DOI 10.

1007/s11094-019-01954-9
Pharmaceutical Chemistry Journal, Vol. 53, No. 1, April, 2019 (Russian Original Vol. 53, No. 1, January, 2019)

BISMUTH OXIDE NANOPARTICLES

IN DRUG DELIVERY SYSTEMS

Krzysztof Szostak,1 Patryk Ostaszewski,1 Jolanta Pulit-Prociak,1,*

and Marcin Banach1

Original article submitted July 13, 2018.

The paper presents the overlook on bismuth oxide nanoparticles as a potential material applied in medicine-re-
lated fields of science. First, the types of drug delivery systems are described. General properties of bismuth
oxide are considered as well. The main part of article is devoted to bismuth oxide-based systems intended for
drug delivery and medical imaging purposes. It has been confirmed by many scientists that bismuth oxide
nanoparticles are a promising material for drug delivery systems and for enhancing the properties of other
products in medical applications.
Keywords: bismuth oxide; drug delivery; nanoparticles; medicine; imaging.

1. INTRODUCTION ately given to an infected organ or administrated systemati-

The rapid growth of medicine, medical engineering and
other related fields stimulated the development of new meth-
ods for drugs delivery. Creation of a drug delivery system
(DDS) refers to development of formulations or devices, by
which the introduction of therapeutic substances is improved
in respect of their efficiency and safety. Also, the rate, time
and place of drug release in the body are controlled. Addi-
tionally, controlled-release technology (CRT) has been de-
veloped that focuses on the fabrication of new devices and
improvement of concepts and techniques used in drug deliv-
ery processes. This way of action is directly related to the
fact that, from the technological point of view, development
of new drug molecules is expensive and time consuming.
That is why it is more preferably to manage well known
drugs and to develop new method of making them more ac-
cessible [1].
In general, a drug delivery system concentrates on the re-
lation between drug and patient. As mentioned above, this
relation may be considered as distribution of substances for
therapeutic purpose or development of devices used for this
purpose. There are many routes of drug administration which
depend on several factors. The group of three most important
factors includes the effect desired, the type of product, and
the type of disease. Therapeutic substances may be immedi-
1
Faculty of Chemical Engineering and Technology, Cracow University of
Technology, 24 Warszawska St., 31 – 155 Cracow, Poland.
*
e-mail: jolantapulit@indy.chemia.pk.edu.pl
cally, targeting a sick organ.
Drugs may be distributed via following administration
routes. The most common and one of the oldest ways is oral
route. This method is favored because of the easiness of ad-
ministration and high acceptance and comfort for patents [2].
Parenteral route is another way of drugs administration. This
refers to giving therapeutic substances in a way other than
oral. The group of parenteral administration methods in-
cludes intramuscular, intravenous, intra-arterial and subcuta-
neous routes. This method is believed to be crucial way.
Moreover, many new drugs are designed to be administrated
via these routes [3]. Drugs can also be transported through
the skin. In the transdermal route, the pharmaceutical sub-
stance is applied on the body surface, in particular, on the
skin or mucous membrane. This method depends mainly on
local effects. A great advantage of transdermal route is that
digestive tract and liver metabolism are omitted and
pharmaceuticals are introduced directly in the systemic cir-
culation [4]. Inhalation route is another way of drugs admin-
istration, by which pharmaceutical substances primarily
reach lungs. That is why this route is mainly chosen when re-
spiratory diseases are treated [5].
According to Ostwald – Freundlich equation, a signifi-
cant increase in the solubility of chemical substances is
achieved by particle size reduction. This is due to the fact
that smaller particles have a higher vapor pressure because
their surface is increased in ratio to their volume [6]. Hence,
it is highly desired to develop new formulations of known
drugs which would be more bioavailable to human organs.

