Green biosynthesis of superparamagnetic magnetite Fe3O4 nanoparticles and biomedical applications in targeted anticancer drug delivery system: A review

Yen Pin Yew; Kamyar Shameli; Mikio Miyake; Nurul Bahiyah Bt Ahmad Khairudin; Shaza Eva Bt Mohamad; Takeru Naiki; Kar Xin Lee

doi:10.1016/j.arabjc.2018.04.013

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Review article

13 (

); 2287-2308

doi:

10.1016/j.arabjc.2018.04.013

Green biosynthesis of superparamagnetic magnetite Fe₃O₄ nanoparticles and biomedical applications in targeted anticancer drug delivery system: A review

Yen Pin Yew^{^a}, Kamyar Shameli^{^a,⁎}, Mikio Miyake^{^b}, Nurul Bahiyah Bt Ahmad Khairudin^{^a}, Shaza Eva Bt Mohamad^{^a}, Takeru Naiki^{^c}, Kar Xin Lee^{^a}

a Department of Environmental Engineering and Green Technology, Malaysia-Japan International Institute of Technology, Universiti Teknologi Malaysia, Jalan Sultan Yahya Petra, 54100 Kuala Lumpur, Malaysia

b Japan Advanced Institute of Science and Technology (JAIST), Japan

c Department of Biomedical Engineering, Faculty of Engineering, Okayama University of Science, Japan

⁎Corresponding author. kamyarshameli@gmail.com (Kamyar Shameli),

Received: 2018-2-21, Accepted: 2018-4-18, Published: 2018-01-01

Disclaimer:
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.

Peer review under responsibility of King Saud University.

Abstract

This review discussed about the green biosynthesis of magnetite nanoparticles (Fe₃O₄-NPs) and the biomedical applications, which mainly focus on the targeted anticancer drug delivery. Fe₃O₄-NPs have been studied and proved that Fe₃O₄-NPs can be used in various fields of application, due to “superparamagnetic” property that Fe₃O₄-NPs possessed. In targeted drug delivery system, drug loaded Fe₃O₄-NPs can accumulate at the tumor site by the aid of external magnetic field. This can increase the effectiveness of drug release to the tumor site and vanquish cancer cells without harming healthy cells. In order to apply Fe₃O₄-NPs in human body, Fe₃O₄-NPs have to be biocompatible and biodegradable to minimize the toxicity. So, green biosynthesis plays a crucial role as the biosynthesized Fe₃O₄-NPs is safe to be consumed by human because the materials used are from biological routes, such as plant extract and natural polymer. However, biosynthesis using plant extract is the most popular among them all as plant extract can act as both reducing and stabilizing agents in the synthesizing process of nanoparticles. This approach is not merely simple, yet economic and less waste production, which is environmental friendly. Several biomedical applications of Fe₃O₄-NPs are included in this review, but anticancer drug delivery study is discussed in detail. The criteria for Fe₃O₄-NPs to be used as drug delivery vehicle are discussed so as to study the optimum condition of Fe₃O₄-NPs in drug delivery application. Many researches showed the promising results of Fe₃O₄-NPs in treating cancer cells via in vitro study. Hence, this review is significant which summarize the vital points of Fe₃O₄-NPs in targeted anticancer drug delivery system. Conclusions have been made according to the literature reviewed and some points of view were proposed for future study.

Keywords

Green biosynthesis

Superparamagnetic

Magnetite nanoparticle

Anticancer

Targeted drug delivery

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1 Introduction

In recent times, researchers have discovered the huge potential behind nanotechnology and ever since it has played a vital role in this world. Nanotechnology is assuredly gaining in popularity owing to the benefits and potential it can provide to human. In the past decades, nanotechnology started with material industry yet its credibility remained low (Hanus and Harris, 2013). As time goes by, nanotechnology becomes progressively influential in various fields of applications, from environmental to food industry, now even develop in biomedical field which shows great potential in the future clinics (Beloqui et al., 2016).

To date, there is still no detailed study of green synthesis of Fe₃O₄-NPs using biological routes and usage of Fe₃O₄-NPs in biomedical field. Therefore, this review was conducted to highlight the green biosynthesis of Fe₃O₄-NPs using plant extract and other biological materials. Then, application of Fe₃O₄-NPs, particularly biomedical application in drug delivery will be discussed for better understanding of their uses in this modern technology.

1.1

1.1 Superparamagnetic iron oxide nanoparticles (magnetite nanoparticles)

Iron oxides exist in many forms in nature, such as iron(III) oxide (FeO), hematite (α-Fe₂O₃) and maghemite (γ-Fe₂O₃). In fact, magnetite is the most popular and useful iron oxide which has been employed in various field of applications. Magnetite is a kind of mineral and it is one of the most common natural occurring iron oxide with chemical formula Fe₃O₄. The crystal structure of magnetite shows an inverse spinel pattern with alternating and tetrahedral-octahedral layers. This means that Fe²⁺ species of Fe₃O₄ occupy half of the octahedral lattice sites as a result of greater ferrous crystal field stabilization energy (CFSE). On the other hand, Fe³⁺ species occupy the other octahedral lattice sites and all the tetrahedral lattice sites (Blaney, 2007).

Besides, magnetite is also very well known as the strongest magnetic mineral on earth (Harrison et al., 2002). This fascinating characteristic attracts much attention from researchers all around the world. Magnetite has a property that it is ferromagnetic at room temperature and the Curie temperature is 850 K (Teja and Koh, 2009). However, the magnetic behavior of Fe₃O₄-NPs depends strongly on the synthesis method. Additionally, the size and morphology of magnetite crystal play an important role which influence the magnetic properties of magnetite (Lin et al., 2006; Song et al., 2012). Hence, optimum parameters of Fe₃O₄-NPs has to be ascertained for better application.

Superparamagnetic nanoparticles is so famous nowadays because of the properties possessed, where the nanoparticles are magnetized up to their saturation magnetization when an external magnetic field is applied, yet they will not show any magnetic interaction once the magnetic field is eliminated (Wahajuddin, 2012). Surprisingly, Fe₃O₄-NPs exhibit this interesting behavior too. Apart from that, Fe₃O₄-NPs are biocompatible, biodegradable and potentially non-toxic to human (Zhang et al., 2013; Zhao et al., 2009). These characteristics show a great potential of Fe₃O₄-NPs in future biomedical applications.

It is well recognized that Fe₃O₄-NPs are advantageous to our lives. However, different properties of Fe₃O₄-NPs contribute to their versatility in different applications. For example, the optimal size of nanoparticles is 50 nm in diameter for efficient endocytosis in drug delivery application (Bamrungsap et al., 2012). Therefore, a lot of synthesis methods have been reported which can synthesize Fe₃O₄-NPs with desired properties. For instance, co-precipitation method (Petcharoen and Sirivat, 2012; Shen et al., 2014), sol-gel method (Lemine et al., 2012), hydrothermal synthesis (Haw et al., 2010; Li et al., 2014b; Li et al., 2013a ), solid state synthesis (Paiva et al., 2015), flame spray synthesis (Kumfer et al., 2010), thermal decomposition (Chin et al., 2011), solvothermal (Luo et al., 2015) and so on. All these physical and chemical methods arouse numerous issues comprising high production cost, use of toxic chemicals and yield of hazardous by-products (Hussain et al., 2016). Thus, synthesizing nanoparticles using green method is introduced lately to cope with the problems that caused by conventional approaches.

As discussed, Fe₃O₄-NPs hold several fascinating characteristics, such as superparamagnetic behavior, biocompatible and biodegradable, hence numerous studies have been done in order to maximize the potential usage of Fe₃O₄-NPs in various fields of applications. The study of Fe₃O₄ nanofluid on thermal conductivity and viscosity with the presence of external magnetic source and electric field, has also gaining popular in heat transfer applications (Sheikholeslami and Sadoughi, 2017; Sheikholeslami and Shehzad, 2017, 2018; Sheikholeslami and Vajravelu, 2017 ). Fig. 1 shows the possible applications of Fe₃O₄-NPs to be used in the fields of catalyst (Azarifar et al., 2016; Gawande et al., 2013; Wang et al., 2015 ), water remediation (heavy metal ion removal) (Hardani et al., 2015; Venkateswarlu et al., 2014b; Venkateswarlu and Yoon, 2015b ), lithium ion battery (He et al., 2016; Liu et al., 2017), magnetic storage media (El Ghandoor et al., 2012), and last but not least, the biomedical applications (Kandelousi and Ellahi, 2015; Karimzadeh et al., 2017; Narayanan et al., 2011 ). All these researches give promising results and provide a platform for Fe₃O₄-NPs which their unique features offer tremendous potential for their vast application.

Applications of magnetite nanoparticles (Fe3O4-NPs).

