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Synthesis of cisplatin encapsulated Zinc oxide nanoparticles and their

application as a carrier in targeted drug delivery

Article  in  Ceylon Journal of Science · March 2020

DOI: 10.4038/cjs.v49i1.7707

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Ceylon Journal of Science 49(1) 2020: 71-79
DOI: http://doi.org/10.4038/cjs.v49i1.7707

RESEARCH ARTICLE

Synthesis of cisplatin encapsulated zinc oxide nanoparticles and their application as a carrier
in targeted drug delivery

H.M.I. Abayarathne1, S.P. Dunuweera2 and R.M.G. Rajapakse1,*

Department of Chemistry, University of Peradeniya, Peradeniya 20400, Sri Lanka.

1

Department of Chemistry, Temple University, 1901N, 13th St, Philadelphia, PA 19122, USA.
2

Received: 31/05/2019 ; Accepted: 16/01/2020

Abstract: Cisplatin is a frequently used anticancer drug that INTRODUCTION

has been developed as the first platinum-based anticancer drug.
The cis configuration enables the coordination complex to be Zinc oxide occurs as a mineral zincite in nature and is
covalently binding to one or two DNA strands and thus cross- the most important zinc compound with many industrial
linking the DNA strands, causing the cells to die in a programmed applications. The pigment in white paints is zinc oxide
manner. Cisplatin is administered as an IV infusion in saline and is used in the production of enamels, white inks, white
solution for medication of solid malignity. Anticancer drugs glue, opaque glasses, rubber products, and floor tiles,
usually have a variety of side effects, but an encapsulation of the and many other products. It is also used in cosmetics,
drug in a suitable host material minimizes the side effects while soaps, pharmaceuticals, dental cements, batteries,
improving the efficacy of the drug due to its slow release only electrical equipment, and in piezoelectric equipment.
at the target. The aim of this research is to develop a simple, but Other applications are as a flame retardant, plastic UV
effective mechanism for the preparation of porous zinc oxide absorber and a reagent in analytical chemistry and in the
nanoparticles (PZnO NPs) using the forced hydrolysis method preparation of the majority of zinc salts. The compound is
reaction of zinc acetate dihydrate with deionized water in used in medicine as an antiseptic, astringent, and topical
diethylene glycol (DEG) media. This synthesized PZnO NPs were protector (Moezzi et al., 2012; Jiang et al., 2018). ZnO
then characterized by Scanning Electron Microscopy (SEM), has three crystal structures: hexagonal wurtzite, cubic
Energy Dispersive X-Ray Analysis (EDX), Fourier Transform zinc-blende and a rarely observed cubic rock-salt type.
Infrared Spectroscopy (FT-IR), Particle Size Analysis and Powder The most thermodynamically stable structure, under
X-Ray Diffraction (PXRD). The encapsulation of cisplatin within ambient conditions, is the wurtzite form (Ashrafi and
the porous zinc oxide nanoparticles was confirmed by X-ray Jagadish, 2007). The zinc-blend structure is metastable
Fluorescence (XRF), SEM, EDX, and FT-IR studies. Our results and can only be stabilized on cubic substrates by epitaxial
show that the synthesized nanoparticles have the hexagonal growth, whereas the cubic rock-salt structure is usually
wurtzite structure as confirmed by PXRD. The average particle only stable under extreme pressure (Özgür et al., 2005).
size as determined by light scattering is 52.4 ± 0.1 nm SEM ZnO is a common material used in nanotechnology and
images show porous spherical morphology with aggregated versatile architectures of ZnO can be easily synthesized
particles. XRF data of the cisplatin encapsulated product show simply by wet-chemical and autoclaving or hydrothermal
a Pt: Cl ratio of 1:2 showing cisplatin encapsulation without any technologies. The use of zinc oxide nanoparticles in
fragmentation or other chemical change. The presence of NH3 in cancer has been well investigated in various biomedical
the encapsulated product is also apparent from FT-IR data. The applications. Anticancer activity of ZnO NPs has been
encapsulation of the anti-cancer drug cisplatin to PZnO NPs and demonstrated through the generation of ROS and also
its pH dependence on the release of the drug from PZnO NPs through apoptosis (Rasmussen et al., 2010; Qu and Morais,
was studied by measuring the amount of Pt released as a function 2001). However, zinc is needed for the action of more than
of the time which was done using Inductively Coupled Plasma 300 enzymes; as such, it is involved in many of the body’s
Atomic Emission Spectroscopy (ICP-AES) at λmax 265.94 nm. enzymatic and metabolic functions. There are more than
The encapsulation efficiency of Cisplatin into PZnO NPs was 2,000 transcription factors in gene expression that enable
found to be 50.52%. The percentage of Cisplatin released from zinc to retain its structural integrity and bind to DNA
PZnO NPs during the first 7 hours was < 6.30% in the acetate/ (Prasad, 1998; Prasad, 1993). Zinc’s role in cancer has
phosphate buffer at pH 4.0, 5.0, 6.0, 7.0 and 8.0. The maximum now been developed in human studies as a link between
zinc deficiency and cancer. Compared to healthy people,
release of 8.64% was observed at pH = 6.0 after 24 hours.
zinc status is now reported to be compromised in cancer
Keywords: Anticancer drug; cisplatin; encapsulation; porous patients. Several researchers reported a drop of zinc in
zinc oxide nanoparticles; slow release.
plasma of cancer patients (Inutsuka and Araki, 1978). The
decrease in plasma zinc in cancer is believed to be due to