48
0091-150X/19/5301-0048 © 2019 Springer Science+Business Media, LLC
Bismuth Oxide Nanoparticles in Drug Delivery Systems
Nanoparticles are among the most common advanced
ways of drugs delivery. They make it possible to ensure tar-
geted delivery of pharmaceutical substances directly to spe-
cific cells. They can play the role of individually designed
carriers. Nanoparticles with average size less than 100 nm
have a great potential as different chemicals carriers. Owing
to greater ratio of the surface area to volume they exhibit en-
hanced reactive activity. For this reason, one may consider
them as favorable biomedical materials. The group of widely
used nanocarriers includes, among others, liposomes, solid
lipids, dendrimers, polymers, and silicon, carbon or magnetic
nanoparticles [7]. The average size of liposomes does not ex-
ceed 300 nm. These spherical vesicles are composed mainly
of phospholipids and steroids. It turned out that liposomes in-
creased the solubility of some low-soluble drugs, which re-
sulted in enhancing their pharmaceutical properties. These
carriers surround and enclose the therapeutic substance in the
encapsulation process. The drug release from the core de-
pends on various factors such as liposome composition, pH,
osmotic gradient, and environment. Their great advantage is
the elongated time of residence, which leads to increased du-
ration of the drug action [8]. The group of solid lipids con-
tains solid lipid nanoparticles (SLNs), nanostructured lipid
carriers (NLCs) and lipid drug conjugates (LDCs). Their
structure is based on a solid lipid matrix. Solid lipid
nanoparticles are made of highly purified triglycerides, their
complex mixtures, or waxes. Various surfactants may be
added in order to enhance their stability. They exhibit a good
physical stability and tolerability. Due to their structure, re-
lated drugs are efficiently protected and released in con-
trolled manner. However, the fact that most drugs are hardly
dissolved in lipids, these carriers are characterised by low
loading capacity [9]. Nanostructured lipid carriers and lipid
drug conjugates have been developed as products of SLN
modification in order to overcome their limitations. In gen-
eral, NLCs and LDCs constitute a mixture of solid and liquid
lipids. Such nanocarriers are mainly used in skin treatments
[10].
2. PROPERTIES AND APPLICATIONS OF BISMUTH
OXIDE
As mentioned above, nanoparticles are commonly used
as drug carriers in modern ways of drug delivery. This is as-
sociated with better physical and chemical parameters in re-
lation to macromolecules, which is a result of the larger sur-
face area to volume ratio. Nanoparticles can also have unique
chemical properties in comparison with their macro counter-
parts. At present, nanoparticles are very popular in both sci-
ence and industry. However, there are some nanoparticles
and their composites that are not so much popularized. This
group includes bismuth oxide nanoparticles which will be
the focus of this work.
Bismuth oxide is a p-type semiconductor with unique
physical and chemical properties, such as large energy ban-
49
dgap in a range of 2.00 – 3.96 eV, high refractive index, di-
electric permittivity, photoconductivity, and photolumi-
nescence. That is why it has potential applications in many
areas such as solid state fuel cells, photovoltaic cells, high
temperature superconductors, photocatalysts, gas sensors,
and optical coatings [11]. Bi2O3 is present in five crystallo-
graphic polymorphs i.e., a-Bi2O3 (monoclinic), b-Bi2O3
(tetragonal), g-Bi2O3 (body-centered cubic), d-Bi2O3 (cubic),
and e-Bi2O3 (triclinic). Two of these forms are stable, these
are a-Bi2O3 at room temperature and d-Bi2O3 at high tem-
peratures, while the rest are metastable phases [12]. Bismuth
oxide nanoparticles can be produced using bismuth(III) ni-
trate hexahydrate as precursor in a wide range of processes
including precipitation [13], hydrothermal or solvothermal
method [14, 15], sol-gel methods [16], and flame spray py-
rolysis [17]. Beside basic spherical nanoparticles which are
the most popular, there are several other types of
Bi2O3 nanostructures such as nanowires [18], nanofibers
[19], nanoflakes [20], and nanospheres [15].
Moving on to bismuth oxide nanospheres, Qin, et al. [15]
carried out the synthesis of such nanostructures. These stud-
ies showed that bismuth oxide nanospheres with diameters in
the range of 100 – 200 nm exhibited good photocatalytic ac-
tivity under visible light irradiation, which is very desirable
for modern photocatalytic materials. In addition, this mate-
rial showed highly efficient antibacterial activity against S.
aureus (minimum bactericidal concentration within