1.2

1.2 Green biosynthesis

Generally, green synthesis of nanotechnology means the synthesizing of nanomaterials or nanoparticles without using hazardous chemicals that produce toxic by-products. In other words, green method is an eco-friendly technique to synthesize nanoparticles where it is not harmful to the environment and human health. It is true that conventional methods can fabricate nanoparticles in huge quantities with desired morphology and size. However, these methods require high cost production, complicated and outdated procedures (Patra and Baek, 2014). In contrast to the conventional chemical and physical methods, green synthesis has many benefits such as facile, simple manufacturing procedure, fast, economic and less waste production.

Green biosynthesis of nanoparticles employs the bottom-up approach where the metal atoms assemble to form clusters and then eventually the nanoparticles. The biological compounds present in green materials may act as both reducing and capping agents that can stabilize the nanoparticles during the synthesis process. This can control the size and shape of the nanoparticles which can be used in various applications. Fig. 2 shows the simple process of nanoparticles synthesis where the materials needed are metal salt (precursor) and green substrate only. Various parameters such as concentration of metal salt, concentration of green substrate, time and temperature for reaction and pH of the solution can be altered during the nanoparticles synthesis process in order to obtain properties that are needed for respective applications.

Green biosynthesized Fe₃O₄-NPs can possess better characteristics, such as higher biocompatibility and biodegradability, compared to physically synthesized Fe₃O₄-NPs. Hence, they can be utilized in biomedical application due to the special surface coating of green materials, which is not only non-toxic and biocompatible yet also allow targeted drug delivery with Fe₃O₄-NPs localization at particular area. Toxicity towards human body can be minimized because the green materials used for synthesizing Fe₃O₄-NPs are safe to be consumed, and thus it would be beneficial in biomedical applications. Besides, Fe₃O₄-NPs can conjugate with drugs, enzymes or proteins which can be directed to targeted tissue, organ or tumor with the aid of external magnetic field, or can be heated in alternating magnetic fields for hyperthermia treatment (Mahdavi et al., 2013a).

2 Plant extract

In this review, green biosynthesis of Fe₃O₄-NPs will be focused. Fig. 3 shows the green materials that have been used by researchers in synthesizing Fe₃O₄-NPs and will be discussed in detail. There are a lot of successful studies where Fe₃O₄-NPs can be synthesized using different biological routes, however plant extract is the most extensively used in green synthesis because it can be obtained easily, large-scale production, cost effective and environmental benign (Iravani, 2011). In addition, extracts from plants can act as reducing and stabilizing agents in the nanoparticles synthesis which might be due to the presence of phytochemicals. Phytochemicals are compounds that are produced by plant itself. Table 1 summaries different parts of plants in synthesizing Fe₃O₄-NPs, such as leaves, fruits, fruit peels, roots, seeds and etc. They contain a notable amount of phytochemicals such as flavonoid, xanthophylls, carotenoids, anthocyanins and phenolic acids which are believed to be participated in nanoparticle synthesis.

Materials of green biosynthesis of Fe3O4-NPs.

Table 1 Fe₃O₄-NPs synthesized using different part of plants.

Part	Name	Size range/Average size	Morphology	Saturation magnetization (M_s) value (emu/g)	References
Plant	Soya bean sprouts	∼8 nm	Spherical	37.1 at 300 K 44.7 at 1.7 K	Cai et al. (2010)
	Aloe vera	93–227 nm	Spherical	74.1–75.9	Ngernpimai et al. (2012)
	Aloe vera	∼6–30 nm	Agglomerated irregular	56.3–74.1 at 293 K	Phumying et al. (2013)

Marine plant	Sargassum muticum	18 ± 4 nm	Cubic	22.1	Mahdavi et al. (2013b)
	Kappaphycus alvarezii	14.7 ± 1.8 nm	Spherical	–	Yew et al. (2016)
	Padina pavonica	10–19.5 nm	Spherical	–	El-Kassas Hala et al. (2016)
	Sargassum acinarium	21.6–27.4 nm	Spherical	–	El-Kassas Hala et al. (2016)

Seed	Grape Seed Proanthocyanidin (GSP)	∼30 nm	Irregular shape	56.6 at 298 K	Narayanan et al. (2011)
	Syzygium cumini	9–20 nm	Agglomerated spherical	∼13.6 at r.t.	Venkateswarlu et al. (2014a)

Leaf	Carob	4–8 nm	Well monodisperse	–	Awwad and Salem (2012)
	Tridax procumbens	–	Irregular shape - rough surfaces	–	Senthil and Ramesh (2012)
	Artemisia annua	3–10 nm	Spherical	20.7 at 300 K	Basavegowda et al. (2014a)
	Caricaya Papaya	33 nm (from XRD)	Agglomerated plate like structure with coarsened grains and capsule like	–	Latha and Gowri (2014)
	Perilla frutescens	∼50 nm	Spherical	25.2 at 300 K	Basavegowda et al. (2014b)
	Euphorbia wallichii	10–15 nm	Spherical	23.1 at r.t.	Atarod et al. (2015)
	Green tea	5.7 ± 4.1 nm	Spherical	16.7 at 300 K	Xiao et al. (2015a)
	Zea mays L. (ear leaves)	–	Aggregated spherical	1.4	Patra et al. (2017)
	Sesbania grandiflora	25–60 nm	Agglomerated non-spherical	–	Rajendran and Sengodan (2017)
	Rubus glaucus Benth	40–70 nm	Aggregated Spherical	–	Kumar et al. (2016)
	Calliandra haematocephala	∼85.4–87.9 nm	Bead-like spherical	–	Sirdeshpande et al. (2018)
	Lagenaria siceraria	30–100 nm	Cubic	–	Kanagasubbulakshmi and Kadirvelu (2017)

Fruit peel	Plantain peel	30–50 nm	Spherical	15.8 at r.t.	Venkateswarlu et al. (2013)
	Punica Granatum	D = 40 nm L = above 200 nm	Rod	∼22.7	Venkateswarlu et al. (2014b)
	Rambutan	100–200 nm	Agglomerated, spinel	–	Yuvakkumar and Hong (2014)
	Ananas comosus	10–16 nm	Agglomerated spherical	21.7 at r.t.	Venkateswarlu and Yoon (2015a)
	Citrullus lanatus	<17 nm	Agglomerated spherical	28.4 at r.t.	Venkateswarlu and Yoon (2015b)
	Citrus aurantium	17–25 nm	Slightly elongated	All show no sizable hysteresis at r.t. (40–60)	Bano et al. (2016)
	Punica granatum		Slightly rod-shaped		Bano et al. (2016)
	Malus domestica		Spherical		Bano et al. (2016)
	Citrus limon		Spherical		Bano et al. (2016)

Fruit	Passiflora tripartita	18.2–24.7 nm	Spherical	∼13.2	Kumar et al. (2014a)
	Averrhoa carambola	1.9–3.1 nm	Spherical	31.3 at r.t.	Ahmed et al. (2015)
	Lemon	14–17 nm	Spherical	31.4–61.8 at r.t	Bahadur et al. (2017)
	Couroupita guianensis	17 ± 10 nm	Spherical	0.1 at r.t	Jha (2017)

Root	Mimosa pudica	60–80 nm	Agglomerated rough spherical	55.4 at r.t.	Niraimathee et al. (2016)

Stolon	Potato	40 ± 2.2 nm	Cubic	28.8	Buazar et al. (2016)

Waste	Tea residue	5–25 nm	Cuboid/pyramid	6.9 at r.t.	Lunge et al. (2014)
	Rice straw	9.9 ± 2.4 nm	Aggregated spherical	–	Khandanlou et al. (2013)
	Coffee waste hydrochar	10–40 nm	Spherical	–	Khataee et al. (2017)
	Acacia mearnsii (biochar)	18–35 nm	Uneven	3.2 memu/g at 300 K	Khan et al. (2015)

Gum	Arabic gum	70–80 nm	Spherical	44.2 at r.t.	Horst et al. (2017)

Abbreviations: D, diameter; L, length; r.t., room temperature.

2.1

2.1 Plant

Based on the table, different size, shape and magnetic properties of Fe₃O₄-NPs can be synthesized using different types of plants, and these physical characteristics can work effectively at different uses. Ngernpimai et al. and Phumying et al. studied on the Fe₃O₄-NPs synthesized by using Aloe vera but with different conditions. Fe₃O₄-NPs prepared by Ngernpimai et al. were passed through the serial centrifugation steps and the size of spherical nanoparticles decrease with increasing degree of centrifugation (Ngernpimai et al., 2012). However, with various reaction time and temperature controlled by Phumying et al., a smaller size and irregular shape of nanoparticles were produced (Phumying et al., 2013).

