18
Int. J. Mol. Sci. 2019, 20, 1804 11 of 18
The study results revealed that all 10 ligands inhibited As(III) methylation, but only five inhibit
MAs(III) methylation, indicating differences in their mechanism of action. The authors proposed
that AS3MT
AS3MT suffers suffers different
different conformational
conformational changeschanges during
during the the two methylation
two methylation steps thatsteps that may
may account
account for the differential action of the inhibitors (Figure 2).
for the differential action of the inhibitors (Figure 2).

(a) (b)
Figure2. 2. (a)
Figure (a) The
The structure
structure of
of an
an As(III)
As(III) S-adenosylmethionine
S-adenosylmethionine methyltransferase:
methyltransferase:insights
insightsinto the
into
mechanism of arsenic biotransformation (4FS8). (b) Crystal structure of human catechol
the mechanism of arsenic biotransformation (4FS8). (b) Crystal structure of human catechol
O-methyltransferasechain:
O-methyltransferase chain:AAwith
withbound
boundSAMSAM(S-adenosyl
(S-adenosylmethionine)
methionine)and
andDNC
DNC(PDB(PDBcode:
code:
3BWM).
3BWM).

>3BWM:A|PDBID|CHAIN|SEQUENCE
>3BWM:A|PDBID|CHAIN|SEQUENCE
GDTKEQRILNHVLQHAEPGNAQSVLEAIDTYCEQKEWAMNVGDKKGKIVDAVIQEHQPSV
GDTKEQRILNHVLQHAEPGNAQSVLEAIDTYCEQKEWAMNVGDKKGKIVDAVIQEHQPSVLLEL
LLELGAYCGYSAVRMARLLSPGARLITIEINPDCAAITQRMVDFAGVKDKVTLVVGASQDIIPQLK
GAYCGYSAVRMARLLSPGARLITIEINPDCAAITQRMVDFAGVKDKVTLVVGASQDIIPQLKKKYDV
KKYDVDTLDMVFLDHWKDRYLPDTLLLEECGLLRKGTVLLADNVICPGAPDFLAHVRGSSCFEC
DTLDMVFLDHWKDRYLPDTLLLEECGLLRKGTVLL ADNVICPGAPDFLAHVRGSSCFECTHYQSFL
THYQSFLEYREVVDGLEKAIYKGP
EYREVVDGLEKAIYKGP
>4FS8:A|PDBID|CHAIN|SEQUENCE
>4FS8:A|PDBID|CHAIN|SEQUENCE
MPCSCASGCQKSKNGGSTPSIRDHVADYYGKTLQSSADLKTSACKLAAAVPESHRKILADIA
MPCSCASGCQKSKNGGSTPSIRDHVADYYGKTLQSSADLKTSACKLAAAVPESHRKILADIADEVLE
DEVLEKFYGCGSTLPADGSLEGATVLDLGCGTGRDVYLASKLVGEHGKVIGVDMLDNQLEVAR
KFYGCGSTLPADGSLEGATVLDLGCGTGRDVYLASKLVGEHGKVIGVDMLDNQLEVARKYVEYHA
KYVEYHAEKFFGSPSRSNVRFLKGFIENLATAEPEGVPDSSVDIVISNCVCNLSTNKLALFKEIHRV
EKFFGSPSRSNVRFLKGFIENLATAEPEGVPDSSVDIVISNCVCNLSTNKLALFKEIHRVLRDGGELYFS
LRDGGELYFSDVYADRRLSEAAQQDPILYGECLGGALYLEDFRRLVAEAGFRDVRLVSVGPVDVS
DVYADRRLSEAAQQDPILYGECLGGALYLEDFRRLVAEAGFRDVRLVSVGPVDVSDPQLRKLVPDVQ
DPQLRKLVPDVQFYSCTFRCFKVATLEATREDYGQSATYLGGIGEEFKLDRFFTFPREKPVRVDRN
FYSCTFRCFKVATLEATREDYGQSATYLGGIGEEFKLDRFFTFPREKPVRVDRNTAEIIRHSRLHQW
TAEIIRHSRLHQWFSVSAEQQHMGLFKANDSYALLHAPLSMQVEQLVSGAAALEHHHHHH
FSVSAEQQHMGLFKANDSYALLHAPLSMQVEQLVSGAAALEHHHHHH

5.5.Arsenic
ArsenicReduced
ReducedToxicity
Toxicity and
and Arsenic
Arsenic Nanoparticles
Nanoparticles Used
Used asas Delivery
Delivery System
System into
into thethe Human
Human
Body Body
Recently,
Recently,basicbasicQSAR
QSARwas wasusedusedforforpredicted
predictedmolecular
molecularfeatures
featuresofofnanoparticles,
nanoparticles,usuallyusually
renamed
renamed as nano-QSAR. Classical QSAR models, as convertors of chemical information, showsome
as nano-QSAR. Classical QSAR models, as convertors of chemical information, show some
disadvantages
disadvantages in in
predicting
predicting thethe
features of nanomaterials,
features of nanomaterials, especially theirtheir
especially toxicity [60,61].
toxicity During
[60,61]. the
During
last decades high interest in the development of “theranostic pharmaceuticals”
the last decades high interest in the development of “theranostic pharmaceuticals” was observed, was observed, allowing
for the initial
allowing fordiagnostic
the initialand probing and
diagnostic of a specific
probingpharmacological target. Regarding
of a specific pharmacological these
target. applications,
Regarding these
arsenic was used in the form of arsenic radioisotopes, with considerable interest
applications, arsenic was used in the form of arsenic radioisotopes, with considerable interest in the field of nuclear
in the
medicine [85]. medicine [85].
field of nuclear
InInnuclear
nuclearmedicine,
medicine,“theranostics”
“theranostics”are arechemical
chemicalcompounds
compounds(radionuclides)
(radionuclides)with withsimilar
similar
structural
structural features, but different radioactive disintegration properties, such as: (i) aone
features, but different radioactive disintegration properties, such as: (i) one with positron-
with a
orpositron-
gamma-emitting nuclide for positron-emission tomography (PET); (ii)
or gamma-emitting nuclide for positron-emission tomography (PET); (ii) single-photon single-photon emission
computed
emission tomography diagnostic imaging;
computed tomography and imaging;
diagnostic (iii) one with
and an electron-,
(iii) one with alpha-, or Auger-emitting
an electron-, alpha-, or
nuclide [85]. From many radioisotopes, radioisotopes of arsenic offer an alternative
Auger-emitting nuclide [85]. From many radioisotopes, radioisotopes of arsenic offer an alternative radionuclide-based
theranostic system. Arsenic
radionuclide-based has unique
theranostic system.chemical
Arsenic and biochemical
has unique chemicalproperties that make properties
and biochemical it notable for
that
novel diagnostic or therapeutic radiopharmaceuticals [85].
make it notable for novel diagnostic or therapeutic radiopharmaceuticals [85].
Even
Evenif ifarsenic
arsenictrioxide
trioxidehashasbeen
beenapproved
approvedfor forthe
thetreatment
treatmentofof refractory
refractory acute
acute promyelocytic
promyelocytic
leukemia
leukemia it was mentioned that it is difficult to apply to other cancers, such as solid tumors,ininpart
it was mentioned that it is difficult to apply to other cancers, such as solid tumors, part
because
becauseofofthetherapid
rapid renal
renalclearance
clearance and
anddose-limiting
dose-limiting toxicity [74].
toxicity [74].
Int. J. Mol. Sci. 2019, 20, 1804 12 of 18