4 – 16 mg mL-1) and outstanding photocatalytic bactericidal
performance toward E. coli upon visible light irradiation
(only 10% E. coli could survive after 2-h exposure to visible
light). This results suggests that bismuth oxide nanospheres
can be highly efficient visible-light-driven photocatalysts for
bacterial inactivation. These antibacterial properties might be
the result of appearance of photogenerated reactive oxidative
species, which could cause the leakage of intracellular con-
tent by attacking the bacterial cell wall and membrane, even-
tually resulting in bacterial death [15].
Zhong, et al. [21] also carried out research on the use of
bismuth nanospheres decorated with Ag for water condition-
ing. These studies showed that silver-decorated bismuth ox-
ide nanospheres exhibit excellent photocatalytic activity in
comparison to nonmodified Bi2O3 nanospheres. Under visi-
ble light irradiation, Cr(VI) was completely removed after
10, 40, and 100 minutes using 2.5, 5.0, and 10 wt%
Ag/Bi2O3 nanocomposite, respectively. At the same time, a
mixture of 2.5 wt% silver nanoparticles with nonmodified
Bi2O3 nanospheres was used to reduce Cr(VI) under the
same conditions. This system allowed about 70% of the
chromium content to be removed after 120 min, which barely
improved photocatalytic activity of single-component
Bi2O3 nanospheres. The results obtained with 2.5 wt%
Ag/Bi2O3 nanospheres look very promising for the future in
water purification from heavy metals [21].
Studies carried out by Hernandez-Delgadillo, et al. [22]
showed that aqueous colloidal bismuth oxide nanoparticles
50
inhibited both the growth and biofilm formation of C. albi-
cans. Fungi of Candida genus are among the most common
biofilms associated with human disease episodes, which
causes both superficial and systemic disorders. This biofilm
is often found in both children and elderly patients with defi-
cient immune systems, also the mortality rate is about
30 – 50% when systemic candidiasis develops, which shows
importance of these studies. It turned out that Bi2O3 nanopar-
ticles reduced the number of fungi by 85% compared to ref-
erence sample. At the same time two commonly used anti-
fungal agents such as 2% chlorhexidine and 1% terbinafine
reached inhibition level at 44% and 51% respectively. Be-
sides this effect, nano-Bi2O3 produced twice as good effect
as bulk Bi2O3 when compared to nontreated cells, which sug-
gests that nanostructured bismuth oxide can be effective anti-
fungal agent [22].
3. BISMUTH OXIDE BASED DRUG DELIVERY
SYSTEMS
As mentioned to improve the effectiveness of drugs, they
should be delivered to the place where they should work.
Nanoparticles of bismuth oxide can be used as a carrier that
transports drugs to the right place in the body and then re-
leases it itself, also helping to treat the disease, because it is
biocompatible and porous. Due to these properties and the
high amount of bismuth, its oxide nanoparticles have been
tested in respect of cancer treatment.
Ovsyannikov, et al. [23] carried out tests for using the
obtained spherical bismuth oxide nanoparticles of 35 nm size
as a cancer cell fighting agent. It was suggested to use a com-
bination of obtained nanospheres with photodithazine – a
photosensitizer that has targeted delivery properties. Be-
tween the nanoparticles and the photosensitizer a stable
“host – quest” complex arises, where Bi2O3 is the host and
photodithazine is the guest. It was suggested that this com-
plex will be accumulated in tumour tissue and the irradiation
of that area with x-rays of suitable energy produces partial
destruction of the tumour, and the presence of bismuth as
heavy element must improve this effect [23].
In the study carried out by Stewart et. al. [24], a
radiosensitizing capacity of bismuth oxide was demonstrated
on highly radioresistant 9L gliosacroma cells. Particles ob-
tained by the researchers appeared as 50 – 70 nm thick plates
with an area of 48.7 ± 4.5 cm2 g-1. The results of Monte
Carlo simulations showed that the platelet morphology of
Bi2O3 nanoparticles is most effective for nanoparticle-en-
hanced radiotherapy as compared to spherical and cubic
shaped particles. Additional result was that the dose of en-
hanced factor reported by simulation study was smaller than
the biological sensitisation enhancement ratio demonstrated
by cell survival experiments [24].
Zhu et. al. [26] reported on the research about hybrid
nanogels formed from bismuth oxide quantum dots and poly-
vinyl alcohol (PVA) for purposes of temperature sensing,
Krzysztof Szostak et al.
dual-modal imaging and drug delivery. Researchers used the
60
Co x-ray source to irradiate the obtained Bi2O3@PVA