2.2

2.2 Marine plant

Marine plant, which is also known as seaweed or algae, can be utilized to synthesize Fe₃O₄-NPs. Seaweed is important to marine life because seaweed provides food and habitat where it can be found in a lot of countries in South-East Asia. It is well known that seaweed is a food source in our daily life due to their abundance of lipids, minerals, some vitamins and particular bioactive substances, such as proteins, polyphones and polysaccharides which have the potential in medical uses. Besides, marine algae can be divided into two groups, which are microalgae and macroalgae. Macroalgae (seaweed) are plant-like organisms and normally they are used in nanoparticles synthesis. The phytochemicals presence in seaweed can act as metal-reducing agents and capping agents to supply a robust coating on the metal nanoparticles in a single step. Mahdavi et al. studied on the brown seaweed (Sargassum muticum) in synthesizing Fe₃O₄-NPs. The synthesis procedure was very simple by mixing FeCl₃ solution to the brown seaweed extract, where Fe₃O₄-NPs were immediately produced with the reduction process. The major components such as sulphate, hydroxyl and aldehyde group presence in seaweed may lead to the reduction of Fe³⁺ and stabilize the nanoparticles. Meanwhile, the pH of the solution decreased during the synthesis process, which indicated the participation of –OH group in the reduction process. There is also a possibility that the sulphate group reduce the metal ions by oxidation of aldehyde groups in the molecules to carboxylic acids. The cubic shape of Fe₃O₄-NPs were produced in this study with particle size of 18 ± 4 nm. Saturation magnetization value was 22.1 emu/g with negligible coercivity symbolize the superparamagnetic properties of Fe₃O₄-NPs.

2.3

2.3 Leaf

Most of the researchers used leaves to study the green synthesis of Fe₃O₄-NPs. Rajendran et al. studied on the preparation of Fe₃O₄-NPs by using Sesbania grandiflora leaf extract to be used as a photocatalyst for chemical oxygen demand (COD) removal. The preparation steps were very simple where the ferrous chloride (FeCl₂) was added to the heated leaf extract and stirred. The paste form sample was underwent calcination at 500 °C for 2 h to remove all the impurities and eventually the nanoparticles were stored. The authors found that by raising the concentration of leaf extract, the rate of reduction and the reduction of precursor into nanoparticles increased. The maximum amount that they used was 20% of leaf extract and it was the optimum condition which analyzed by UV–visible spectroscopy (UV–vis). Besides, the leaves of Andean blackberry (ABL) which is also known as Rubus glaucus Benth, can also be used to synthesize Fe₃O₄-NPs. Kumar et al. added sodium hydroxide (NaOH) solution to adjust the pH of the mixed solution of leaf extract and iron precursor solution to pH 10–11. The mix solution was stirred at around 75–80 °C until black color solution was observed. The resulting nanoparticles were centrifuged thrice at 5000 rpm and washed for several times, then nanoparticles were dried and stored. The synthesized Fe₃O₄-NPs were found to be spherical in shape and aggregating in nature with size range from 40 to 70 nm. This article shows that the polyphenolic compounds present in the leaf extract are most probably responsible to the formation of clusters and aggregation of the nanoparticles which act as capping and stabilizing agents. These synthesized Fe₃O₄-NPs has been used as an efficient photocatalyst for the degradation of methylene blue, congo red and methylene orange and play a role as mild antioxidant agent.

2.4

2.4 Fruit peel

Fruit peel is the skin of a fruit which protect the flesh of fruit from the environment and also microbes. Fruit peels can be used as natural fertilizer because most of them are too thick which cannot be eaten by human. However, researchers always make use of natural sources and study about fruit peel in synthesizing nanoparticles. Plenty of favorable studies had been done by using fruit rind extract to synthesize Fe₃O₄-NPs. Venkateswarlu et al. researched on the fruit peel pulp extract of Ananas comosus (pineapple) and Citrullus lanatus (watermelon) in synthesizing Fe₃O₄-NPs. Both of the experiment showed that the synthesized Fe₃O₄-NPs were spherical in shape with an average size of around 17 nm. Fig. 4 showed the TEM image of Fe₃O₄-NPs synthesized using watermelon peel pulp extract which were agglomerated owing to the presence of hydroxyl groups from the extract. The synthesized Fe₃O₄-NPs also possessed magnetic properties with saturation magnetization of 21.7 emu/g and 28.4 emu/g for pineapple and watermelon respectively. The surface of Fe₃O₄-NPs were further functionalized with ligand in order to utilize the synthesized Fe₃O₄-NPs in heavy metal removal effectively, which were cadmium(II) for pineapple and mercury(II) for watermelon. By comparing to other reported research, the results showed that surface modified Fe₃O₄-NPs were one of the best result in adsorption capacity. The advantages of employing ferromagnetic property of Fe₃O₄-NPs are the simple separation process from large-volume samples by using an external magnetic field instead of filtration or centrifugation, thus the isolation process is rapid and easy. Besides, the nanoparticles also demonstrates easy recyclability without significant loss of heavy metal removal efficiency.

TEM image of (a) DHPCT@Fe3O4 MNPs and (b) the particle size histogram. Reproduced with permission (Venkateswarlu and Yoon, 2015b).

2.5

2.5 Seed

In addition, seeds from fruit are kind of fruit waste material and they can act as green solvent, reducing and capping agent in synthesizing Fe₃O₄-NPs. There is a study done by Venkateswarlu et al. who utilized Syzygium cumini (S. cumini) seed to produce Fe₃O₄-NPs. During the green synthesis process, S. cumini extract acts as reducer because there is carbohydrates and polyphenols which reduce Fe³⁺ salt to Fe₃O₄ by simple reduction reaction. In this study, XRD was performed to study the crystallinity and purity of the Fe₃O₄-NPs. However, Raman spectroscopy characterization was also done to confirm the formation of Fe₃O₄ without presence of any impurity. The significant peak at around 670 cm⁻¹ indicated the A_1g modes of Fe₃O₄. Besides, peaks that can be found at about 538 (T_2g), 306 (E_g) and 194 cm⁻¹ (T_2g) were also the characteristic bands of Fe₃O₄. Brunauer, Emmett, Teller (BET) surface area analysis was studied and the result showed that the surface area was 3.517 m²/g. The pore size distribution revealed that majority of the mesoporous had a size of approximately 2 nm. Hence, this green synthesized mesoporous Fe₃O₄-NPs have potential in various applications, such as biomedical, catalysis and separation field.

2.6

2.6 Fruit

Bahadur et al. had done a study on using lemon juice to synthesize Fe₃O₄-NPs. Lemon juice was chosen to act as the source of citric acid for controlling size and surface capping purpose. The modified co-precipitation technique can be used to produce water dispersible Fe₃O₄-NPs which is the fundamentals for nanoparticles to be used in biomedical applications. The size of synthesized Fe₃O₄-NPs can be controlled by tuning the amount of reducing agent, where 11 nm and 15 nm of Fe₃O₄-NPs were fabricated in this study. Based on XRD results, there were 7 significant peaks can be observed, which were located at 2θ = 30.07°, 35.51°, 43.33°, 53.44°, 57.18°, 62.88°, and 74.02°. All these peaks corresponded to the purity of synthesized Fe₃O₄-NPs. Besides, optical properties of Fe₃O₄-NPs was analyzed using UV–vis spectrometer. The optical energy band gap varied from 2.6 eV (15 nm) to 2.8 eV (11 nm) for direct transition and 1.7 eV (15 nm) to 1.82 eV (11 nm) for indirect transition. This indicates that the energy band gap of Fe₃O₄-NPs depended on the particle size. Thus, the direct and indirect energy band gap values of Fe₃O₄-NPs were in the range of 1.7–2.8 eV, and these band gap values showed that the Fe₃O₄-NPs were grouped as semiconductor.

2.7

2.7 Stolon and root

According to recent study, there are a few novel research where the part of plants have never been used in Fe₃O₄-NPs synthesis, such as stolon (potato), root and gum. Buazar et al. studied the mechanism of Fe₃O₄-NPs formation using potato. Potato is a tuberous crop and it is rich in carbohydrates. Starch-rich potato extract plays an important role as capping and reducing agents in the formation of Fe₃O₄-NPs. The reaction started with addition of NaOH and elicited the oxidation of starch in alkaline solution. These oxidations produced electrons that reduced Fe⁺ ions to Fe⁰ nanoparticles. Meanwhile, the starch primary hydroxyl groups were oxidized to carboxyl group. Moreover, the problem of aggregation of nanoparticles in water was overcome as Fe₃O₄-NPs dissolved in potato extract easily. Thus, enhanced dispersion and steric protection of mediated Fe₃O₄-NPs through multifunctional starch-rich potato extract would reduce the particle size (40 ± 2 nm). Furthermore, Niraimathee et al. researched on the production of Fe₃O₄-NPs by using Mimosa pudica root extract. The sample was analyzed by UV–vis, where the presence of iron oxide was confirmed at the sharp absorbance peak of 294 nm. The magnetic properties of Fe₃O₄-NPs were enhanced by controlling the pH of the solution to pH 9 with the addition of NaOH. The VSM result showed that the M_s value of the synthesized Fe₃O₄-NPs was found to be 55.40 emu/g, which is considered high compared to other studies. It was observed that the magnetization decreased from the plateau value and got to zero while the magnetic field was removed. Thus, this phenomenon indicated that the Fe₃O₄-NPs possessed superparamagnetic behavior because the Fe₃O₄-NPs correlated with the single-crystal domain, where only one orientation of the magnetic moment was shown.