Zongjun Zhang et al. developed a new arsenic-based nano-drug using porous silica shells
by using a “one-pot” synthesis method. The authors mention that “this process can be easily
reproduced and scaled up because no complicated synthesis and purification steps are involved.
This core–shell embedding method endows nanodrugs with high loading capacity (57.9 wt%) and
a prolonged pH-responsive releasing profile, which is crucial to increase the drug concentration at
tumor sites and improve the drug efficacy” [74]. Nickel(II) arsenite nanocomplexes (NiAsOx) are
prepared as ATO-based prodrugs in microemulsion prior to further silica shell coating (NiAsOx@SiO2 ).
The nanocomposites are then modified with zwitterionic ligands (denoted as NiAsOx@SiO2 -ZW),
which render colloid stability over biological conditions and increased half-life in blood
Animal studies indicated that NiAsOx@SiO2 -ZW nanocomposites effectively suppressed the tumor
growth compared with free ATO. Regarding the cytotoxicity of arsenic-loaded nanoparticles it was
mentioned that “after 48 h incubation with these three cell lines (Fig. 5), both NiAsOx@SiO2 (IC50 = 0.58,
2.26, 38.08 µM, respectively) and NiAsOx@SiO2 -ZW (IC50 = 2.73, 9.52, 42.10 µM, respectively) showed
better arsenic bioavailability and significantly higher cytotoxicity than free ATO (IC50 = 13.79, 25.42,
47.52 µM, respectively)”. Regarding the in vivo behavior of nanodrugs, the results suggested that
NiAsOx@ SiO2 -ZW may be more effective for the accumulation in solid tumor sites compared to
NiAsOx@SiO2 through the EPR effect. In vivo therapy showed that the treatment of NiAsOx@SiO2 -ZW
effectively suppressed the tumor growth, resulting in a mean tumor volume. It should be noted that
the NiAsOx@SiO2 -ZW was more effective in suppressing tumor growth than free ATO.
Another important part to reducing arsenic toxicity in the body is represented by the elimination
of it in water. One of the simplest and cheapest processes for arsenic removal from water, also being
considered a natural process, is the process in which water is passed over a sand filter. The affinity
of arsenic for iron and manganese ions explained the arsenic removal present in underground water
by simply passing over a filterable bed formed by sand, a process determined by the presence of
significant concentrations of iron and manganese ions in this type of water. The process of arsenic
removal consists in its retaining due to the presence of iron hydroxo-oxides or manganese oxides.
In the aqueous solution arsenic is found either in the arsenate As(III) form or arsenite As(V) form.
The mechanism on which it is based, the process of arsenic removal from water through adsorption
predominantly depends on the nature of the adsorbent material. Selective adsorption using biological
materials, mineral oxides, activated carbon, and industrial waste or polymeric resins has generated
enthusiasm leading to good results [86,87]. Even if the surface chemistry of carbon depends on the
activation conditions, temperature, by the way of refining the structure of pores (micro- and mesopores)
formed, which can lead to specific surfaces around 2000 m2 g−1 , this does not mean that they are the
determinant factor of activated carbon’s high adsorption capacity [88–90].
Arsenic species present in water limit the performance of many adsorbent materials, most of
which are much more suitable for removing As(V) than As(III) [91]. Since arsenic species present a
good affinity for iron, iron oxides/hydroxides have been extensively studied in order to understand
arsenic adsorption behavior. Traditional methods used to remove arsenic from water are generally
expensive and present a major inconvenience of generating by-products. Thus, attention is granted
to implement new methods of reducing/recovering arsenic from aqueous solutions by developing
clean technologies.
In recent years, implementing at large scale the arsenic removal from aqueous solutions by
adsorption, it has been necessary to develop advanced adsorbent materials with applications in
this process. In order to improve the adsorption properties of materials, new methods of chemical
modification of the inorganic or organic adsorbents were developed by functionalization of such
materials with different extractants dissolved in different solvents.
Presently, the used methods are: wet method (the diluted extractants dissolved in different
solvents is kept in contact with the solid support, the liquid phase being absorbed by the support),
dry method (the extractant is diluted with the solvent, put in contact with the solid support, after which
the solvent is removed through slow evaporation under vacuum), modifier addition method (this
Int. J. Mol. Sci. 2019, 20, 1804 13 of 18

method is an hybrid between the dry and the wet method), and the column dynamic method, which
presents the advantages of a short time of functionalization correlated with an increased efficiency of
the adsorption process [92–97].
In order to apply these methods, the extractants should be liquid or kept in a liquid form by
adding a proper solvent; the extractant and the solvent must have a minimum solubility; the support
must be prepared for the impregnation and the functionalization method does not have to modify the
extractants or the support properties [98].
Frequently used as solid supports are macroporous polymeric resins with a rigid three-dimensional
structure (XAD-type resins), appropriate to incorporate higher quantities of extractants due to the proper
specific surface area, great mechanical resistance, and low solvent swelling during the functionalization
process. These amberlite resins are used at the large-scale, being produced as: styrene-divinyl benzene
aromatic copolymer (XAD-2, XAD-4, etc.), aliphatic methacrylate copolymer (XAD-7, XAD-8, etc.),
and divinyl benzene aromatic copolymer (XAD-12, XAD-16, etc.) [92].

6. Conclusions and Perspective

Serious health problems caused by arsenic toxicity, it mechanisms of neurotoxicity, and how the
treatment or other methods could be able to reduce the concentration of arsenic in the brain are unclear.
In this paper, we presented the possibility of a new approach of arsenic removal.
Exposure of high quantities of arsenic, lead, and manganese has negative effects affecting the
whole body. It was proved that exposure to arsenic can induce genotoxicity and cancer, which affect
the liver, skin, kidneys, or brain. Arsenic’s inorganic form is linked with impairing memory and its
effect was studied on spatial memory, proving that long-term exposure affects brain performance.
Arsenic-induced toxicity can be partially explained considering the induced apoptotic effect in the
hippocampus. Experiments performed during the last decade proved that acute psychosis can be
induced by arsenic exposure, with severe symptomatology: hallucinations, disorganized thinking,
and obsessive-compulsive symptoms. By treating patients with a combination of antipsychotic and
antidepressant drugs a significant improvement of the acute psychosis and obsessive-compulsive
symptoms was observed.
In silico approaches of arsenic toxicity represent a new way to identify its neutralization in
the human body. Regarding this aim, bioinformatics (various database, predictive ADMET) and
cheminformatics (quantitative chemical structure-biological activity relationship (QSAR), molecular
docking, high-throughput screening) tools were clearly recognized as very useful tools.
A different approach is represented by the usage of arsenic trioxide as an active drug for the
treatment of promyelocytic leukemia, where the nanodrugs can inhibit the growth of solid tumors.
These effects are very important, besides these principal effects happening without adverse side effects.
Even if arsenic trioxide has been approved for the treatment of refractory acute promyelocytic leukemia
it was mentioned that it is difficult to apply to other cancers, such as solid tumors, in part because of the
rapid renal clearance and dose-limiting toxicity. For future usage of arsenic trioxide as an antitumoral
drug it is important to develop arsenic-based nanodrugs by in situ coating of arsenic nanocomplexes
with porous silica shells or with some other drug carriers.
Water is an essential element for life and for many for natural processes; our existence and our
economic activities are totally dependent on this precious resource. Moreover, globally, water represents
a limited resource. Despite the numerous efforts and financial resources invested to find solutions,
millions of people around the world are predisposed to daily consumption of arsenic-polluted water.
We used iron-based oxide materials synthesized by combustion or calcination, as well as
unconventional materials (sludge obtained from remediation of wastewater with a high content of
metallic oxides, especially iron), but also some modern materials (commercially- or chemically-modified
synthetic polymers) in the process of arsenic removal from water. At the same time, the possibility of
closing the cycle by inerting the waste, resulting in arsenic immobilization into vitreous matrices in
order to obtain useful products, was presented.
Int. J. Mol. Sci. 2019, 20, 1804 14 of 18

Conflicts of Interest: The authors declare no conflict of interest.

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 materials
Article
New Generation of Antibacterial Products Based on
Colloidal Silver
Bogdan Pascu, Adina Negrea *, Mihaela Ciopec *, Corneliu Mircea Davidescu, Petru Negrea,
Vasile Gherman and Narcis Duteanu
Faculty of Industrial Chemistry and Environmental Engineering, Politehnica University of Timisoara, 2 Piata
Victoriei, RO 300006 Timisoara, Romania; ioan.pascu@upt.ro (B.P.); corneliu.davidescu@upt.ro (C.M.D.);
petru.negrea@upt.ro (P.N.); vasile.gherman@upt.ro (V.G.); narcis.duteanu@upt.ro (N.D.)
* Correspondence: adina.negrea@upt.ro (A.N.); mihaela.ciopec@upt.ro (M.C.)