*Corresponding Author’s Email: [email protected]

https://orcid.org/0000-0003-3943-5362
This article is published under the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
72 Ceylon Journal of Science 49(1) 2020: ??-??

increased tumor requirements of the element, especially than other organic systems, such as micelles, liposomes,
when the tumors have a high DNA synthesis rate, which polymersomes or, possibly, non-porous inorganic materials
is partly dependent on zinc (Abnet et al., 2005; Lee et (Beletsi et al., 2008; Gryparis et al., 2007), the solid
al., 2004; Prasad et al., 1998 and Abdulla, 1979). Zinc nature of the carrier provides the trapped species with a
is necessary for normal tissue proliferation, but opinions high level of protection against external aggression and
differ on the role of zinc in the induction and proliferation the deficiency of zinc can be managed. The aim of this
of malignant cells. A high intake of zinc has been reported research is to develop a simple, but effective mechanism for
to reduce the incidence of some malignant tumors such the preparation of porous zinc oxide nanoparticles (PZnO
as stomach and esophageal cancers (Fong et al., 1996; NPs) using the forced hydrolysis reaction of zinc acetate
Fong et al., 1997; Newberne et al., 1997 and Grattan dihydrate with deionized water in diethylene glycol (DEG)
and Freake, 2012). In addition, electrostatic properties media. The well-characterized synthesized nanoparticles
are another useful feature of ZnO NPs. This property is were used to encapsulate the anticancer drug cisplatin. The
used for demonstrate anti-cancer activity where ZnO NPs cisplatin’s ability to damage DNA is shown in Figure 1.
exhibit a different type of surface charge behavior due Cisplatin is a small drug molecule which contains a
to the presence of chemisorbed neutral hydroxyl groups. platinum (II) ion in the middle of a flat square with two
Protons move out of the particle surface in an aqueous chloride ions and two ammonia molecules making up the
medium at high pH, leaving a negatively charged surface corners in cis configuration. It is approved for human use
with partially bonded oxygen atoms (ZnO-). Protons from in 1978 and it was the first of a completely new type of
the environment are transferred to the particle surface at anticancer drug that based on coordination complex. It
low pH, leading to a charged positive surface (ZnOH2+) is extremely effective and is a common treatment for
(Degen and Kosec, 2000). In physiological conditions, testicular and ovarian cancers (Sadler and Guo, 1998).
these nanoparticles carry a strong positive surface charge The cis configuration (Figure 2a) enables the coordination
(Abercrombie and Ambrose, 1962). However, cancer complex to be covalently binding to one or two DNA
cells have a high concentration of anionic phospholipids strands and thus cross-linking the DNA strands, causing
(phosphatidylserine) on their external membranes and have the cells to die in a programmed manner. The alternative
great potential for negative membranes (Vallabhapurapu isomer, transplatin (Figure 2b), is not a useful drug and is
et al., 2015). Hence, cancer cells can electrostatically supposed to be disabled before reaching DNA (Rajapakse
interact with positively charged ZnO NPs. This interaction and Dunuweera, 2017).
promotes the cellular absorption, phagocytosis, and
cytotoxicity of these nanoparticles (Biplab et al., 2016). However, cisplatin has some side effects such as
ZnO NPs has also been investigated for the loading of drugs changes in the taste of food, diarrhea, kidney damage,
for better cellular absorption and synergistic activity. ZnO nerve damage, nausea and vomiting, hearing loss, hair loss
NP surface modifications have been carried out to further and a decrease in blood cell production in the bone marrow
improve its stability and increase the selectivity of specific (Astolfi et al., 2013; Oun et al., 2018). In order to limit
cells. Given all aspects, PZnO NPs are one of the most these toxic effects of cisplatin, we have developed a method
promising materials for clinical use in cancer treatment as in which cisplatin is encapsulated in porous ZnO NPs for
they demonstrate a significantly higher loading capacity targeted delivery to cancerous cells and to slow release,