2.8

2.8 Gum

On the other hand, study of using gum Arabic (GA) to produce Fe₃O₄-NPs is also another successful research. Horst et al. studied about the possible mechanism of the Fe₃O₄-NPs formation. There are 2 types of interactions expected to happen between the polysaccharides from the gum and iron oxide nucleus, which are electrostatic and/or hydrophobic interactions. Another feasibility is the formation of complex, due to the bridging from biopolymer to the Fe₃O₄ nucleus. In the initial stage of synthesis process, the media is acidic owing to the iron salt precursor in contact with polymeric moieties. NH₄OH is then added to increase the pH and the first Fe₃O₄ nucleus is produced. In such conditions, Fe₃O₄ and GA show opposite surface charge. Besides, it is high possible that electrostatic interaction occur where FTIR data confirmed the interaction between carboxylic groups of GA and hydroxyl groups of Fe₃O₄ was via hydrogen bonding. As both polymer and iron oxide have negative charge at the higher pH of Fe₃O₄, steric interactions might occur too which responsible for the GA binding. Steric interactions is crucial to illustrate the stabilization mechanism of Fe₃O₄-NPs by the polymeric moieties. The hydrophilic nature of GA-Fe₃O₄ can be explained by thinking that the GA chains bind to the Fe₃O₄ in the way that charged (mostly negative) functional groups remained surface exposed, showing electrostatic repulsion between nanoparticles. This situation may take place if not all the functional groups of the biopolymer are interacting with the Fe₃O₄ surface groups.

2.9

2.9 Plant waste

Furthermore, the applications of Fe₃O₄-NPs might depend on the substrate used as well. Rice straw, fruit peels and coffee waste hydrochar are natural waste which we might think they are worthless. But, the Fe₃O₄-NPs synthesized by waste can be useful too. Based on studies, Fe₃O₄-NPs prepared by tea residue, coffee waste hydrochar and corn Zea mays can be used in arsenic removal (Lunge et al., 2014), Acid Red 17 (azo dye) removal (Khataee et al., 2017) and drug delivery applications (Patra et al., 2017) respectively. All these studies show that Fe₃O₄-NPs capped with green substrate have a promising potential in various kind of applications in the future.

3 Other green materials

Green biosynthesis is not restricted to plant synthesizing nanoparticles only, yet utilization of other green materials such as natural polymer, amino acid, vitamin, enzyme and fungi, assist in Fe₃O₄-NPs synthesis too. Table 2 shows some of the green substrates in synthesizing various size and shape of Fe₃O₄-NPs.

Table 2 Fe₃O₄-NPs synthesized by other green substrates.

Green substrate	Name	Size range/average size	Morphology	Saturation magnetization (M_s) value (emu/g)	References
Glucose	α-D-glucose	∼12.5 nm	Roughly spherical shape	71.3 at 5 K 60.5 at 300 K	Lu et al. (2010)
	Maltose	12.1 ± 2.1 nm	Spherical	43.1 at r.t.	Demir et al. (2013)
	Sucrose	4–16 nm	Spherical	14.8–29.6 at 7 KOe	Sun et al. (2009)
	α-D-maltose	9.7 ± 1.0 nm	Spherical-like, rod-like, and dendritic nanostructure with some extent of agglomeration	37.4	Demir et al. (2014)
	α-D-mannose	13.1 ± 0.3 nm		59.1
	α-D-galactose	12.4 ± 0.3 nm		58.1
	α-D-lactose	3.8 ± 0.21 nm		22.0
	D-glucose	Twig = 10–20 nm L = 10–100 nm	Coral like	–	Qin et al. (2011)

Vitamin	Nicotinic acid (N. acid)	0 g N.acid L = 270 nm, D = 20 nm 1g N.acid L = 300 nm, D = 30 nm 2.5 g N.acid L = 350 nm, D = 40 nm	Nanorod	0 g = 55.0 1 g = 30.0 2.5 g = 4.0	Attallah et al. (2016)
	Ascorbic acid	15 ± 4 nm	Irregular	–	Nene et al. (2016)

Enzyme	Urease	19 ± 5 nm Thickness  < several nm L > 100 nm Section = 10 ± 4 nm	60 °C = nanosphere 40 °C (2h) = nanosheets 40 °C (1h), 60 °C (1h) = nanorods	52.6 27.6 15.8	Shi et al. (2014)

Fungi	Yeast	16 nm	Wormhole-like	22.1 at r.t.	Zhou et al. (2009)

Natural polymer	Sodium alginate	27.2 nm	Uniform and spherical	62.1	Gao et al. (2008)
	Chitosan	22.0 ± 7.8 nm	Nearly Spherical	65 at r.t.	Shrifian-Esfahni et al. (2015)
	Agar	20–30 nm	Non spherical aggregated	18.7–25.3 at r.t.	Hsieh et al. (2010)

Polysaccharides	Starch	Less than 10 nm	Spherical	36.2 at 300 K	Chang et al. (2011)
	Carboxymethyl cellulose sodium	More than 10 nm	Spherical	35.8 at 300 K	Chang et al. (2011)
	Agar	More than 10 nm	Spherical	20.4 at 300 K	Chang et al. (2011)
	Pectin	5–18 nm	Cubic	53–54 at 300 K	Namanga et al. (2013)

Amino acid	Arginine	Fe/Ar (1:1) = 18–26 nm Fe/Ar (1:2) = 9–15 nm	Spherical	51.7 at 300 K 39.9 at 300 K	Wang et al. (2009)
	L-arginine	2–15 nm	Mixture of nanorods and rounded particles	∼35–50	Theerdhala et al. (2010)
	L-arginine	13 nm	Irregular	49.9 at r.t.	Lai et al. (2010)
	L-methionine	4.6 ± 2.6 nm	Spherical	65 at r.t.	Belachew et al. (2016)
	L-serine	5.9 ± 1.6 nm	Spherical	85 at r.t.	Belachew et al. (2017)
	L-lysine	4.0 nm	Spherical	–	Park et al. (2009)
	L-glutamic acid	5.5 nm	Spherical	–	Park et al. (2009)
	L-cysteine	38 ± 5 nm	Spherical	66.7 at 300 K	Cao et al. (2014)

Organic acid	L-(+)-Tartaric acid	19.5 ± 4.2 nm	Spherical	∼ 60 at r.t.	Hadian-Dehkordi and Hosseini-Monfared (2016)

Clay	Montmorillonite	8–13 nm	Spherical	12.1–32.4 at r.t.	Kalantari et al. (2014)

Others	Perlite (soil)	Less than 100 nm	Irregular	14.7 at r.t.	Shirkhodaie et al. (2016)
	Usnic acid	10 nm	Spherical	–	Grumezescu et al. (2013)

Abbreviations: L, length; D, diameter; r.t., room temperature.

3.1

3.1 Glucose

As predicted, shape, particle size and magnetic properties of synthesized Fe₃O₄-NPs are different based on different kinds of green materials used, just as Table 1. This might due to the distinct condition used during the synthesis procedure and it depends on the properties of green substrates possessed as well. According to Table 2, glucose is the most popular to be used in synthesizing Fe₃O₄-NPs. Demir et al. researched the effect of 5 different types of saccharides on the characteristics of synthesized Fe₃O₄-NPs, including mannose, maltose, lactose, galactose and fructose. All the saccharides played a role as bifunctional agents (both as the precursor of the reducing agent and the source of coating agent), except for fructose. Fructose did not show any characteristics of Fe₃O₄ because fructose is a non-reducing monosaccharide. Based on TEM results, the particle size of synthesized Fe₃O₄-NPs varied from 3.8 to 13.1 nm and the morphology of the nanoparticles were a mixture of slightly agglomerated spherical-like, rod-like, and dendritic nanostructure. The magnetization measurements were also carried out to study the magnetic properties of synthesized Fe₃O₄-NPs. Fe₃O₄-NPs that prepared with galactose, mannose and maltose possess superparamagnetic characteristics. However, saturation magnetization value of Fe₃O₄-NPs synthesized with maltose (M_s ∼ 40 emu/g) was lower than galactose and mannose (M_s ∼ 60 emu/g). The Fe₃O₄-NPs prepared by lactose along with its low crystallinity resulted in weaker magnetization (M_s = 20 emu/g), while for Fe₃O₄-NPs prepared by fructose, the magnetization was very weak even at high fields. This is explained by the crystallinity of samples which analyzed using XRD. The magnetization depends on the crystallinity of nanoparticles where the higher the crystallinity of Fe₃O₄-NPs, the higher the magnetization. However, these magnetization is smaller than that of bulk particles (∼92 emu/g). This is due to the presence of surface spin disorder and spin canting effects, which happen when the surface to volume ratio of particle increases while the particle size decreases. As a result, the saccharides coated Fe₃O₄-NPs have a potential in biomedical applications such as magnetic resonance imaging.