Received: 15 February 2020; Accepted: 25 March 2020; Published: 29 March 2020


Abstract: The main objective of the present paper is the green synthesis of colloidal silver by
ultrasonication starting from silver nitrate and using soluble starch as the reducing agent. Soluble
starch has been used during synthesis because it is a cheap and environmentally friendly reactive.
Silver colloid has been characterized by physicochemical methods: UV–VIS spectroscopy, Scanning
Electron Microscopy and Energy Dispersive X-Ray spectroscopy. This colloidal material was prepared
in order to prove and establish its toxicity on heterotrophic bacteria. Toxicity tests were carried
out using test cultures with and without silver colloid with different concentrations. This way
was possible to establish the minimum silver concentration that presents a toxic effect against used
bacteria. Quantitative evaluation of bacterial growth was performed by using the Most Probable
Number method. By counting the bacterial colony number, the antibacterial effect was determined
for colloidal silver deposited onto the cotton gauze by adsorption. During the present study, we
optimized the adsorption specific parameters: solid:liquid ratio, temperature, contact time, colloidal
silver concentration. By thermodynamic, equilibrium and kinetic studies, the adsorptive process
mechanism was established.

Keywords: colloidal silver; adsorption; band aid; ultrasonic; soluble starch; antibacterial effect

1. Introduction
Technological development from the last decade lead to extensive usage of colloidal silver
in different fields increasing the number of possible applications. Due to the mechanical and
physical-chemical properties, colloidal silver is used in several fields: electronics, electrotechniques,
biotechnology, bioenergy, textile and optical industries, pharmacy, medicine and environmental
protection [1,2]. An extensive literature review proved that colloidal silver has a large number of
applications: antibacterial agent [3,4], antifungal agent [5], antiviral agent [6], air disinfection [7],
water disinfection [3], ground water biological wastewater treatment [8] and surface disinfection
(antimicrobial paints, plastic catheters, gel formulation for specific usage, packing paper for food
preservation, clinical clothing) [3].
Schematically, colloidal silver applications are presented in Figure 1.

Materials 2020, 13, 1578; doi:10.3390/ma13071578 www.mdpi.com/journal/materials

 Materials 2020, 13, x FOR PEER REVIEW  2 of 25 

Materials 2020, 13, 1578 2 of 22

Figure 1. Silver colloidal applications.  

Figure 1. Silver colloidal applications. 
A versatile material with multiple uses in textile and medical fields is cotton because it is a soft
materialA versatile material with multiple uses in textile and medical fields is cotton because it is a soft 
and has good adsorbent properties [2,9–11]. A big problem for usage of textile materials in
the material and has good adsorbent properties [2,9–11]. A big problem for usage of textile materials in 
medical field is represented by the fact that all textile materials are exposed to several viruses
andthe medical field is represented by the fact that all textile materials are exposed to several viruses and 
bacteria [12]. Protective level of gauze is dependent on external layer hydrophobicity; such layer
beingbacteria 
called[12].  Protective  level 
the protective layer.of Ifgauze  is  dependent 
the protective on isexternal 
layer layer  hydrophobicity; 
not resistive such  layer 
to a microorganism’s presence,
being called the protective layer. If the protective layer is not resistive to a microorganism’s presence, 
it may pose a risk for the health of the patients. Different microorganisms can grow exponentially if the
it may pose a risk for the health of the patients. Different microorganisms can grow exponentially if 
temperature and humidity are optimal. Starting from this point, it is possible to reduce and minimize
the  temperature  and  humidity  are  optimal.  Starting  from  this  point,  it  is  possible  to  reduce  and 
the infections with different pathogen agents by using different textile materials with improved
minimize  the  infections  with  different  pathogen  agents  by  using  different  textile  materials  with 
antimicrobial properties [13–18]. Experimental data proved that some metals, such as silver or gold,
improved antimicrobial properties [13–18]. Experimental data proved that some metals, such as silver 
or some metallic
or  gold,  oxides
or  some  (titanium
metallic  oxides oxide, zincoxide, 
(titanium  oxidezinc 
or cooper
oxide  or oxide)
cooper present
oxide) good antimicrobial
present  good 
activity [2,16–29].
antimicrobial activity [2,16–29]. 
By By 
correlating
correlating this
this observation with the 
observation  with  thenecessity 
necessityfor for different
different  textile
textile  materials
materials  with  with
good  good
antimicrobial properties, we aim to prepare a new type of medical bandage by modifying a cotton
antimicrobial properties, we aim to prepare a new type of medical bandage by modifying a cotton 
bandage with an antimicrobial layer of colloidal silver. In the newly prepared medical bandages, an 
bandage with an antimicrobial layer of colloidal silver. In the newly prepared medical bandages,
improved antimicrobial property silver layer was introduced by adsorption. 
an improved antimicrobial property silver layer was introduced by adsorption.
Colloidal silver can be prepared using physical methods (evaporation, condensation) [30,31], or 
Colloidal silver can be prepared using physical methods (evaporation, condensation) [30,31],
chemical  methods  (microwave  synthesis,  microemulsion  techniques,  chemical  reduction)  [32–35], 
or chemical methods (microwave synthesis, microemulsion techniques, chemical reduction) [32–35],
photochemical  methods  [36–38],  biological  methods  using  some  microorganisms  (Pseudomonas 
photochemical methods [36–38], biological methods using some microorganisms (Pseudomonas
stutzeri) [39,40] or different plant extracts: Garcinia mangostana [35], Cinnamomum tamala [41]. 
stutzeri) Such colloidal material can be obtained only if the colloid stabilization is realized rapidly after 
[39,40] or different plant extracts: Garcinia mangostana [35], Cinnamomum tamala [41].
Such colloidal material can be obtained only if the colloid stabilization is realized rapidly after
silver reduction. Reduction process can be realized by using different reducing agents: sodium citrate, 
silver reduction.
ascorbate  Reduction
[42],  sodium  process can
borohydride  [43], be realizedhydrogen, 
elemental  by using different 
differentpolyols, 
reducing N,N agents: sodium
dimethyl 
citrate, ascorbate
formamide  [42], [32], 
(DMF)  sodium borohydride
ascorbic  [43],
acid,  poly  elemental
(ethylene  hydrogen,copolymers 
glycol)–block  different polyols, N,N dimethyl
[44],  hydrazine, 
ammonium formate [34]. 
formamide (DMF) [32], ascorbic acid, poly (ethylene glycol)–block copolymers [44], hydrazine,
ammonium In the present paper, soluble starch has been used as the reducing agent because it is a green 
formate [34].
reactant and due to its low price. Reduction process was conducted using ultrasonication in order to 
In the present paper, soluble starch has been used as the reducing agent because it is a green
assure and maintain proper contact between reagents, due to the propagation of ultrasonic waves in 
reactant and due to its low price. Reduction process was conducted using ultrasonication in order
liquid  media.  In  this  propagation  process,  it  was  observed  that  compression  cycles  alternate  with 
to assure and maintain proper contact between reagents, due to the propagation of ultrasonic waves
lower pressure cycles when a liquid rarefication is observed leading at cavitation process [45]. During 
in liquid media. In this propagation process, it was observed that compression cycles alternate
the compression cycle, high temperature is created in the liquid. In addition, it was observed that 
with lower pressure cycles when a liquid rarefication is observed leading at cavitation process [45].
During the compression cycle, high temperature is created in the liquid. In addition, it was observed
that during cavitation the contact surface between solid support and liquid molecules increases.
Cavitation phenomenon occurred simultaneously in several points inside of the liquid, leading to high
temperatures and pressures which are responsible for further physical-chemical modifications [46,47].
Materials 2020, 13, 1578 3 of 22

The aim of the present paper was to prepare a medical bandage with antimicrobial properties
by deposition of colloidal silver on cotton gauze. After preparation of such advanced medical
bandages, antimicrobial activity has been tested. These tests were carried out by studying the behavior
of environmental heterotroph microorganisms when they are exposed to different colloidal silver
concentrations. Heterotroph microorganisms were used because they have a good resistance to different
drugs, different structures and different metabolism.