Figure 1: Illustration of DNA damaging mechanism of cisplatin. Cisplatin binds to Adenine (A) and Guanine (G) N atoms in inter-
stand and intra-stand A-Pt-G crosslink thus damaging DNA.
H.M.I. Abayarathne et al. 73

(a) (b)

Figure 2: Chemical structures of (a) cisplatin and (b) transplatin.

only at their vicinity. The main hypothesis of this work is PZnO NPs thus obtained were characterized by PXRD
that under low pH conditions prevailing in cancer cells ZnO (Siemens D5000 powder X-ray diffractometer), Laser Light
dissolves slowly releasing cisplatin, only at the vicinity of Scattering based Particle Size Analysis (CILAS Particle
cancer cells, whereas ZnO is stable at physiological pH Size Analyzer NANO DS), FT-IR (Shimadzu IR-Prestige
values of blood and healthy cell media. In this way, only 21 Instrument) with the KBr pellet method and SEM (EVO
the minimum dosage required can be targeted towards LS15 OXFORD X-act Scanning Electron Microscope) and
cancer cells, avoiding its toxic effects on healthy normal EDX studies.
cells and increasing the bioavailability and efficacy of the
Encapsulation and Characterization
drug. In fact, we are the pioneers in using non-toxic porous
inorganic oxide and carbonate nanomaterials for targeted In the encapsulation of cisplatin drug into the ZnO
delivery of anticancer drugs for slow- and steady-release nanoparticle, 0.50 g of ZnO nanoparticles were dispersed
only at the cancerous cells (Dunuweera and Rajapakse, in a 50 mL of cisplatin injection solution and kept stirring
2016; Ranathunge et al., 2019; Dunuweera and Rajapakse, for 24 hours to facilitate cisplatin encapsulation. The
2017 and Weerasuriya et al., 2017). There we used CaCO3, product was subsequently separated by centrifuging and
MgO and hydroxyapatite nanomaterials as drug carriers. washed several times with distilled water and dried in a
All of them were successful in pH triggered drug release vacuum oven at 60 ˚C for two days. The encapsulation of
only at the cancerous cells with the additional benefit of cisplatin was confirmed by the X-ray fluorescence (XRF)
supplying essential metal ions such as Ca2+ and Mg2+ to and Fourier Transform Infrared (FT-IR) Spectroscopy,
cancer patients. This is the first time study of use of ZnO Scanning Electron Microscopy (SEM) and Energy
nanomaterials for the same purpose where it also has the Dispersive X-ray (EDX) analysis of the products obtained.
additional benefit of supplying essential Zn to the cancer
patients to circumvent the problem of zinc deficiency Release Kinetics of Encapsulated product
usually encountered in them and to use zinc as a therapeutic Cisplatin encapsulated PZnO NPs (0.20 g each) were
agent also. placed in cellulose dialysis tubes (molecular size cut off of
MATERIALS & METHODS 11000) and were placed in beakers containing 200 mL of
buffer solutions with pH values of 4.0, 5.0, 6.0, 7.0, and 8.0
Materials and placed on a thermostatic shaker maintained at 37 °C
and 100 rpm. 10 mL of supernatant solution was withdrawn
Zinc acetate dihydrates [Zn(CH3COO)2.2H2O], diethylene at one hour time intervals for 7 hours and also at 24 hours,
glycol (DEG), cisplatin [cis-PtCl2(NH3)2] were the main while an equal volume of fresh buffer solutions was added
chemicals used. All the chemicals except cisplatin were of to maintain the constant volume. Platinum content of the
analytical grade and were purchased from Sigma-Aldrich buffer supernatant was determined using Atomic Emission
and used without further purification. Cisplatin injection Spectroscopy (AES) (Dunuweera and Rajapakse, 2016).
bottles containing 1% cisplatin in saline water was The calibration curve was developed in order to find
purchased from Sri Lanka Pharmacy, Kandy, Sri Lanka. the concentration of platinum which is released by the
Synthesis and Characterization of PZnO NPs encapsulated product using standard solutions made from
40 mg L-1 standard cisplatin solution.
Porous zinc oxide nanoparticles were synthesized using
the forced hydrolysis method (Eixenberger et al., 2017). RESULTS AND DISCUSSION
Zinc acetate dihydrate (1.000 g) was added to diethylene The particle size analysis was carried out using LASER
glycol (DEG), (100 mL), and the solution was brought to light scattering based Particle Size Analysis. The instrument
85 ˚C. Next Deionized water (0.30 mL) was added, and the gives the plot of the hydrodynamic radius of the colloidal
solution was heated to 155 ˚C and held for 2 hours while particles in the suspension which is represented in the
stirring (300 rpm). Upon cooling to room temperature, x-axis of the plot as shown in Figure 3. The y-axis of the
the product was collected by centrifugation at 5000 rpm, plot represents the parameter called Q3% which represents
subsequently washed several times with ethanol, and the the percentage of particles with a given hydrodynamic
product obtained was dried for 24 hours at 60˚C in an oven. radius. It can be inferred that the colloidal solution contains
Then, the final product was calcined at 500 ˚C for 5 hours.
74 Ceylon Journal of Science 49(1) 2020: 71-79