3.2

3.2 Polysaccharides

On the other hand, Chang et al. did a study on the synthesis of superparamagnetic Fe₃O₄-NPs using polysaccharides, including soluble starch, carboxymethyl cellulose sodium (CMC) and agar. These three polysaccharides acted as stabilizer during the synthesis procedure to enhance the stability, biocompatibility and biodegradability. TEM images showed that the approximately 10 nm spherical Fe₃O₄-NPs were capped by polysaccharide. Polysaccharides could form hybrids with metal ions owing to their high number of coordinating functional groups (hydroxyl and glucoside groups). Hence, most of the iron ions were associated closely with polysaccharides molecules, where nucleation and initial crystal growth of Fe₃O₄-NPs might then occur preferentially on polysaccharides. Besides, polysaccharides present dynamic supramolecular associations facilitated by inter- and intra-molecular hydrogen bonding, which play a role as template for the nanoparticles growth. The size of Fe₃O₄-NPs synthesized by soluble starch is less than 10 nm, whilst the other two showed a larger size. This phenomenon might be related to the structure of polysaccharides; in aqueous state, soluble starch is mainly composed of branched amylopectin, whereas CMC and agar contain more linear-polysaccharide structure. So, soluble starch has more interactions with iron ions than CMC and agar, which caused more restriction on the growth of Fe₃O₄-NPs. It is known that the magnetization of Fe₃O₄ is very sensitive to the microstructure. Fe₃O₄ particles are called single-domain particles when the Fe₃O₄ particles are smaller than the critical size. Thus, as the particle size decreases below the critical single-domain size, the particles exhibit superparamagnetic attributes. Nevertheless, when the magnetizations of particles are random (without any definite direction), each of the particles suppresses the exchange interaction between the particles. This lack of hysteresis is very crucial for recognition of a sample with superparamagnetic properties. VSM results showed that all the Fe₃O₄-NPs prepared by soluble starch, CMC and agar exhibited good saturation magnetization, even though Fe₃O₄-NPs synthesized by CMC and agar had slightly larger hysteresis loop and coercivity.

3.3

3.3 Clay

Clay is a natural soil or rock material which commonly used in making pottery and some constructions products, such as bricks and tiles. However, clay can be used as the supporting materials for nanoparticles synthesis. Kalantari et al. synthesized Fe₃O₄-NPs by using montmorillonite (MMT) as a solid support. The shape and size of Fe₃O₄-NPs can be controlled by altering the amount of NaOH (1.50–12.50 mL) as reducing agent in the medium. Fe₃O₄-NPs were prepared through coprecipitation by addition of base to Fe²⁺ and Fe³⁺ salts solution. The chemical reaction equation can be written as Fe²⁺/Fe³⁺/MMT + 8OH⁻ → Fe₃O₄/MMT + 4H₂O. The presence of Fe₃O₄ can be confirmed by using XRD analysis. However, XRD analysis also showed that the basal spacing expanded from 1.47 to 2.85 nm by increasing the weight percent (wt%) of Fe₃O₄-NPs content in MMT matrix from 1.0 to 12.0 wt%. The 2θ° of XRD patterns shifted from 8.75° to 7.46°, where the basal spacing of pristine MMT was 1.24 nm at 2θ°, 8.83°. This indicated that the iron ions might penetrate into the interlayer space of MMT via ion-exchange and then were reduced to Fe₃O₄-NPs by addition of NaOH. Hence, the interlayer space might act as microreactor and size controller. Besides, the intensities of XRD peak (2θ° = 8.83° to 7.46°) decreased gradually, and the highly ordered parallel lamellar structure of MMT was disrupted by the formation of Fe₃O₄-NPs. Based on TEM results, the Fe₃O₄-NPs were in the interlayer space or on the surface of MMT. The size of Fe₃O₄-NPs decreased as the amount of NaOH increased. The charged Fe₃O₄-NPs are bounded to the surface of MMT via electrostatic force owing to the high density of ion-exchange sites on MMT. The Fe₃O₄-NPs aggregate in the MMT is in direct correlation with the smaller primary nanoparticles dimension. Moreover, the magnetic properties of Fe₃O₄/MMT NCs increased from 12.1 to 32.4 emu/g as the Fe₃O₄ content increased, which indicated more Fe₃O₄ were caged in the MMT layers. Besides, LAPONITE is a kind of nanoclay smectite which has layered structure similar to natural hectorite. Ding et al. had synthesized LAPONITE®Fe₃O₄-NPs (LAP-Fe₃O₄-NPs) via co-precipitation method for in vivo magnetic resonance imaging of tumors. LAP-Fe₃O₄-NPs possessed good colloidal stability, which is about 2-fold increase of T₂ relaxivity than naked Fe₃O₄-NPs. The XRD patterns of LAP, Fe₃O₄-NPs and LAP-Fe₃O₄-NPs were shown in Fig. 5a, where it can be noticed that the intensity of peak decreased as a result of Fe₃O₄-NPs loading. Fig. 5b is the FTIR spectra of LAP, Fe₃O₄-NPs and LAP-Fe₃O₄-NPs. The peaks at 586–598 cm⁻¹ of Fe₃O₄-NPs and LAP-Fe₃O₄-NPs corresponded to the Fe-O vibration of magnetic core, and the Si-O stretching vibration band of LAP in LAP and LAP-Fe₃O₄-NPs were located at 1016–1019 cm⁻¹. Both of the results proved that the synthesized nanomaterials are composite of LAP and Fe₃O₄-NPs.

XRD pattern (a) and FTIR spectroscopy (b) of LAP, Fe3O4, and LAP-Fe3O4-NPs. Reproduced with permission (Ding et al., 2016).

4 Biomedical applications of Fe₃O₄-NPs

Green synthesized Fe₃O₄-NPs are capable to be used in various applications as reported in literature. However, biomedical applications of Fe₃O₄-NPs are more concerned by experts nowadays as human health is threaten due to several issues, such as pollutions, processed food industry, weather change and unbalance lifestyle. These issues may cause plenty of serious diseases, and one of the most popular diseases is cancer. Fig. 6 summarize the potential biomedical applications of Fe₃O₄-NPs, including antibacterial, tissue engineering and hyperthermia. They also play important roles as magnetic resonance imaging (MRI) contrast agent (Li et al., 2014a; Sun et al., 2016), photothermal therapy of tumors (Li et al., 2015), magnetofection agent and can be used for magnetic bioseparation and DNA molecule detection.

Examples of biomedical applications of Fe3O4-NPs.

It is well known that silver nanoparticles have excellent antibacterial properties. However, based on several studies, Fe₃O₄-NPs can act as an antibacterial agent too. Patra et al. studied on the green synthesized Fe₃O₄-NPs by using corn ear leaves with the application of antibacterial (Patra et al., 2017). Antibacterial activity was determined by standard disc diffusion method using five different foodborne bacteria, which were Bacillus cereus ATCC 13061, Escherichia coli ATCC 43890, Listeria monocytogenes ATCC 19115, Staphylococcus aureus ATCC 49444, and Salmonella typhimurium ATCC 43174. The results revealed that Fe₃O₄-NPs (25 µg) and standard antibiotics (kanamycin and rifampicin at concentration 5 µg/disc) did not exhibit any antibacterial activity if tested separately with five foodborne pathogenic bacteria. Antibacterial activity can be observed when Fe₃O₄-NPs mixed with standard antibiotics kanamycin where all the foodborne pathogenic bacteria showed inhibition zones in the range of 9.87 and 18.86 nm in diameter. Besides, when Fe₃O₄-NPs combined with rifampicin, the antibacterial activity can only be observed against Staphylococcus aureus ATCC 49444, with inhibition zone of 20.90 mm. This suggests that the Fe₃O₄-NPs combined with conventional antibiotics can exert synergistic effect, which reduce the doses of antibiotics and thus decrease the phenomenon of resistant bacterial and mammalian cell toxicity.

Another potential biomedical application of Fe₃O₄-NPs is hyperthermia treatment. Horst et al. had characterized the Gum Arabic synthesized superparamagnetic Fe₃O₄-NPs with magnetocalorimetric assays to study the potential of their formulations for magnetic hyperthermia therapy under radiofrequency fields. Magnetocalorimetric assays were carried out in a wide range of frequency and amplitude. Specific absorption rate (SAR) was 218 W/g Fe, which was identified at field frequency of 260 kHz and the amplitude of 52 kA/m. This results revealed the feasibility of the Fe₃O₄-NPs to be applied in tumor ablation treatments. By using the linear response theory and restricting field parameters to the accepted biomedical window, it is found that the estimated maximum useful value is 74 w/h Fe at amplitude of 12 kA/m and field frequency of 417 kHz. On top of that, the fascinating physicochemical properties of these Fe₃O₄-NPs such as small size, polydispersity and stability in aqueous colloid suspensions transformed the Fe₃O₄-NPs to an efficient device for hyperthermia treatment (Horst et al., 2017).