2. Materials and Methods

2.1. Biocide Efect of Colloidal Silver Solution

Long time usage of silver particles proved that they present a good biocide effect against a large
spectrum of Gram-positive and Gram-negative bacteria. Starting from this observation, our aim was to
test the biocide effect of prepared colloidal silver. During the experiments we used colloidal solutions
with silver concentrations between 1.2 µg L−1 and 116 mg L−1 .
The material designed by us is a new material, therefore it is preferable for the toxicological
tests to be carried out using bacterial inoculations that come from natural environments with a
broader spectrum of Gram-positive and Gram-negative bacteria. Thus, an inoculum of water from
the Bega River has been used, which contains a wide spectrum of Gram-positive and Gram-negative
bacterial species. These bacteria were grown using a solid non-selective growth medium plate count
agar—Himedia (Enzymatic Digest of Casein 5.0 g/L; Yeast Extract 2.5 g/L; Dextrose (Glucose) 1.0 g/L;
Agar 15.0 g/L; Final pH: 7.0 ± 0.2 at 298.15 K), preparing two different types of cultures: test cultures
were prepared on plates with different colloidal silver content, and control cultures prepared on plates
without colloidal silver content.
Bacteria cultures were prepared in two different ways, for control cultures (3 repeats) in Petri
dishes containing 10 mL plate count agar growth medium were introduced 1 mL of bacterial inoculum
and 1 mL distilled water. For test cultures (3 repeats) in Petri dishes containing 10 mL plate count
agar were introduced 1 mL bacterial inoculum, and 1 mL from colloidal solution. All used Petri dishes
were incubated at 303 K for 48 hours. After incubation the quantitative bacterial growth was estimated
using the Most Probable Number method (counting the bacterial colonies) by comparing it to the
bacterial control culture.

2.2. Antibacterial Activities

Studies of antibacterial properties of colloidal silver were conducted by using test medical bandages
on which surface colloidal silver had been deposited by using a thermostatic bath. The influence of
different parameters (solid material: liquid ratio, silver initial concentration and temperature) were
evaluated on the adsorptive capacity of medical bandage used during tests. Optimum ratio solid:liquid
was established by varying the number of gauze pieces (with dimension of 20 × 20 mm) between 5 and
70 for the same volume of colloidal silver (25 mL) with a concentration of 50 mg L−1 . All adsorption
experiments were carried out at pH 4 and 273 K. Time contact and temperature influences on adsorption
capacity were studied by varying the contact time between 1 and 6 hours and the temperature between
298 and 318 K for the optimum solid:liquid ratio = 30 pieces of gauze: 25 mL colloidal silver at pH 4.
Equilibrium concentration was established by using different initial concentration of colloidal
silver (5, 10, 15, 25, 40, 50, 60 and 75 mg L−1 ) for the same solid:liquid ratio = 30 pieces of gauze: 25 mL
colloidal silver. All adsorptions were carried out at 298 K, pH = 4 for 4 hours.
From all batch experiments medical bandages were extracted from solutions and in the obtained
solutions we determined silver residual concentration by atomic absorption spectroscopy (Varian
SpectrAA 280 FS). Obtained pieces of medical bandages were dried at 303 K for a minimum of 24 h
and tested for antimicrobial effect for further usage in the medical field.
Antibacterial tests on the prepared medical bandages were performed on Bega river heterotrophic
bacteria cultures (Gram positive and Gram negative bacteria). All bacterial cultures were obtained on
Materials 2020, 13, 1578 4 of 22

a solid non-selective growth medium (plate count agar), making two types of cultures: test cultures
(3 repeats) using silver impregnated medical bandages, and control cultures in which were used
un-impregnated medical bandages with the same shape and size like the samples used in test cultures.
Medical bandage pieces were placed into the Petri dishes at a distance of 2 cm from dish walls, after that
was added the plate count agar medium and the entire system was inoculated with 600 µL of Bega
water, with content of heterotrophic bacteria. The obtained system was incubated at 303 K for 48 h.
After incubation we evaluated the growth of the bacteria for test cultures and for control cultures.

2.3. Synthesis of Colloidal Silver

2.3.1. Effect of Precursor: Reducer Ratio

Colloidal silver synthesis was carried out by using soluble starch (analytical purity, Merck) as
the reducing agent. An important factor during synthesis is represented by the ratio between silver
precursor, reducing agent and water. As a precursor for colloidal silver preparation, silver nitrate was
used, analytic grade from Merck. During synthesis, different quantities of reducing agent were used:
0.5, 1, 2 and 4 g, respectively, for the same quantities of silver precursor (4 g) and solvent volume has
been kept constant for all experiments (20 mL of distilled water). By using these quantities of reagents
we obtained ratios: 0.25:2; 0.5:2; 1:2; 2:2. During preparation, all samples were mixed for a minimum of
60 minutes at 353 K using an ultrasonic bath with a power of 320 W.

2.3.2. Effect of Ultrasonication Time

Through preliminary attempts were conducted experiments for sonication time up to 240 minutes,
but the obtained results were similar with the results obtained for 90 minutes. Based on that,
in the present research paper the sonication time was varied between 30 and 90 minutes. Effect of
ultrasonication time was studied by varying the mixing time from 30 to 90 minutes at 353 K for a ratio
of silver precursor:reducing agent = 1:2.

2.3.3. Effect of Ultrasonication Temperature

Temperature influence has been studied by varying the temperature between 333 and 353 K, for an
ultrasonication time of 60 minutes using a ratio of silver precursor:reducing agent:water = 1:2:10.

2.4. Characterization of Colloidal Silver Materials

Presence of silver particles into the prepared silver colloid was proved by recording the UV–VIS
spectra using Varian Cary 50 spectrophotometer, and by recording the scanning electron micrographs
using a Quanta FEG – 250 Scanning Electron Microscope.

2.5. Kinetics and Thermodynamic Studies

Kinetics of the colloidal silver adsorption process on medical bandages have been studied by
modeling obtained experimental data with two kinetic models: pseudo-first-order model [48] and
pseudo-second-order one [49,50].
It is well known that the activation energy represents the minimum kinetic energy of reactants in
order to react. Activation energy can be evaluated from Arrhenius equation:

Ea
ln k2 = ln A − (1)
RT

where: k2 —speed constant (g min−1 mg−1 ), A—Arrhenius constant (g min mg−1 ), Ea —activation
energy (kJ mol−1 ), T—absolute temperature (K), R—ideal gas constant (8314 J mol−1 K−1 ).
Materials 2020, 13, 1578 5 of 22

Adsorption processes can be characterized and optimized by evaluating the free Gibbs energy,
enthalpy and entropy. Values of thermodynamic function Gibbs free energy (∆G0 ) can be calculated by
using the following relation:
∆G◦ = ∆H◦ − T · ∆S◦ (2)

where: ∆G0 —free Gibbs energy standard variation (kJ mol−1 ), ∆H0 —standard enthalpy variation (kJ
mol−1 ), ∆S0 —standard entropy variation (J mol−1 K−1 ), T—absolute temperature (K).
From linear dependence ln kd versus 1/T (depicted in Figure 11) were evaluated the variations of
standard enthalpy and entropy:
∆S◦ ∆H◦
ln Kd = − (3)
R RT
where: ∆H0 —standard enthalpy variation (kJ mol−1 ), ∆S0 —standard entropy variation (J mol−1 K−1 ),
T—absolute temperature (K) and R—ideal gas constant (8314 J mol−1 K−1 ).
Equilibrium constant was calculated as the ratio between the equilibrium adsorption capacity and
the equilibrium concentration:
q
Kd = e (4)
Ce
Adsorption isotherms represent a useful tool for adsorption process analysis and optimization.
Material maximum adsorption capacity was evaluated by modeling obtained experimental data with
three different adsorption isotherms: Langmuir isotherm (monolayer adsorption), Freundlich isotherm
(developed for heterogeneous surfaces) and Sips isotherm which at limits can describe Langmuir of
Freundlich isotherms [51–54]. Kinetic models are used to identify the adsorption mechanism and to
determine speed-limiting stages, including mass transport processes and chemical reactions [55].
Langmuir isotherm is based on three hypotheses: adsorption process is a monolayer adsorption,
all superficial active sites are identical, housing one single metallic ion, capacity of one molecule to be
adsorbed on surface is independent of the occupancy of the neighboring places [52,56].
Nonlinear form of Langmuir isotherm is expressed by equation [52]:

qL KL Ce
qe = (5)
1 + KL Ce

where: qe —equilibrium adsorption capacity (mg g−1 ), Ce —metallic ion equilibrium concentration
(mg L−1 ), qL —Langmuir maximum adsorption capacity (mg g−1 ), KL —Langmuir constant.
Dimensionless constant RL is characteristic for Langmuir isotherm, being called separation factor
or equilibrium parameter, which can be evaluated by using relation:

1
RL = (6)
1 + KL Co

where: RL —separation factor, KL —Langmuir constant (L mg−1 ), C0 —silver initial concentration

(mg L−1 ).
Freundlich isotherm is an empiric one and is used developed for heterogeneous surfaces [51]:
1/nf
qe = KF Ce (7)

where: qe —equilibrium adsorption capacity (mg g−1 ), Ce —metallic ion concentration at equilibrium
(mg g−1 ), KF and nF —characteristic constants, which can be associated with relative adsorption capacity
of adsorbent and adsorption intensity, respectively.
Sips model [53], which at its limits describes the Langmuir and Freundlich models, is described
by relation:
1/n
q KS C e S
qe = s 1/n
(8)
1 + KS Ce S
Materials 2020, 13, 1578 6 of 22

where: qs —maximum adsorption capacity (mg g−1 ), Ks —constant linked with material adsorption
capacity, ns —heterogeneity factor.
Starting from Sips isotherm parameters was evaluated a dimensionless parameter—separation factor:

1
RS = 1/nS
(9)
1 + KS C0

where: Rs —separation factor, Ks —constant linked with material adsorption capacity, ns —heterogeneity
factor, C0 —metallic ions initial concentration.
Essential characteristics of Sips isotherms are determined by Rs values: if Rs > 1 adsorption is
unfavorable, Rs = 1 adsorption process is a linear one, 0 < Rs < 1 adsorption process is a favorable one,
if Rs = 0 adsorption is an irreversible one.

3. Results and Discussion

3.1. Synthesis of Colloidal Silver

Colloidal silver can be obtained by using chemical, physical, photochemical and biological
methods. Chemical synthesis consists of the reduction of silver precursors in the presence of some
stabilizing agents. Colloidal silver synthesis by reduction of silver nitrate is a two stage process: in first
one small silver particles are formed and in second one the dimension of these particles is increasing.

3.1.1. Influence of Precursor: Reducing Agent

The influence of the ratio of silver precursor:reducing agent during colloidal silver synthesis was
studied using 4 different samples with ratios: 0.2:2, 0.5:2, 1:2 and 2:2. After preparation, for all colloidal
Materials 2020, 13, x FOR PEER REVIEW  7 of 25 
silver samples the UV–VIS spectra were recorded (Figure 2) in the spectral range of 700–300 nm.

 
Figure 2. UV–VIS absorption spectra for different precursor:reducing agent: water ratios.
Figure 2. UV–VIS absorption spectra for different precursor:reducing agent: water ratios. 
Data presented in Figure 2 show that the recorded UV–VIS spectra presents a large band around
Data presented in Figure 2 show that the recorded UV–VIS spectra presents a large band around 
420 nm, which is specific for the presence of colloidal silver particles [2,57].
420 nm, which is specific for the presence of colloidal silver particles [2,57]. 
The reddish brown color became more intense simultaneously with the increase of the ratio of 
silver precursor:reducing agent, leading at an increase of silver concentration in colloidal solution. 
The  increase  of  silver  concentration  is  proved  by  the  increase  of  the  specific  band  from  UV–VIS 
spectra. 
Colloidal  silver  obtained  for  the  ratio  of  silver  precursor:reducing  agent  being  2:2  has  a  high 
viscosity,  observing  the  presence  of  non‐reacted  starch.  For  the  ratio  of  silver  precursor:reducing 
Materials 2020, 13, 1578 7 of 22

The reddish brown color became more intense simultaneously with the increase of the ratio of
silver precursor:reducing agent, leading at an increase of silver concentration in colloidal solution.
The increase of silver concentration is proved by the increase of the specific band from UV–VIS spectra.
Colloidal silver obtained for the ratio of silver precursor:reducing agent being 2:2 has a high
viscosity, observing the presence of non-reacted starch. For the ratio of silver precursor:reducing agent
being 1:2, it has a normal consistence, without non-reacted starch. Based on this observation, we can
conclude that the best results are obtained by using the ratio of silver precursor:reducing agent being
1:2. For any further experiments this ratio is used.

Materials 2020, 13, x FOR PEER REVIEW 
3.1.2. Influence of Ultrasound Time 8 of 25 

The optimum sonication time for the synthesis of colloidal silver obtained for the chosen ratio
was established (Figure 3).

Figure 3. UV–VIS absorption spectra for different ultrasound times.  

Data presentedFigure 3. UV–VIS absorption spectra for different ultrasound times. 
in Figure 3 show the presence of a colloidal silver specific band located at
approximately 420 nm for all three used times [2,57]. It can also be observed that the best results are
Data 
obtained forpresented  in  Figure  3 
synthesis conducted forshow  the  presence 
60 minutes. of  this
Based on a  colloidal  silver 
observation wespecific 
decidedband  located 
that all furtherat 
approximately 420 nm for all three used times [2,57]. It can also be observed that the best results are 
syntheses will be carried out for 60 minutes.
obtained for synthesis conducted for 60 minutes. Based on this observation we decided that all further 
3.1.3. Influence of Ultrasound Baths Temperature
syntheses will be carried out for 60 minutes. 
Another important parameter for colloidal silver preparation is synthesis temperature. In order
toInfluence of Ultrasound Baths Temperature 
determine the optimum synthesis temperature, all syntheses were carried out at three different
temperatures: 333, 343, 353 K. After preparation, we recorded the VIS spectra in order to prove the
Another important parameter for colloidal silver preparation is synthesis temperature. In order 
presence of silver particles into the prepared colloidal solutions (Figure 4).
to determine the optimum synthesis temperature, all syntheses were carried out at three different 
temperatures: 333, 343, 353 K. After preparation, we recorded the VIS spectra in order to prove the 
presence of silver particles into the prepared colloidal solutions (Figure 4). 
 Materials 2020, 13, x FOR PEER REVIEW  9 of 25 

Materials 2020, 13, 1578 8 of 22

Figure 4. UV–VIS absorption spectra for different ultrasound bath temperatures.  

From the recorded VIS spectra, it was observed that the increase of temperature has a beneficial
Figure 4. UV–VIS absorption spectra for different ultrasound bath temperatures. 
effect, leading to an increase of silver concentration in colloidal silver. By corroborating all these results
with theFrom the recorded VIS spectra, it was observed that the increase of temperature has a beneficial 
recorded SEM micrographs, we can conclude that the optimum temperature for colloidal silver
effect,  leading 
preparation is 353to K,an  increase 
because at of 
thissilver  concentration 
temperature in  colloidal 
silver particles withsilver.  By  corroborating 
low dimensions all  these 
and relatively
results 
good with  the 
dispersion wererecorded  SEM  micrographs,  we  can  conclude  that  the  optimum  temperature  for 
obtained.
colloidal silver preparation is 353 K, because at this temperature silver particles with low dimensions 
3.2. Characterization of Colloidal Silver Materials
and relatively good dispersion were obtained. 
SEM and EDX Characterization
3.2. Characterization of Colloidal Silver Materials 
The prepared material was characterized using Scanning Electron Microscopy (SEM) and by
SEM and EDX Characterization 
Energy Dispersive X-ray spectroscopy (EDX). SEM microscopy was used to analyze surface morphology
(FigureThe 
5a) and EDX (Figure
prepared  5b)was 
material  was characterized 
used to prove the presence
using  of silver
Scanning  ions inMicroscopy 
Electron  the synthesized material.
(SEM)  and  by 
From the SEM image presented in Figure 5a, the presence of some white spots were
Energy  Dispersive  X‐ray  spectroscopy  (EDX).  SEM  microscopy  was  used  to  analyze  surface observed
which were associated with silver presence. Analyzing the SEM picture from Figure 5 we can observe
morphology (Figure 5a) and EDX (Figure 5b) was used to prove the presence of silver ions in the 
that the silver particles present a size distribution between 70.82 nm and 142.00 nm. Presence of silver
synthesized material. 
particles was proved by recording the EDX spectra, in which the peaks for silver and for starch specific
elements were present. Nitrogen presence is associated with incomplete reduction of silver nitrate,
or due to its excess. The presence of oxygen atoms in the EDX spectra can be explained by considering
that the silver adsorption onto the cotton surface has been realized in air, so during the process some
silver atoms get oxidized.
Materials 2020, 13, 1578 9 of 22