PZnO NPs with sizes varying in a wide range of 20 nm to for 2 days in vacuum oven ). It also contains the vibration
1704 nm with an optimum value of 52 nm above a 90% band of Zn˗O at 488 cm-1. The FT-IR data suggest the
confidence level. Also, 10% of particles are smaller than encapsulation of cisplatin in pours zinc oxide nanoparticles.
the 41 nm, half are smaller than the 105 nm and half are Due to encapsulation, Zn-O vibration band has been shifted
greater than the 105 nm, 90% of the particles are smaller from 475 cm-1 to 488 cm-1.
than the 423 nm. XRF and FT-IR are both bulk analytical techniques
The PZnO NPs synthesized in this work was which can measure the composition of bulk samples.
characterized using Powder X-Ray Diffraction and the However, SEM analysis is a surface analytical technique
X-Ray Diffractogramme obtained is shown in Figure 4a. detecting a few micrometer widths from the surface and
The sample contains an essentially hexagonal wurtzite therefore EDX detects the elements present close to the
structure as the major phase. The main characteristic peaks surface of the porous zinc oxide nanoparticles. EDX is also
of hexagonal wurtzite are at 2θ of 31.718˚, 34.423˚, 36.225˚, an analytical technique used for elemental analysis and
47.644˚, 56.658˚, 62.824˚, 66.430˚, 67.848˚, 68.978˚ which relies on the interaction of backscattered X-ray radiation
correspond to the diffractions from (100), (002), (101), and a sample. The capacity for characterization in EDX
(102), (110), (103), (200), (112) and (201) crystallographic is high because of the fact that each element has a unique
planes (JCPDS card number 36-1451), which can be atomic structure, allowing a unique set of peaks on the
clearly seen (Wojnarowicz et al., 2016). Application of the electromagnetic emission spectrum. PZnO NPs consists of
Debye-Scherrer Equation to the major PXRD peak gives zinc (Zn) and oxygen (O) and the presence of Zn and O in
the crystallite size to be 18.87 nm. According to Figure 4b the EDX spectrum as shown in Figure 6 is a clear indication
hexagonal wurtzite structure of zinc oxide nanoparticles that the presence of ZnO in the sample. Also, peak possibly
have not changed after encapsulation and also strongest omitted at 0.272 keV may be due to carbon (C) because we
peaks observed at 2θ values lie approximately at the used zinc acetate.dihydrate [Zn(CH3COO)2.2H2O] for the
same previous 2θ values (Wojnarowicz et al., 2016). The synthesis and also hydrogen (H) cannot be detected using
presence of cisplatin cannot be determined from PXRD as EDX. The SEM images of porous zinc oxide nanoparticles
cisplatin is present in a non-crystalline form in the restricted are shown in Figure 7: (a), (b), (c) and (d). As is evident
environment of zinc oxide pores. from particle size determination of the suspension, discrete
particles are present in the suspension. But according to
As evidenced from the FT-IR spectrum, provided in
these SEM images, it can be clearly seen that the zinc
Figure 5a, the absorption band at 475 cm-1 is due to Zn˗O
oxide sample contains more of microparticles rather than
vibration which confirms the presence of the ZnO (Rana et
nanoparticles because the aggregation of PZnO NPs by
al., 2016). Around 3500 cm-1 a broadband appears which
solid-solid interactions to form more stable microparticles.
is due to O˗H starching vibration of H2O vapor adsorbed
Also, the SEM images clearly show that the sample contains
onto PZnO NPs which can take place due to its hydrophilic
spherical shape particles and the morphology of the PZnO
nature and other bands appear due to impurities of fused
NPs shows a good porous nature which can give a clear
KBr. The FT-IR spectrum of the encapsulated product
indication that these particles, though larger in size, can be
obtained (Figure: 5b) clearly shows the presence of N˗H
used as a host material for encapsulation of cisplatin. The
anti symmetric and symmetric stretching vibration at 3334
SEM images obtained for PZnO NPs after encapsulation is
cm-1 and 3477 cm-1, respectively (FT-IR spectrum of the
shown in Figure 7: (e) and (f). They show less porosity and
encapsulated product was recorded after drying at 60 ˚C

Figure 3: Particle Size Distribution of synthesized PZnO NPs.