Tissue engineering is also one of the important applications in biomedical field in repairing, replacing or regenerating parts of or whole tissues. According to the research done by Gil et al. (2015), they had constructed cell sheets using Fe₃O₄-NPs with the presence of magnetic force. It is observed that the magnetically labelled cells moved towards the magnet and gathered on the bottom of the nonadherent plate in situ, which then constructing a sheet-like structure, in the presence of external magnetic field without using artificial polymer scaffolds. It is reported that the cell sheet constructs were not adhered to the culture plate, which can be easily removed from the surface of culture plate without utilizing any detachment procedure. Besides, nanospheres showed better internalization efficiency, and the labelled cells exhibit strong transportation reaction with external magnetic fields, compared to nanorods. The results of this research confirm the evolution of magnetic-responsive nano-biomaterials which applicable in tissue engineering or cellular therapies.

Fe₃O₄-NPs are well known with its superparamagnetic properties where they are suitable for magnetic bioseparation, especially in cell separation. Based on the research reported by Lu et al. (2014), they had synthesized polyethylenimine (PEI)-coated Fe₃O₄-NPs for the separation and enrichment of lung cancer cell from sputum samples, and then cytopathology analysis was performed. Exfoliative cytopathology analysis gave a result which the percentage of positive cells increased from 6.3% in untreated sputum samples to 38.5% in sputum samples treated with the PEI-coated Fe₃O₄-NPs. This outcome presents the promising application of PEI-coated Fe₃O₄-NPs in enrichment of lung cancer cells from sputum for cytopathology analysis.

Furthermore, Fe₃O₄-NPs can be utilized as magnetofection agent. In this case, magnetofection is developed where the nucleic acid drugs combine with superparamagnetic iron oxide nanoparticles to form magnetoplexes. The production of magnetoplexes can be quickly accumulated on the targeted sites with the aid of additional magnetic field and as a consequences, the transfection efficiency can be enhanced. Liu et al. reported their research where DMSPION-G6/DNA/PEI ternary magnetoplexes was prepared for in vitro gene delivery (Liu et al., 2011). The results showed that the DMSPION-G6/DNA/PEI ternary magnetoplexes exhibited enhanced transfection efficiencies in three cell lines, including COS-7, 293 T and HeLa cells. By utilizing DMSPION-G6/DNA/PEI ternary magnetoplexes, the incubation time needed was shorten and DNA dose required decreased when magnetic field was employed. This revealed that high-level transgene performance was accomplished, which time and dose issues were resolved when magnetofection was used. Another result from Prussian blue staining analysis showed that addition of magnetic field could accumulate the magnetoplexes rapidly to the surface of target cells and then improved the magnetoplexes uptake by the cells. Xiao et al. reported that Fe₃O₄-NPs can be functionalized with plasmid DNA to develop nanohybrid systems for nucleic acid therapy. Nanohybrids were produced by merging the dendrimers complexes, plasmid DNA (dendriplexes) and poly(styrene) sulfonate-coated Fe₃O₄-NPs via electrostatic interactions. The outcome of the study showed that the nanohybrids can transfect NIH 3T3 cells, and the level of gene expression was highly dependent on the dendrimer generation, plasmid DNA concentration and the amine to phosphate group ratio. The best system was found out to be the dendriplex-coated Fe₃O₄-NPs formed by generation 6 dendrimers at an amine to phosphate group ratio of 10. The analyzed results revealed that the nanohybrids possess the potential as an effective gene delivery nanomaterials (Xiao et al., 2015b).

Moreover, Fe₃O₄-NPs can be employed in deoxyribonucleic acid (DNA) molecule detection application. Sun et al. fabricated a chemiluminescence (CL) biosensor for ultrasensitive determination of DNA (Sun et al., 2017). Core-shell Fe₃O₄@SiO₂ – graphene oxide (Fe₃O₄@SiO₂@GO) polymers were prepared in this study. The principle of this CL biosensor was the adsorption recognition function between Fe₃O₄@SiO₂@GO polymers and DNA. The results of the adsorption capacity of Fe₃O₄@SiO₂@GO achieved the maximum value of 3.24 × 10⁻⁹ mol/g. The binding process of the polymers and DNA comply with the Langmuir isotherm equation and pseudo second order sorption kinetics. The selectivity and sensitivity of DNA detection was notably enhanced by applying the CL technique, where the reactions of complementary base pair between Fe₃O₄@SiO₂@GO-DNA and complementary nucleotide chains were studied. Based on the promising results obtained, the Fe₃O₄@SiO₂@GO-DNA-CL biosensor is applicable in diagnosing human genetic diseases and provide advisable treatment.

Lastly, the potential biomedical application of Fe₃O₄-NPs via targeted drug delivery system will be discussed. There are a few types of drugs can be integrated with Fe₃O₄-NPs, such as anticancer and anti-inflammatory. One of the studies showed that indomethacin (a poorly water-soluble non-steroidal anti-inflammatory drug) conjugated with Fe₃O₄-NPs incorporated into electrospun nanofiber composites of two cellulose derivatives. The results showed that the composite nanofiber exhibit superparamagnetism at room temperature, and the presence of Fe₃O₄-NPs in the nanofiber did not affect the drug release process, which was found to be mainly controlled by the polymeric carrier matrix properties (Wang et al., 2012). Therefore, the magnetic drug loaded nanofibers have a potential in medicine applications, particularly targeted drug delivery in digestive system.

5 Utility of Fe₃O₄-based nanoparticles as drug delivery vehicles

Lately, human health is threatened with miscellaneous diseases and new drugs have to be invented to solve this crucial issue. Hence, Fe₃O₄ is gaining popularity in drug delivery system due to the excellent magnetic properties possessed which is also known as superparamagnetism. Besides, in order to utilize the Fe₃O₄-NPs as drug delivery vehicle, they have to exhibit a few significant properties which cannot be neglected and will be discussed in this section.

5.1

5.1 Criteria of Fe₃O₄-based nanoparticles to be used in drug delivery

5.1.1

5.1.1 Superparamagnetic

The basic requirements for Fe₃O₄-based nanoparticles to be used in drug delivery application are presented in Fig. 7, comprising magnetic properties, shape, size and surface characteristics, which are the important matters in this section. First, Fe₃O₄-based nanoparticles are well known as magnetic nanoparticles and they can be guided easily to a specific site by the aid of magnetic field that improve its local concentration. This is one of the advantages which can enhance the drug delivery efficacy as well as reduce the side effects of chemotherapeutic drugs. In addition, superparamagnetic behavior is a must for magnetic nanoparticles to exert its maximum effect in the application of drug delivery. Actually, superparamagnetic nanoparticles possess zero net magnetic moment without the presence of external magnetic field. This can be a great benefit in tumor targeting as the propensity of self-aggregation is minimized outside the targeted site (Chertok et al., 2008). Thus, the anticancer drug can be delivered perfectly to the desired region without damaging healthy tissues.

Criteria of nanocarrier in drug delivery application.

5.1.2

5.1.2 Shape of nanoparticles

Furthermore, shape of Fe₃O₄-based nanoparticles is one of the important features that has to be taken into consideration in drug delivery. The issue that researchers concern the most is to prolong the nanoparticles in targeted site as well as perform great cellular cytotoxicity. Besides, the blood circulation time, cellular uptake and biodistribution may change based on the shape of nanoparticles. Plenty of studies had been done to research on the nanoparticles shape particularly for anticancer drug delivery. Filomicelles is the one which found to own higher anticancer drug encapsulation capacity and apoptotic efficiency in comparison with spherical micelles. One of the studies tested an in vivo antitumor activity of various shapes of micelle, and the results showed that filamentous micelles exhibit the highest DOX loading capacity and encapsulation efficiency. Besides, the filamentous DOX-loaded micelles reveal the highest safety to human body and the greatest therapeutic effects to artificial solid tumors (Chen et al., 2012). There are also many other shapes of nanoparticles that had been synthesized in drug delivery study, such as rod shape, worm shape and bead shape. In literature, non-spherical and rod-shaped nanoparticles possess a longer blood circulation time compared with the spherical nanoparticles. This might due to the rod-shaped particles cause a lower phagocytic activity of macrophages than spherical ones (Wahajuddin, 2012). However, spherical nanoparticles exhibit significant advantages than rods, according to the research with sub-100 nm nanoparticles. The spherical nanoparticles can provide an even surface coating and conjugation of ligands in surface modification, which mean more drug can be loaded on the surface of nanoparticles for better drug release at the targeted site and hence show a greater cellular toxicity. Based on literature, most of the nanoparticles synthesized are spherical in shape for the in vitro study in treating various kinds of cancerous cells. All the studies show significant cytotoxicity and effectiveness in inhibiting cancer cells growth, which reveal the promising potential of nanoparticles to be used in drug delivery application.