Materials 2020, 13, x FOR PEER REVIEW  10 of 25 

 
(a) SEM image 

(b) EDX spectra 

Figure 5. SEM image (a) and Energy Dispersive X-ray (EDX) spectra (b) for synthetized colloidal silver.
Figure  5.  SEM  image  (a)  and  Energy  Dispersive  X‐ray  (EDX)  spectra  (b)  for  synthetized  colloidal 
3.3. Application
silver.  of the Colloidal Silver

3.3.1.From the SEM image presented in Figure 5a, the presence of some white spots were observed 
Biocide Effect of Colloidal Silver Solution
which were associated with silver presence. Analyzing the SEM picture from Figure 5 we can observe 
Biocide character of synthesized colloidal silver was performed on a bacterial community obtained
that the silver particles present a size distribution between 70.82 nm and 142.00 nm. Presence of silver 
from the environment, presenting a large biodiversity and higher resistance to environmental factors.
particles 
Figure was  proved 
6 shows by  recording 
the bacterial growth the  EDX 
in the spectra, 
control andin  which 
test the  peaks 
cultures. In the for  silver 
control and  for 
culture starch 
(without
specific elements were present. Nitrogen presence is associated with incomplete reduction of silver 
colloidal silver), the average number of bacterial cells (colony forming unit) per mL was 9320 CFU.
nitrate, or due to its excess. The presence of oxygen atoms in the EDX spectra can be explained by 
In the test sample (with colloidal silver) it was observed that the bacteria grew up when colloidal
considering that the silver adsorption onto the cotton surface has been realized in air, so during the 
silver concentration was under 50 mg L−1 . Based on this observation it was considered that the
toxic concentration is 50 mg L−1 . Due  to this, all further experiments were carried out at this
process some silver atoms get oxidized. 
silver concentration.
3.3. Application of the Colloidal Silver 

Biocide Effect of Colloidal Silver Solution 
 obtained  from  the  environment,  presenting  a  large  biodiversity  and  higher  resistance  to 
environmental factors. Figure 6 shows the bacterial growth in the control and test cultures. In the 
control culture (without colloidal silver), the average number of bacterial cells (colony forming unit) 
per mL was 9320 CFU. In the test sample (with colloidal silver) it was observed that the bacteria grew 
up  when 
Materials 2020, 13, 1578colloidal  silver  concentration  was  under  50  mg  L .  Based  on  this  observation  it 10
−1 was 
of 22
considered that the toxic concentration is 50 mg L . Due to this, all further experiments were carried 
−1

out at this silver concentration. 

(a)
 

(b)
Materials 2020, 13, x FOR PEER REVIEW  12 of 25 
 

(c)  10000
8000
6000
Colony forming unit (CFU)

4000
2000
0

Coloidal silver concentration
 
Figure 6.Figure 6. Bacterial inhibition zone image and total colony units. a) – Control; b) – 50 mg Ag colloidal/L; 
Bacterial inhibition zone image and total colony units. (a)—Control; (b)—50 mg Ag colloidal/L;
(c)—CFUc) – CFU vs colloidal silver concentration. 
vs colloidal silver concentration.

3.3.2. Antibacterial Activities 
To  prove  the  antibacterial  properties  of  medical  bandages  with  silver,  colloidal  silver  was 
deposited  on  medical  bandages  by adsorption.  For  the  adsorption  process  we  established  specific 
parameters: ratio solid adsorbent:colloidal solution, contact time, temperature, initial concentration 
of colloidal silver and the influence of these parameters on adsorption capacity of medical bandages. 
In  addition,  the  adsorption  mechanism  by  equilibrium,  kinetic  and  thermodynamic  studies  was 
Materials 2020, 13, 1578 11 of 22

3.3.2. Antibacterial Activities

To prove the antibacterial properties of medical bandages with silver, colloidal silver was deposited
on medical bandages by adsorption. For the adsorption process we established specific parameters:
ratio solid adsorbent:colloidal solution, contact time, temperature, initial concentration of colloidal
silver and the influence of these parameters on adsorption capacity of medical bandages. In addition,
the adsorption mechanism by equilibrium, kinetic and thermodynamic studies was established.

3.3.3. Influence of Solid:Liquid Ratio

Influence of ratio solid adsorbent:colloidal silver on adsorption capacity was established by
changing the numbers of medical bandages immersed into the colloidal silver solution. In these
experiments we changed the number of samples introduced in 25 mL of colloidal silver solution with a
concentration of 50 mg L−1 . Experiments were carried out at 298 K, for a contact time of 4 h and13 of 25 
Materials 2020, 13, x FOR PEER REVIEW  pH 4.
In Figure 7 is presented the influence of the ratio of solid:liquid over adsorption capacity.

Figure 7. Influence of solid (S):liquid (L) ratio on adsorption process efficiency.

Figure 7. Influence of solid (S):liquid (L) ratio on adsorption process efficiency. 
From Figure 7 we can observe that with the increase of the solid:liquid ratio, adsorption efficiency
has increased, until a ratio of solid:liquid = 0.3 g:25 mL when a plateau is reached. This plateau
From  Figure  7  we  can  observe  that  with  the  increase  of  the  solid:liquid  ratio,  adsorption 
corresponds to an adsorption capacity of 70 %. This ratio corresponds to 30 pieces 20 × 20 mm of
efficiency has increased, until a ratio of solid:liquid = 0.3 g:25 mL when a plateau is reached. This 
medical bandages. Based on this observation all further experiments were carried out by using the
plateau corresponds to an adsorption capacity of 70 %. This ratio corresponds to 30 pieces 20 × 20 
optimum solid:liquid ratio.
mm of medical bandages. Based on this observation all further experiments were carried out by using 
the optimum solid:liquid ratio. 
3.3.4. Influence of Contact Time and Temperature
In Figure 8 the influences of contact time  and temperature on maximum adsorption capacity are
Influence of Contact Time and Temperature 
presented. Data presented in Figure 8 reveal that the temperature and time increase present a similar
In Figure 8 the influences of contact time and temperature on maximum adsorption capacity are 
influence on maximum adsorption capacity. When the contact time and temperature increase, the
presented. Data presented in Figure 8 reveal that the temperature and time increase present a similar 
maximum adsorption capacity increases. After 4 h maximum adsorption capacity remains constant.
influence on maximum adsorption capacity. When the contact time and temperature increase, the 
Temperature influence on maximum adsorption capacity does not have a significant influence, so it is
maximum adsorption capacity increases. After 4 h maximum adsorption capacity remains constant. 
not necessarily to work at temperatures higher than 298 K. Based on these observations we chose the
Temperature influence on maximum adsorption capacity does not have a significant influence, so it 
optimum conditions: time—4 h and temperature of 298 K.
is not necessarily to work at temperatures higher than 298 K. Based on these observations we chose 
the optimum conditions: time—4 h and temperature of 298 K. 
Materials 2020, 13, x FOR PEER REVIEW 
Materials 2020, 13, 1578 14 of 25 
12 of 22

Figure 8. Influence of contact time and temperature on adsorption capacity.

 
Figure 8. Influence of contact time and temperature on adsorption capacity. 
3.3.5. Kinetics Studies
Based on the obtained experimental data we established the kinetic mechanism for silver adsorption
Kinetics Studies 
process. Colloidal silver adsorption process kinetics on medical bandages were established by using
two Based 
kineticson  the  obtained 
equations: experimental model
pseudo-first-order data  we 
[48]established  the  kinetic  mechanism 
and pseudo-second-order for  silver 
model [49,50].
adsorption  process. 
Experimental Colloidal 
data silver  using
were modeled adsorption  process 
the linear formskinetics 
of these on  medical Speed
equations. bandages 
constantwere 
for
established by using two kinetics equations: pseudo‐first‐order model [48] and pseudo‐second‐order 
pseudo-first-order model was determined from linear representation of ln(qe – qt ) versus time, and the
model [49,50]. 
speed constant  for pseudo-second-order was determined from linear representation of t/qt versus time.
Experimental data were modeled using the linear forms of these equations. Speed constant for 
Based on the modeled data presented in Figure 9 we determined the kinetic parameters associated
pseudo‐first‐order model was determined from linear representation of ln(q e – qt) versus time, and the 
with the adsorption process for used kinetic models (Table 1). Based on the obtained correlation factors
speed  constant  for  pseudo‐second‐order  was  determined  from  linear  representation  of  t/qt  versus 
we established the kinetic model which had better described the studied adsorption process.
time.  Based  on  the  modeled  data  presented  in  Figure  9  we  determined  the  kinetic  parameters 
associated  with 
Table 1. the  adsorption 
Kinetic process 
parameters for  used  kinetic 
for the adsorption models 
of colloidal silver(Table  1).  Based  on  the  obtained 
onto material/textile/cotton.
correlation  factors  we  established  the  kinetic  model  which  had  better  described  the  studied 
adsorption process.    Pseudo-First Order
qe,exp k1 qe,calc
Temperature (K) R2
(mg g−1 ) (min−1 ) (mg g−1 )
298 2.16 0.246 1.06 0.9839
308 2.38 0.322 1.81 0.8906
318 2.55 0.430 2.03 0.9133
Pseudo-Second Order
qe,exp k2 qe,calc
Temperature (K) R2
(µg g−1 ) (g mg−1 ·min−1 ) (mg g−1 )
298 2.16 13.52 2.58 0.9974
308 2.38 17.83 3.03 0.9803
318 2.55 21.13 3.15 0.9831
 Materials 2020, 13, x FOR PEER REVIEW  15 of 25 
Materials 2020, 13, 1578 13 of 22