H.M.I. Abayarathne et al. 75

(b)
(a)
Figure 4: (a) PXRD pattern obtained for synthesized PZnO NPs (b) PXRD pattern obtained for cisplatin encapsulated zinc oxide
nanoparticles.

(a) (b)

Figure 5: (a) FT-IR spectrum of the synthesized zinc oxide nanoparticles. (b) FT-IR spectrum of cisplatn encapsulated ZnO
nanoparticles.

Figure 6: EDX spectrum of synthesized PZnO NPs.

76 Ceylon Journal of Science 49(1) 2020: 71-79

somewhat changed the morphology of the particles surface (1)

which may be an indication that the encapsulation process
has successfully taken place.
Where, E = Encapsulation Efficiency (%),C0 = Initial
XRF provides information on the quantitative and Cisplatin Concentration, C1 = Cisplatin Residual
qualitative determination of the types of elements that concentration. Calculated cisplatin encapsulation efficiency
are present in a sample. Our XRF machine is incapable is 50.52%. In general, cancer cells have a low pH value
of detecting elements with atomic number less than compared to normal cells. There are many explanations as
13. Therefore, it shows that the product formed is free to why this is so, but it is usually due to the higher rate of
of impurities containing the element with an atomic cell differentiation. Erratic and uncontrolled growth occurs
number higher than 13. The XRF spectra of the cisplatin where the supply of oxygen is low. As a result, the tumor
encapsulated ZnO NPs product, shown in Figure 8, cells have no choice but to undergo anaerobic respiration,
clearly indicates the presence of Zn, Pt, and Cl with the which leads to the formation of lactic acid. This process
Pt: Cl atomic ratio of approximately 1:2. However, XRF changes the tumor cell’s pH profile (pH is lower between
is incapable of detecting N and H. 1:2 Pt:Cl ratio is the 5.0 and 6.0). This change in pH can be used to initiate a
correct atomic ratio of Pt and Cl in cisplatin and hence XRF targeted drug delivery mechanism and to slowly release the
data suggest the presence of cisplatin in pours ZnO NPs. drug under acidic pH conditions. According to Figure 9(a),
The determination of encapsulation efficiency was done synthesized porous zinc oxide nanoparticles may be stable
by conducting AES analysis on the supernatant solution in all pH values. However, the released percentage slightly
to obtain the platinum concentration corresponding to the increase at pH=6.0. Here, we can ignore the release profile
concentration of cisplatin. Equation (1) is used to calculate obtained at pH = 8.0 because usually, the human body
the encapsulation efficiency. does not attain pH = 8.0 basicity in any organ or any part.

Figure 7: (a), (b), (c), (d) are SEM images of aggregated synthesized PZnO NPs and (e), (f) are SEM images of cisplatin
encapsulated PZnO NPs.
H.M.I. Abayarathne et al. 77

Figure 8: XRF spectra of cisplatin encapsulated ZnO nanoparticles.

(a) (b)

Figure 9: (a) Anticancer drug release profile for each different pH and time intervals (b) Cisplatin concentration released during first
7 hours for acidic pH values.

However, if we consider the drug release profiles of pH is also a positive factor to reduce toxicity and side effects
= 4.0, 5.0, 6.0, and 7.0, it can be observed that during the for the body by the drug. PZnO NPs can release the drug in
first 7 hours which is crucial when it comes to anticancer small quantities within a longer period, preventing toxicity
drug delivery, the release of cisplatin from PZnO NPs is risks. Since we used 1000 ppm of cisplatin solution in
in a very slight amount. Even at pH = 7.0 (neutral pH), this encapsulation experiment and around 505 ppm were
we can see only 5.54% of total drug encapsulated in PZnO encapsulated, the concentration of cisplatin encapsulated
NPs is released after 7 hours. pH of healthy tissues in the can be considered acceptable for release over a long period
human body is about 6.8–7.3 and it can be inferred that the of time. Considering the release of the drug during the first
release of drug from PZnO NPs will not give harmful side 7 hours at acidic pH values, as shown in Figure 9(b), we
effect in comparison to the drug administered in free form can see that the release is not completely uniform. At pH
without encapsulation. Therefore, we can get an indication = 5.0 we can see a release which fluctuates negatively and
that the side effects can be reduced up to a certain extent positively it may be due to different porosity of synthesized
by encapsulation. Further, during acidic pH values, the zinc oxide nanoparticles, higher porosity in some particles
release of cisplatin from PZnO NPs is slower. This is contains more cisplatin, therefore, an average uniform
may be due to the fact that PZnO NPs is stable at low pH release is observed. But, at pH = 6.0 and 4.0, we can see the
values. This property can be taken into a positive use by almost uniform release of cisplatin except during 5–6 hours
selectively binding PZnO NPs encapsulated cisplatin to the at pH = 6.0. At these pH values, the particles are more
cancer cells, then, the obtained slow release can be used to stable and therefore the only diffusion takes place which
reduce the dosage cycles given for cancer treatment which explains the very slow release of cisplatin concentration
78 Ceylon Journal of Science 49(1) 2020: 71-79