5.1.3

5.1.3 Size of nanoparticles

The dimensions of nanomaterial act an important role in determination of total cell uptake in drug delivery system. Hence, optimum size of nanodrug carrier has to be figured out in order to maximize the cells uptake rate and intracellular concentration in mammalian cells. In general, a 50 nm diameter of nanomaterial is expected to be the optimal one, but not towards all kinds of cells. A larger nanoparticle, such as larger than 50 nm, could bind with high affinity to a huge number of receptors and might limit the binding of additional nanoparticles. In contrast, a 40–50 nm nanoparticle is able to assemble and bind sufficient receptors to produce membrane wrapping favourably. However, the effectiveness of size of nanomaterial in cell uptake depends on the types of cell as well, because each cell type owns a distinct phenotype. On the other hand, the size of nanoparticles dictates the half-life in the blood circulation. For example, a particle that has a size larger than 200 nm will concentrate in spleen or it will be taken up by phagocytic cells of the body. While a particle with a size smaller than 10 nm, it will be removed by renal clearance. In literature, particles lie in the size range of 10–100 nm are believed to be the optimum. They have a longer circulation times in the body as they can evade the reticuloendothelial system in the body as well as penetrate through very small capillaries. For the superparamagnetic nanoparticles, small size nanoparticles are capable to improve permeability and retention effect, which can lead to maximal accumulation of nanoparticles at the targeted site. However, superparamagnetic nanoparticles with a size smaller than 2 nm are not advisable for medical use. The reason is that the nanoparticles in this range of size have the potential to diffuse through cell membrane readily and thus causes intracellular organelles damage. This situation not merely can exhibit toxic effects, but endanger human life. Different shapes and sizes of nanoparticles have to be avoided because as they move through narrower capillaries, agglomeration might occur which may lead to clogging in blood system. Hence, the size of nanoparticles has to be controlled during the preparation stage so that they can be utilized effectively as a drug carrier.

5.1.4

5.1.4 Surface modification and stability

Besides, surface properties is also one of the important factors which can influence the performance of nanoparticles in drug delivery. Generally, nanoparticles used in delivery in vivo ought to possess good antifouling property which can defy nonspecific adsorption of protein or other biological macromolecules. This can thus prolong the blood circulation time by undergoing adequate surface functionalization of nanoparticles (Ma et al., 2017). In fact, most of the synthesized Fe₃O₄-NPs undergo surface modification before loading with any drug because this is essential for them to play the role as a drug carrier. There are many materials can be used to modify the surface of nanoparticles by coating, particularly polymer. This coating process can increase the colloidal stability of nanoparticles and improve the dispersity. In comparison to the uncoated Fe₃O₄-NPs, bare Fe₃O₄-NPs can be oxidized easily under ambient conditions (Ali et al., 2016). Besides, bare Fe₃O₄-NPs tend to agglomerate owing to their high specific surface area versus respective volume and strong inherent magnetic dipole interactions, eliciting rapid total clearance by the reticuloendothelial system (RES) (Hu et al., 2018). Moreover, surface-engineered nanoparticles can provide a surface for linkage between drug molecules and targeting ligands. Blood circulation time can also be increased by preventing the clearance through RES and thus makes the nanoparticles biocompatible which exhibit lower toxicity towards human body. In general, the stability of Fe₃O₄-NPs in the biomedical application can be improved by undergoing surface coating. However, most of the coating approaches showed some drawback because they are complicated, time consuming and some even require high energy (high pressure and high temperature) (Li et al., 2017). Hence, proper manner of coating need to be done to maintain the desirable properties of Fe₃O₄-NPs in drug delivery application. Fe₃O₄-NPs with a positive surface charge possess a better properties as compared to neutral and negative charge. It is reported that the cell membrane owns a slight negative charge and cell uptake is driven by electrostatic attractions. Hence, positively charged nanoparticles are better because they can be taken up at a faster rate. However, as aforementioned, the intake of nanoparticles depends on cell type.

5.1.5

5.1.5 Drug loading and release

Drug loading should be done in the way that the functionality of drug is not affected. In the meantime, drug loaded nanoparticles should release the drug at the targeted site at an appropriate rate without harming the healthy cells. There are few ways to load the drug on nanoparticles, such as conjugating the drug molecules on the surface of nanoparticles or encapsulating the drug molecules together with the coating material. For conjugation of drug on the surface of nanoparticles, the linking process can be divided into two groups, which are conjugation via cleavable covalent linkage and via physical interactions. Covalent linkage incorporate the combination of drug molecule with functional groups present on the surface of nanoparticles, which have been coated with polymer. Linker can also be used to attach the drug molecule to the nanoparticles. This method can enhance drug loading capacity and also preserve the functionality of the drug, and thus efficacy. Physical interactions such as electrostatic interactions, hydrophobic and hydrophilic interactions can lead to conjugation of drug molecules on the surface of nanoparticles. This phenomenon happens when there is different of charges. For example, the Fe₃O₄-NPs coated with cationic polymer can interact electrostatically with negatively charged DNA. Besides, lipophilic drugs can link with the Fe₃O₄-NPs readily if the Fe₃O₄-NPs coated with hydrophobic polymers, and this can enhance the drug release as the coating degrades. As a drug delivery system, Fe₃O₄-NPs should be able to release their drug payload at optimal condition. However, there are a few drawbacks on the drug release which cannot be neglected. Most of the drug payload released rapidly upon injection into the in vivo situation because the drug is loaded on the surface of Fe₃O₄-NPs, such as burst effect. As a result, low entrapment efficiency causes only small amount of drug reached the targeted site and the effectiveness of drug in killing cancer cells could not perform well. On the other hand, highly stable conjugation between drug molecules and surface of Fe₃O₄-NPs could elicit failure of drug release at the targeted site. Hence, researches should be done to overcome these kinds of problems in order to eradicate the tumor effectively. Furthermore, Fe₃O₄-NPs should be designed in a way that not only release the chemotherapeutic drug in eliminating cancer cells, but should also study the non-toxicity, biodegradability and sterility as they will be used in drug delivery system.

5.2

5.2 Targeted anticancer drug delivery

A targeted drug delivery system is illustrated in Fig. 8. The drug loaded Fe₃O₄-NPs is consumed by human through parenteral drug administration. It is shown that the drug loaded Fe₃O₄-NPs are injected into the blood capillary and located at the targeted site (cancer cells/tumor) by the aid of external magnetic field. This can help to accumulate the drug and release the drug at the desired site, and thus increase the efficacy in treating cancer cells without harming neighbour healthy cells.

Targeted drug delivery system using drug loaded Fe3O4-NPs.

Table 3 shows the examples of Fe₃O₄-based nanoparticles as an anticancer drug vehicle in treating different kinds of cancer cell line using various anticancer drugs in these recent years. Every study modified the surface of Fe₃O₄-NPs with distinct materials, such as chitosan, polymer and silica. All the results show the potential and promising application of Fe₃O₄-NPs in anticancer drug delivery system, which cancerous cells were eradicated after treating with drug loaded Fe₃O₄-NPs.

Table 3 Examples of anticancer drug loaded Fe₃O₄-NPs used in drug delivery.