(a) 

(b) 

 
Figure 9. Kinetic studies. (a) pseudo-first-order; (b) pseudo-second-order.
Figure 9. Kinetic studies. (a) pseudo‐first‐order; (b) pseudo‐second‐order. 
Analyzing the kinetic parameters obtained when experimental data were modeled with
pseudo-first-order model, it was observed that the correlation coefficient is lower than 1, meaning that
Table 1. Kinetic parameters for the adsorption of colloidal silver onto material/textile/cotton. 
this kinetic model is not describing the studied adsorption process. In addition, we calculated the
maximum adsorption, which had lower values Pseudo‐First Order 
compared with the experimentally obtained ones.
Similarly, the experimental q
data were modeled     with the
k1   pseudo-second-order
qe,calc   
R2equation in order
e,exp
Temperature (K)   
(mg g −1)  (min −1)  (mg g
to prove that the model is describing the colloidal silver adsorption on medical −1) 
bandages. Kinetic
parameters (Table 1) associated 298 with pseudo-second-order
2.16  0.246
were  1.06  from
determined 0.9839 
linear dependence
308  2.38  0.322  1.81  0.8906 
of t/qt versus time (Figure 9). From the values of the correlation coefficient close to the unity, it was
318 
proved that the pseudo-second-order model 2.55  0.430 
is describing the studied2.03 
adsorption0.9133 
process. Another
confirmation is represented by the values ofPseudo‐Second Order 
calculated adsorption capacity which are very close to the
experimental ones. qe,exp    k2    qe,calc   
Temperature (K)  R2 
For the studied adsorption process, the(μg g −1) 
activation (g mg −1∙min−1)  (mg g−1) 
energy was evaluated from linear dependence of
lnk2 versus 1/T (Figure 10). In 298  2.16 
this case, the activation 13.52 
energy 2.58 
was evaluated 0.9974 
by using the speed constant
308 
obtained for the pseudo-second-order model,2.38  17.83 
which is accurately 3.03  the0.9803 
describing adsorption process.
318  2.55  21.13  3.15  0.9831 
 confirmation is represented by the values of calculated adsorption capacity which are very close to 
the experimental ones.   
For the studied adsorption process, the activation energy was evaluated from linear dependence 
of lnk2 versus 1/T (Figure 10). In this case, the activation energy was evaluated by using the speed 
constant obtained for the pseudo‐second‐order model, which is accurately describing the adsorption 
Materials 2020, 13, 1578 14 of 22
process. 

Figure 10. ln K2 = f (1/T).  

Figure 10. ln K2 = f (1/T). 
Based on the data from Figure 10 we calculated the activation energy for silver adsorption on
bandages (17.72 kJ mol−1 ).
medicalBased on the data from Figure 10 we calculated the activation energy for silver adsorption on 
medical bandages (17.72 kJ mol−1).   
3.3.6. Thermodynamics Studies of the Adsorption Process
Thermodynamics Studies of the Adsorption Process 
Thermodynamic studies were carried out in the temperature range of 298 to 318 K in order
to confirm if the adsorption process is a spontaneous one. Values of thermodynamic functions are
Thermodynamic studies were carried out in the temperature range of 298 to 318 K in order to 
presented inif Table
confirm  the  adsorption 
2. process  is  a  spontaneous  one.  Values  of  thermodynamic  functions  are 
presented in Table 2.   
From the linear dependence ln k
Table 2. Thermodynamic d versus 1/T we evaluated the variations of standard enthalpy 
parameters for adsorption of silver onto cotton.
and entropy (Figure 11). 
∆G0
∆H 0 (kJ/mole) ∆S0 (J/mole·K) R2
(kJ/mole)
298 K 308 K 318 K
5.7 19.24 0.9999
−11.8 −20.36 −39.68

From the linear dependence ln kd versus 1/T we evaluated the variations of standard enthalpy and
entropy (Figure 11).
Analyzing the data presented in Table 2, we can observe that the Gibbs free energy variation has
negative values, meaning that the studied adsorption process is a spontaneous one. Temperature
increase leads to a decrease of Gibbs free energy value, confirming that the studied adsorption process
is favored by temperature increase. By correlating the small increase of maximum adsorption capacity
with temperature increase and positive values of enthalpy, we can conclude that the studied adsorption
processes are endothermic. A positive value of entropy variation suggests that the studied adsorption
process presents a relatively high disorder at the solid/liquid interface, but the low value of entropy
suggests that major changes of disorder degree are not taking place at the liquid/solid interface.
Materials 2020, 13, 1578
Materials 2020, 13, x FOR PEER REVIEW  17 of 25  15 of 22

 
Figure 11. ln kd = f (1/T).
Figure 11. ln kd = f (1/T). 
3.3.7. Equilibrium Studies
Table 2. Thermodynamic parameters for adsorption of silver onto cotton. 
Figure 12 depicts experimental data modeled with the chosen kinetic isotherms. The obtained
ΔH0 
Materials 2020, 13, x FOR PEER REVIEW  ΔG0  18 of 25 
kinetic parameters are presented in ΔS Table 3.
0 (J/mole∙K)  R2 
(kJ/mole)  (kJ/mole) 
298 K  308 K  318 K 
5.7  19.24  0.9999 
−11.8  −20.36  −39.68 

Analyzing the data presented in Table 2, we can observe that the Gibbs free energy variation has 
negative  values,  meaning  that  the  studied  adsorption  process  is  a  spontaneous  one.  Temperature 
increase  leads  to  a  decrease  of  Gibbs  free  energy  value,  confirming  that  the  studied  adsorption 
process is favored by temperature increase. By correlating the small increase of maximum adsorption 
capacity with temperature increase and positive values of enthalpy, we can conclude that the studied 
adsorption processes are endothermic. A positive value of entropy variation suggests that the studied 
adsorption process presents a relatively high disorder at the solid/liquid interface, but the low value 
of  entropy suggests  that  major  changes of  disorder  degree are  not  taking  place  at  the liquid/solid 
interface. 

Equilibrium Studies 
Figure 12 depicts experimental data modeled with the chosen kinetic isotherms. The obtained 
kinetic parameters are presented in Table 3. 