encapsulated. in esophageal biopsy specimens measured by X-ray

fluorescence and esophageal cancer risk. Journal of
CONCLUSION the National Cancer Institute, 97(4): 301-306. DOI:
PXRD and FT-IR studies have proven that the hexagonal https://doi.org/10.1093/jnci/dji042.
wurtzite structure of porous zinc oxide nanoparticles Ashrafi, A.B.M.A. and Jagadish, C. (2007). Review
was produced using the forced hydrolysis reaction of of zincblende ZnO: Stability of metastable ZnO
Zn(CH3COO)2.2H2O with deionized water in diethylene phases. Journal of Applied Physics, 102(7): 1-12. DOI:
glycol (DEG) media. FT-IR studies show an interaction https://doi.org/10.1063/1.2787957.
between porous zinc oxide nanoparticles and the anticancer Astolfi, L., Ghiselli, S., Guaran, V., Chicca, M., Simoni,
drug cisplatin. SEM images show that the morphological E.D.I., Olivetto, E. and Martini, A. (2013). Correlation
differences between porous zinc oxide nanoparticles and of adverse effects of cisplatin administration in
the anticancer drug cisplatin encapsulated product and patients affected by solid tumours: A retrospective
also it showed that the spherical morphology of zinc oxide evaluation. Oncology reports, 29(4): 1285-1292. DOI:
nanoparticles. PXRD studies have illustrated that anticancer https://doi.org/10.3892/or.2013.2279.
drug encapsulated ZnO NPs retain with same wurtzite Beletsi, A., Klepetsanis, P., Ithakissios, D.S., Kounias,
structure. EDX provided a clear indication that porous S., Stavropoulos, A. and Avgoustakis, K. (2008).
ZnO NPs do not contain any heavy metals or unwanted Simultaneous optimization of cisplatin-loaded PLGA-
impurities and also EDX spectrum gives clear evidence to mPEG nanoparticles with regard to their size and drug
prove that cisplatin is present in nanoparticles. According encapsulation. Current Nanoscience, 4(2): 173-178.
to particle size analysis data, average particle size of ZnO DOI: https://doi.org/10.2174/157341308784340895.
NPs is 52 nm. Cisplatin was successfully encapsulated in Biplab, K.C., Paudel, S.N., Rayamajhi, S., Karna, D.,
porous ZnO NPs which retains its chemical identity within Adhikari, S., Shrestha, B.G. and Bisht, G. (2016).
the confined environment as also explained by XRF studies. Enhanced preferential cytotoxicity through surface
By analyzing the data obtained for in vitro studies, it can be modification: synthesis, characterization and
concluded that the release of cisplatin adsorbed by porous comparative in vitro evaluation of TritonX-100
ZnO NPs slightly increases at pH=6. But during the first modified and unmodified zinc oxide nanoparticles in
seven hours, very mild release of cisplatin was shown all human breast cancer cell (MDA-MB-231). Chemistry
pH values. pH of healthy tissues in the human body is about Central Journal, 10(1): 1-10. DOI: https://doi.
6.8–7.3 and it can be inferred that the release of drug from org/10.1186/s13065-016-0162-3.
PZnO NPs will not give harmful side effect in comparison Degen, A. and Kosec, M. (2000). Effect of pH and
to the drug administered in free form without encapsulation. impurities on the surface charge of zinc oxide in
Therefore, it gives an indication that the side effects can aqueous solution. Journal of the European Ceramic
be reduced up to a certain extent by encapsulation. When Society, 20(6): 667-673. DOI: https://doi.org/10.1016/
considering the all of things, the encapsulated porous ZnO S0955-2219(99)00203-4.
NPs can be delivered to cancer cells in a targeted manner Dunuweera, S.P. and Rajapakse, R.M.G. (2016). Synthesis
and cisplatin can be released in minimum amounts at the of unstable vaterite polymorph of hollow calcium
vicinity of the cancer cells which can reduce the dosage carbonate nanoparticles and encapsulation of the