nanogel to a specified absorbed dose. The nanogels obtained
by scientists were analysed using Infrared spectroscopy (IR),
x-ray photoelectron spectroscopy (XPS), x-ray diffraction
(XRD), Dynamic light scattering (DLS), scanning electron
microscopy (SEM), transmission electron microscopy
(TEM), thermogravimetry analysis (TGA) confirmed the
presence of Bi2O3 quantum dots in the gel and tempera-
ture-responsive photoluminescence profile properties of
Bi2O3 hybrid nanogels. It was concluded that hybrid
nanogels can exhibit a high-resolution fluorescent signal as
response to the change in ambient temperature in a range of
37 – 40°C. The drug temozolomide (TMZ) was loaded into
hybrid nanogels within complexation method and the in vitro
tests for the release of TMZ from the nanogel were carried
out by a dialysis method. The Bi2O3@PVA hybrid nanogels
can accommodate up to 38.3 wt% of TMZ. The release of
TMZ from hybrid nanogels at a temperature of 37°C took
24 h, and the release at photodithazine at a temperature of
40°C was faster by ~19%. Researchers also carried out the
incorporation of hybrid nanogels into mouse melanoma cells
B16F10 and the cell viability upon in vitro treatments was
evaluated. Bi2O3@PVA hybrid nanogels were found to be
able to visualize the cells in dark-field images and to over-
come cellular barriers. Nearly the same signal intensity for
dark-field imagining was even obtained after 360 min expo-
sure. The results of research showed that these hybrid
nanogels have minimal cytotoxicity, and the cytotoxicity de-
creased for the TMZ loaded on them as compared to free
TMZ solution [25].
Bogusz et. al. [27] carried out research on the core-shell
synthesis combined within a-Bi2O3 nanoparticles coated
with methotrexate-immobilized (3-aminopropyl)trimethoxy-
silane (MTX-ATPMS). The a-Bi2O3 nanoparticles were syn-
thesized by via precipitation. Then, the nanoparticles were
coated with ATPMS, and MTX was attached to them. To
analyse the product, XRD and Fourier transform infrared
spectroscopy (FT-IR) were used in order to confirm the im-
mobilization of APTMS and MTX on a-Bi2O3 nanoparticles.
In addition, SEM, scanning transmission electron micros-
copy (STEM), energy dispersive x-ray (EDX), spectroscopy,
and ultraviolet-visible (UV-VIS) spectroscopy were used to
characterize the core-shell nanoparticles. The dimensions of
a-Bi2O3-APTMS-MTX complexes were 54 ± 8 nm and this
conjugate showed more spherical shape than a-Bi2O3 nano-
particles coated with APTMS (which were rather plate-like).
It was shown that a-Bi2O3 nanoparticles were good as ana-
tomical contrast enhancement agents by use of computer to-
mography (CT). The cytotoxicity of the obtained compounds
was ranked as follows: APTMS < MTX < a-Bi2O3-
APTMS < a-Bi2O3 < a-Bi2O3-APTMS-MTX. In addition,
radiosensitizing properties of a-Bi2O3 were confirmed [26].
Bismuth Oxide Nanoparticles in Drug Delivery Systems
Du et. al. [28] carried out research on the synthesis of
Bi2O3 nanoparticles functionalized by hyaluronic acid (HA)
in order to develop CT-imaging-guided radiotherapy of tu-
mors. The obtained nanoparticles were analysed by FT-IR,
XPS, high-resolution transmission electron microscopy
(HRTEM), UV-VIS spectroscopy, inductively coupled
plasma mass spectroscopy (ICP-MS), TEM, and DLS. In ad-
dition, cellular binding and uptake tests were conducted. The
cytotoxicity of HA-Bi2O3 nanoparticles even at a high con-
centration of 400 mg/mL at an exposure time of 24 h was not
high photodithazine (the cell viability was ~90%), and it was
found that the nanoparticles had good hemobiocompatibility.
Results of in vivo tests showed that HA-Bi2O3 nanoparticles
in adopted doses produced no in vivo toxicity effects during
long-term post-administration. These nanoparticles produced
great contrast enhancement in tumour imaging by CT.
Study of the mechanism of radiosensitization enhance-
ment proved in vivo that HA-Bi2O3 nanoparticles exhibited
no toxicity without irradiation, but produced significant dam-
age to tumors under irradiation as a result of total ablation
without any regrowth occurring within 10 days after injec-
tion [27].
CONCLUSION
Bismuth oxide nanoparticles are not well known in appli-
cations related to medical engineering, medical imaging,
drug delivery etc. However, their properties, which are di-
rectly dependent on increased surface to volume ratio. allow
them to be developed by many researchers in this field.
Growing number of studies on application of bismuth oxide
nanoparticles in aforementioned purposes confirms that it is
a promising material for future application.
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