 
Figure 12. Experimental data modeled with adsorption isotherms.
Figure 12. Experimental data modeled with adsorption isotherms. 
Table 3. Kinetic parameters obtained for the used adsorption isotherms.
Table 3. Kinetic parameters obtained for the used adsorption isotherms. 
Langmuir Isotherm
Langmuir Isotherm 
qm,exp (mg/g) KL (L/mg) qL (mg/g) R2
qm,exp (mg/g)  KL (L/mg)  qL (mg/g)  R2 
2.35 0.239 2.30 0.95616
2.35  0.239  2.30  0.95616 
Freundlich Isotherm
Freundlich Isotherm 
KF (mg/g) KF (mg/g)  1/n
1/n
F F  R2  R2
0.725 0.725  0.29 
0.29 0.93262  0.93262
Sips Isotherm 
Sips Isotherm
KS  qS (mg/g)  1/nS  R2 
KS qS (mg/g) 1/nS R2
0.268  2.74  0.3  0.95548 
0.268 2.74 0.3 0.95548

Based on the data listed in Table 3, it was observed that at higher equilibrium concentrations the 
medical 
Based on thebandage’s  maximum 
data listed in Table adsorption  capacity 
3, it was tends  that
observed to  be at
a  higher
constant equilibrium
value,  which  is  the 
concentrations
experimental maximum adsorption capacity (qexp—2.35 mg g−1). 
the medical bandage’s maximum adsorption capacity tends to be a constant value, which is the
The  parameter  1/nF  has  a  subunit  value  (1/nF—0.29),  therefore  the  used  adsorbent  presents  a 
experimental maximum adsorption capacity (qexp —2.35 mg g−1 ). 1 𝑛 0.3, which represents 
good affinity for colloidal silver. Considering the heterogeneity factor 
a  high  deviation  from  unity,  we  conclude  that  the  medical  bandage  adsorbent  presents  a 
heterogeneous surface. In addition, from the presented data it can observed that the lowest value of 
the correlation coefficient was obtained when the experimental data were modeled using Freundlich 
isotherm. In addition, it was observed that the adsorption process is better described by Langmuir 
isotherm (R2 = 0.95616). When experimental data were modeled using the Langmuir isotherm, the 
calculated maximum adsorption capacity (𝑞 2.30 𝑚𝑔 𝑔 ) is close to the experimentally obtained 
Materials 2020, 13, 1578 16 of 22

The parameter 1/nF has a subunit value (1/nF —0.29), therefore the used adsorbent presents a
good affinity for colloidal silver. Considering the heterogeneity factor n1s = 0.3, which represents a
high deviation from unity, we conclude that the medical bandage adsorbent presents a heterogeneous
surface. In addition, from the presented data it can observed that the lowest value of the correlation
coefficient was obtained when the experimental data were modeled using Freundlich isotherm. In
addition, it was observed that the adsorption process is better described by Langmuir isotherm (R2
= 0.95616). When experimental data were modeled using the Langmuir isotherm, the calculated
maximum adsorption capacity (qL = 2.30 mg g−1 ) is close to the experimentally obtained one
(qm, exp = 2.35 mg g−1 ), suggesting that the Langmuir isotherm is describing the adsorption process.

3.3.8. The Material Characterization after Silver Colloidal Adsorption

In order to confirm the presence of silver particles adsorbed onto the cotton medical bandages,
they were characterized by using SEM and EDX (micrographs and EDX spectra are presented in
Figure 13a–d).
Materials 2020, 13, x FOR PEER REVIEW  19 of 25 

(a)

(b)

Figure 13. Cont.

Materials 2020, 13, 1578 17 of 22
Materials 2020, 13, x FOR PEER REVIEW  20 of 25 

(c)

(d)

Figure 13. Figure 13. Characterization of the cotton before and after colloidal silver adsorption. (a) SEM image 

Characterization of the cotton before and after colloidal silver adsorption. (a) SEM image
before adsorption; (b) EDX spectra before adsorption; (c) SEM image after adsorption; (d) EDX spectra 
before adsorption; (b) EDX spectra before adsorption; (c) SEM image after adsorption; (d) EDX spectra
after adsorption. 
after adsorption.
From the recorded SEM images, the presence of silver atoms after adsorption can be observed 
From(Figure 13c), which was also confirmed by EDX spectra because of the silver peak. 
the recorded SEM images, the presence of silver atoms after adsorption can be observed
(Figure 13c), which was also confirmed by EDX spectra because of the silver peak.
3.3.9. Adsorption Process Mechanism – Schematically the mechanism of colloidal silver adsorption 
process is presented in Figure 14. 
Materials 2020, 13, 1578 18 of 22

Materials 2020, 13, x FOR PEER REVIEW  21 of 25 
3.3.9. Adsorption Process Mechanism—Schematically the Mechanism of Colloidal Silver Adsorption
Materials 2020, 13, x FOR PEER REVIEW 
Process is Presented in Figure 14 21 of 25 

 
 
Figure 14. Mechanism of colloidal silver adsorption process.
Figure 14. Mechanism of colloidal silver adsorption process. 
Figure 14. Mechanism of colloidal silver adsorption process. 
After
After  we
we  established
established  the
the  optimum
optimum  conditions
conditions  for
for  silver
silver  adsorption
adsorption  on
on  medical
medical  bandages,
bandages,  we
we 
tested the antibacterial effect in order to prove its usage in the medical field. In this case material
tested the antibacterial effect in order to prove its usage in the medical field. In this case material  pieces we 
After  we  established  the  optimum  conditions  for  silver  adsorption  on  medical  bandages, 
were dried at 303 K for 24 h and used in antibacterial tests (Figure 15).
pieces were dried at 303 K for 24 h and used in antibacterial tests (Figure 15).   
tested the antibacterial effect in order to prove its usage in the medical field. In this case material 
pieces were dried at 303 K for 24 h and used in antibacterial tests (Figure 15).   

           
           
(a)                                                                (b)   
Figure 15.(a)                        test.
Antimicrobial          (a)
     Control
             (b)
     Test.
    (b)   
Figure 15. Antimicrobial test. (a) Control (b) Test. 
Figure 15. Antimicrobial test. (a) Control (b) Test. 
For antibacterial tests, pieces of the produced material were placed in Petri dishes at 2 cm from 
the edges, and were inoculated using 600 μL of inoculum that contains heterotrophs bacteria from 
For antibacterial tests, pieces of the produced material were placed in Petri dishes at 2 cm from 
the  Bega  river.  After  that,  in  each  Petri  dish  was  added  sterile  plate  count  agar  growth  medium. 
the edges, and were inoculated using 600 μL of inoculum that contains heterotrophs bacteria from 
the  Bega  river.  After  that,  in  each  Petri  dish  was  added  sterile  plate  count  agar  growth  medium. 
Materials 2020, 13, 1578 19 of 22

For antibacterial tests, pieces of the produced material were placed in Petri dishes at 2 cm from
the edges, and were inoculated using 600 µL of inoculum that contains heterotrophs bacteria from the
Bega river. After that, in each Petri dish was added sterile plate count agar growth medium. Prepared
Petri dishes were incubated at 303 K for 48 hours. After incubation we observed a good bacterial
growth for non-impregnated medical bandages (Figure 15 a). Bacterial growth was inhibited when the
silver concentration was higher than the minimum toxic concentration.

4. Conclusions
In the present paper was proposed a new route for colloidal silver synthesis by ultrasonication,
using soluble starch as reducing agent and stabilizer. In this case it was not needed to use a pH
regulator. Synthesized colloidal silver was characterized by UV–VIS, SEM and EDX. We investigated
adsorption mechanism, and the possible applications of deposited silver particles on medical bandages.
The adsorption mechanism was investigated by kinetic, thermodynamic and equilibrium studies. Based
on obtained experimental data we determined the optimum adsorption conditions: pH—4, time = 4 h,
temperature 298 K. Silver adsorption process is described by Langmuir, when the maximum adsorption
capacity was 2.30 mg g−1 it was very close to the experimental one. From thermodynamic studies, it
was proven that the silver adsorption on medical bandages is an endothermic and spontaneous process.
As a possible application, we evaluated the biocide effect of colloidal silver and medical bandages
with silver content using heterotrophs bacteria. When the silver concentration was higher than 50 mg
L−1 , it became toxic for heterotrophic bacteria. Similar for medical bandages with silver content it was
proven that the toxic concentration for heterotrophs bacteria was 50 mg of silver.

Author Contributions: Conceptualization: A.N., P.N. and N.D., methodology: A.N., M.C. and C.M.D.,
investigations: B.P., M.C. and V.G., manuscript preparation: A.N. and N.D., supervision P.N. and C.M.D.
All authors have read and agreed to the published version of the manuscript.
Funding: This work was supported by a grant of the Romanian Ministery of Research and Innovation, project
number 10PFE/16.10.2018, PERFORM-TECH-UPT—The increasing of the institutional performance of the
Polytechnic University of Timis, oara by strengthening the research, development and technological transfer
capacity in the field of “Energy, Environment and Climate Change”, within Program 1—Development of
the national system of Research and Development, Subprogram 1.2—Institutional Performance—Institutional
Development Projects—Excellence Funding Projects in RDI, PNCDI III.
Conflicts of Interest: The authors declare no conflict of interest.

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