cycles given at a time period for effective destruction of anticancer drug cisplatin.  Journal of Advances in
cancer cells. Medical and Pharmaceutical Sciences, 10(4): 1-10.
DOI: https://doi.org/10.9734/JAMPS/2016/29784.
ACKNOWLEDGEMENT Dunuweera, S.P. and Rajapakse, R.M.G. (2017).
Encapsulation of anticancer drug cisplatin in vaterite
The authors wish to thank the Department of Chemistry,
polymorph of calcium carbonate nanoparticles for
Faculty of Science, University of Peradeniya for all the
targeted delivery and slow release. Biomedical Physics
facilities provided.
& Engineering Express, 4(1), 015017. DOI: https://doi.
DECLARATION OF CONFLICT OF INTEREST org/10.1088/2057-1976/aa9719.
The Authors declare that there is no conflict of interest. Eixenberger, J.E., Anders, C.B., Hermann, R.J., Brown,
R.J., Reddy, K.M., Punnoose, A. and Wingett, D.G.
REFERENCES (2017). Rapid dissolution of ZnO nanoparticles
induced by biological buffers significantly impacts
Abdulla, M., Biorklund, A., Mathur, A. and Wallenius,
cytotoxicity. Chemical research in toxicology, 30(8):
K. (1979). Zinc and copper levels in whole blood and
1641-1651. DOI: https://doi.org/10.1021/acs.
plasma from patients with squamous cell carcinomas
chemrestox.7b00136.
of head and neck. Journal of surgical oncology, 12(2):
Fong, L.Y., Lau, K.M., Huebner, K. and Magee, P.N. (1997).
107-113. DOI: https://doi.org/10.1002/jso.293
Induction of esophageal tumors in zinc-deficient rats
0120203.
by single low doses of N-nitrosomethylbenzylamine
Abercrombie, M., and Ambrose, E.J. (1962). The
(NMBA): analysis of cell proliferation, and mutations
surface properties of cancer cells: a review. Cancer
in H-ras and p53 genes. Carcinogenesis, 18(8): 1477-
research, 22(5 Part 1): 525-548.
1484. DOI: https://doi.org/10.1093/carcin/18.8.1477.
Abnet, C.C., Lai, B., Qiao, Y.L., Vogt, S., Luo, X.M., Taylor,
Fong, L.Y., Li, J.X., Farber, J.L. and Magee, P.N. (1996).
P.R. and Dawsey, S.M. (2005). Zinc concentration
Cell proliferation and esophageal carcinogenesis in the
 H.M.I. Abayarathne et al. 79
zinc-deficient rat. Carcinogenesis, 17(9): 1841-1848. surface charge density in oxide-based semiconductor
DOI: https://doi.org/10.1093/carcin/17.9.1841. nanoparticles immersed in aqueous solution. IEEE
Grattan, B.J. and Freake, H.C. (2012). Zinc and cancer: transactions on magnetics, 37(4): 2654-2656. DOI:
implications for LIV-1 in breast cancer. Nutrients, 4(7): 10.1109/20.951264.
648-675. DOI: https://doi.org/10.3390/nu4070648. Rajapakse, R.M.G. and Dunuweera, S.P. (2017).
Gryparis, E.C., Mattheolabakis, G., Bikiaris, D. and Discovery, chemistry, anticancer action and targeting of
Avgoustakis, K. (2007). Effect of conditions of cisplatin. Int. J. Clin. Oncol. Cancer Res, 2(3): 65-74.
preparation on the size and encapsulation properties DOI: 10.11648/j.ijcocr.20170203.13.
of PLGA-mPEG nanoparticles of cisplatin.  Drug Rana, N., Chand, S. and Gathania, A.K. (2016). Green
delivery, 14(6): 371-380. DOI: https://doi. synthesis of zinc oxide nano-sized spherical particles
org/10.1080/10717540701202 937. using terminalia chebula fruits extract for their
Inutsuka, S. and Araki, S. (1978). Plasma copper and photocatalytic applications. 
International Nano
zinc levels in patients with malignant tumors of Letters, 6(2): 91-98. DOI: https://doi.org/10.1007/
digestive organs. Clinical evaluation of the Cu/ s40089-015-0171-6.
Zn ratio.  Cancer, 42(2): 626-631. DOI:https://doi. Ranathunge, T.A., Karunaratne, D.G.G.P., Rajapakse,
org/10.1002/1097-0142(197808)42:2<626::AID- R.M.G. and Watkins, D.L. (2019). Doxorubicin
CNCR2820420232 >3.0.CO;2-F. loaded magnesium oxide nanoflakes as pH dependent
Jiang, J., Pi, J. and Cai, J. (2018). The advancing of zinc oxide carriers for simultaneous treatment of cancer
nanoparticles for biomedical applications. Bioinorganic and hypomagnesemia.  Nanomaterials, 9(2): 208.
chemistry and applications, 2018. DOI: https://doi. DOI:  https://doi.org/10.3390/nano9020208.
org/10.1155/2018/1062562. Rasmussen, J.W., Martinez, E., Louka, P. and Wingett,
Lee, D.H., Anderson, K.E., Harnack, L.J., Folsom, A.R. D.G. (2010). Zinc oxide nanoparticles for selective
and Jacobs Jr, D.R. (2004). Heme iron, zinc, alcohol destruction of tumor cells and potential for drug delivery
consumption, and colon cancer: Iowa Women’s Health applications. Expert opinion on drug delivery, 7(9):
Study. Journal of the National Cancer Institute, 96(5): 1063-1077. DOI: https://doi.org/10.1517/17425247.20
403-407. DOI: https://doi.org/10.1093/jnci/djh047. 10.502560.
Moezzi, A., McDonagh, A.M. and Cortie, M.B. (2012). Sadler, P.J. and Guo, Z. (1998). Metal complexes in
Zinc oxide particles: synthesis, properties and medicine: design and mechanism of action. Pure and
applications. Chemical engineering journal, 185: 1-22. Applied Chemistry, 70(4): 863-871. DOI: https://doi.
DOI: https://doi.org/10.1016/j.cej.2012.01.076. org/10.1351/pac199870040863.
Newberne, P.M., Broitman, S. and Schrager, T.F. Vallabhapurapu, S.D., Blanco, V.M., Sulaiman, M.K.,
(1997). Esophageal carcinogenesis in the rat: zinc Vallabhapurapu, S.L., Chu, Z., Franco, R.S. and Qi,
deficiency, DNA methylation and alkyltransferase X. (2015). Variation in human cancer cell external
activity. Pathobiology, 65(5): 253-263. DOI: https:// phosphatidylserine is regulated by flippase activity and
doi.org/10.1159/000164136. intracellular calcium. Oncotarget, 6(33): 34375-34388.
Oun, R., Moussa, Y.E. and Wheate, N.J. (2018). The side DOI: 10.18632/oncotarget.6045.
effects of platinum-based chemotherapy drugs: a review Weerasuriya, D.R.K., Wijesinghe, W.P.S.L. and Rajapakse,
for chemists. Dalton transactions, 47(19): 6645-6653. R.M.G. (2017). Encapsulation of anticancer drug copper
DOI: https://doi.org/10.1039/C8DT00838H. bis (8-hydroxyquinoline) in hydroxyapatite for pH-
Özgür, Ü., Alivov, Y.I., Liu, C., Teke, A., Reshchikov, M., sensitive targeted delivery and slow release. Materials
Doğan, S. and Morkoç, A.H. (2005). A comprehensive Science and Engineering: C, 71: 206-213. DOI: https://
review of ZnO materials and devices.  Journal doi.org/10.1016/j.msec.2016.10.010.
of applied physics, 98(4): 3-12. DOI: https://doi. Wojnarowicz, J., Opalinska, A., Chudoba, T., Gierlotka,
org/10.1063/1.1992666. S., Mukhovskyi, R., Pietrzykowska, E. and Lojkowski,
Prasad, A.S. (1993). Clinical spectrum of human zinc W. (2016). Effect of water content in ethylene glycol
deficiency. Biochemistry of zinc, Springer, Boston, solvent on the size of ZnO nanoparticles prepared
MA, pp. 219-258. DOI: https://doi.org/10.1007/978-1- using microwave solvothermal synthesis.  Journal
4757-9444-1_11. of Nanomaterials,  2016, DOI: http://dx.doi.
Prasad, A.S. (1998). Zinc in human health: an update. The org/10.1155/2016/2789871.
Journal of Trace Elements in Experimental Medicine:
The Official Publication of the International Society
for Trace Element Research in Humans, 11(2‐3):
63-87. DOI: https://doi.org/10.1002/(SICI)1520-
670X(1998)11:2/3<63::AID-JTRA2>3.0.CO;2-5.
Prasad, A.S., Beck, F.W., Doerr, T.D., Shamsa, F.H., Penny,
H.S., Marks, S.C. and Mathog, R.H. (1998). Nutritional
and zinc status of head and neck cancer patients: an
interpretive review. Journal of the American College of
Nutrition, 17(5): 409-418. DOI: https://doi.org/10.1080
/07315724.1998.10718787.
Qu, F. and Morais, P.C. (2001). The pH dependence of the

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