Ref.	Anticancer drug	Surface modification	Drug carrier (shape and size)	Type of Cancer	Cell Line	Results
Malekzadeh et al. (2017)	Quercetin	1. Poly citric acid (PCA) 2. Poly(ethylene glycol) (PEG) 3. Folic acid	Regular spherical shape in the range of 10–15 nm	Cervical	HeLa	Significant cytotoxicity was clearly showed in both HeLa and MDA-MB-231 cells for quercetin loaded nanocarrier, yet nanocarrier did not show any cytotoxicity against cancerous cell lines
Malekzadeh et al. (2017)	Quercetin		Regular spherical shape in the range of 10–15 nm	Breast	MDA-MB-231
Barahuie et al. (2017)	Phytic acid	1. Chitosan	Roughly spherical shape with mean size of 8 ± 3 nm	Colon	HT-29	Have good anticancer potential against colon cancer, do not show any cytotoxicity to normal fibroblast cells
Venugopal et al. (2016)	Doxorubicin	1. Gold coated 2. Gellan gum	Irregular shape with size varied between 75 and 150 nm	Brain	Rat C6 glioma	Doxorubicin loaded NPs killed tumor cells, and the efficacy increase with the presence of magnetic fields
Taghavi et al. (2016)	Deferasirox	1. (3-aminopropyl) trimethoxysilane (APTMS)	Uniform spherical shape which had a size around 44 nm	Breast	MCF-7	The nanocarrier showed excellent cytotoxicity against human leukemia cell line compared to other cell line. Drug loaded NPs showed higher apoptosis-inducing effect in cancer cell lines than free drugs in vitro
				Cervical	HeLa
				Colon	HT-29
				Leukemia	K-562
				Nerve	Neuro-2a
Shahabadi et al. (2016)	Cytarabine	1. Tetraethoxysilane (TEOS)	Almost spherical with uniform average particle size of 23 nm.	Leukemia	HL-60	Drug loaded NPs had better anticancer effect where the study showed double antiproliferative effects on cancerous cell lines compared to free drug
				Leukemia	KG-1
				Lymph	Raji
Pham et al. (2016)	Curcumin	1. cetyl trimethylammonium bromide (CTAB) 2. Chitosan	Spherical in shape with average size of 13–17 nm	Lung	A549	Increase concentration of drug loaded NPs increased the percentage of inhibition. Free curcumin inhibited cancer cells better than drug loaded NPs due to the slow release rate of curcumin from NPs
Rehana et al. (2015)	Paclitaxel	1. L-arginine	Spherical in shape with particle size of 26 nm	Lung	A549	L-arginine coated NPs showed enhanced cytotoxicity effect against cancer cells and lead to apoptosis, compared to other coated NPs. IC₅₀ value of drug loaded L-arginine coated NPs was lower than free drug which showed the effectiveness in inhibiting cancer cells growth
Ghosh et al. (2015)	Diosgenin	1. Citric acid	Monodispersed between 19 and 21 nm	Breast	MCF-7	Diosgenin loaded NPs exhibited better antiproliferative activity (51.08 ± 0.37%) against MCF7 compared to free diosgenin (33.31 ± 0.37%). The drug loaded NPs possessed good migrating inhibiting and apoptosis inducing properties against breast cancer
Kumar et al. (2014b)	Quercetin	1. Dextran	Monodispersed prism like shape with a size of 20 nm	Breast	MCF-7	Quercetin loaded NPs induce apoptosis in MCF-7 cells
Voicu et al. (2014)	Epirubicin (Epi)	–	Highly homogeneous and have a mean diameter of 4 nm	Colon	HCT-8	Lower concentration of Fe₃O₄@Epi (1.95 µg/mL) was needed to obtain tumor cell viability less than 50%, compared to free drug which needed more amount (7.81 µg/mL) to get similar percent of viable tumor cells
Voicu et al. (2014)	Fludarabine (Flu)	–	Highly homogeneous and have a mean diameter of 4 nm	Colon	HCT-8	Flu showed delayed tumor cells inhibitory effect where 31.25 µg/mL of Fe₃O₄@Flu was needed to reduce cell viability for 24 h incubation, yet less amount of Fe₃O₄@Flu (1.95 µg/mL) was sufficient to reduce cell viability after 72 h of incubation
Javid et al. (2014)	Doxorubicin (DOX)	1. polyethylene glycol (PEG) 2. (3-aminopropyl)triethoxysilane (APTES)	Dispersed and spherical with particle size of 27 ± 0.7 nm (DOX) and 30 ± 0.45 nm (PTX)	Ovary	A2780	PTX loaded NPs showed lower cell viability for both cancer cell lines, compared to DOX loaded NPs with the same concentration. The result revealed significant antineoplastic effect as compared to free drugs
Javid et al. (2014)	Paclitaxel (PTX)			Ovary	OVCAR-3
Li et al. (2014c)	Doxorubicin	1. Graphene oxide 2. Pluronic F127	Nanohybrid with a lateral size of ∼110 nm	Cervical	HeLa	The nanohybrid can be up taken by HeLa cells easily and hence showed the cytotoxicity effect towards HeLa cells
Sharma et al. (2014)	Doxorubicin hydrochloride	1. Sodium hexametaphosphate (SHMP)	Roughly spherical in shape with size around 10 nm	Bone	MG63	The anticancer drug from NPs showed sustained release profile in acidic environment, which is suitable to be used as drug carrier to delivery anticancer drug to low pH tumor site
Kubovcikova et al. (2013)	Taxol	1. Poly(D,L-lactide-coglycolide) (PLGA) 2. Pluronic F68	Mostly spherical with diameter of nanoparticles less than 300 nm	Skin	B16 melanoma	Around 90% of growth inhibition was achieved in 3 days by treating cancerous cells with drug loaded NPs
Chen et al. (2013)	Methotrexate	1. Poly(lactide) (PLA) 2. Polyethylene glycol (PEG)	Spherical morphology with an average size of 10 nm and shell thickness of around 3 nm	Breast	MCF-7	NPs showed low cytotoxicity, but drug loaded NPs showed high cytotoxicity against cancer cells, indicating the effectiveness in antitumor activity
Lv et al. (2013)	Evodiamine	1. copolymer methoxy poly(ethylene glycol)–poly(D,L-lactide-co-glycolide) (MPEG–PLGA)	Spherical morphology with an average size of 45 nm	Cervical	HeLa	The drug loaded nanocarrier showed antitumor activity at higher concentration (15–20 µg/mL) and exhibit a more sustained and controlled drug release in the intracellular compartments after cellular internalization
Rose et al. (2013)	Epirubicin hydroxide	1. polyvinyl pyrrolidone (PVP)	Spherical in shape with the particle size of 8–10 nm	Breast	MCF-7	Drug loaded NPs showed the highest growth inhibition in breast cancer cells (81%). PVP coated NPs showed better anticancer activity in breast cancer cell lines than the uncoated NPs
				Leukemia	THP-1
				Prostate	PC-3
				Lung	A549
Fazilati (2014)	Doxorubicin	1. Folic acid	Almost spherical shape with particle size of 43 nm	Ovary	CP70	Free drug showed a lower cytotoxicity against C30 (49.2%) and CP70 (46.6%). Drug loaded NPs have a better effect towards C30 cells, where C30 and CP70 cells reached 91% and 81.8% apoptosis respectively after treating with drug loaded NPs
Fazilati (2014)	Doxorubicin	1. Folic acid	Almost spherical shape with particle size of 43 nm	Ovary	C30
Ding et al. (2013)	10-hydroxycamptothecin (HCPT)	1. MPEG-PLGA copolymer	Nearly spherical in shape with an average diameter less than 100 nm	Cervical	HeLa	The nanoplatform has excellent in vitro antitumor efficacy compared to free drug via apoptosis activation. Cells at targeted site were killed with the aid of external magnetic field, where the drug was directly delivered without affecting the growth of cells at control area
				Lung	A549
				Liver	Hep G2
Dorniani et al. (2013)	6-mercaptopurine	1. Chitosan	Generally spherical with an average diameter of 19 nm	Leukemia	WEHI-3	Drug loaded NPs did not show toxic to normal mouse fibroblast cell line, but showed cytotoxicity effect against cancer cell. Solvent used in preparing drug loaded NPs has an effect in drug release study, where drug solution prepared in dimethyl sulfoxide did not show burst effect, but hot ethanol did
Li et al. (2013b)	5-fluorouracil	1. poly(styrene-alt-maleic acid) sodium Salt (PSMA) 2. Poly-A₁₅ polynucleotides	Truncated octahedral nanostructure with an edge length 22 nm	Bladder	MBT-2	Large scale cancer cells were killed after hyperthermia treatment with cancer cell-specific targeting NPs, which the NPs were prepared by conjugating anticancer drug (5-Fu) and anti-human epidermal growth factor receptor 2 (anti-HER2) antibody

Abbreviations: NPs, nanoparticles.

Besides in vitro, in vivo drug delivery study is also crucial because it is essential to understand how the nanocarriers function in the body to eradicate cancer cells. There are plenty of researches have been done which adopt mouse as subcutaneous tumor model. Lu et al. had prepared a pH-sensitive dual targeting magnetic nanocarrier for chemo-phototherapy in cancer treatment (Lu et al., 2018). They synthesized magnetic graphene oxide (MGO) by depositing Fe₃O₄-NPs on graphene oxide (GO) via chemical co-precipitation method. MGO was then modified with polyethylene glycol (PEG) and cetuximab (CET) to acquire MGO-PEG-CET. An anticancer drug doxorubicin (DOX) was then loaded to MGO-PEG-CET to become MGO-PEG-CET/DOX for anticancer study. The antitumor efficacy of MGO-PEG-CET/DOX was investigated in vivo in xenograft tumor model in mice. The experiment was carried out using BALB/c with subcutaneous CT-26 tumors of 60–100 mm³, which were subjected to treatment with normal saline (control) and DOX in different ways. The images of the tumor-bearing mice were taken on day 0 and 14 which the tumor size differences were recorded. The tumor removed from the mice on day 14 revealed the anti-tumor effects with each treatment, but to a different degree (Fig. 9a). The tumor tissue on day 14 underwent H&E staining and the results showed that necrosis of the cancer cells was most substantial in MGO-PEG-CET/DOX + magnet and MGO-PEG-CET/DOX + magnet + laser group. However, the cells were continue growing for control, DOX and MGO-PEG-CET/DOX groups. The tumor volumes were recorded every day until day 14 and a graph of relative tumor volume after normalizing the tumor volume at each time point with the tumor volume at day 0 was presented (Fig. 9b). It was observed that MGO-PEG-CET/DOX + magnet and MGO-PEG-CET/DOX + magnet + laser groups revealed substantial tumor suppression throughout the observation period (∗p < 0.05), as compared to the control. DOX and MGO-PEG-CET/DOX groups also showed the tumor volume reductions, but both of the groups did not give notable difference in tumor volume from control throughout the experiment. This tells the significance of dual targeting with external magnetic guidance, but still the MGO-PEG-CET/DOX + magnet treatment fail to suppress tumor growth after day 8 with a rapid increase of tumor volume. Hence, laser light was used as photothermal therapy to control the growth of tumor. MGO-PEG-CET/DOX + magnet + laser treatment could inhibit the tumor growth and shrank the size of tumor. Fig. 9c showed the weight of the mice observed throughout the 14 days. However, the mice in control group were noticed to have a better weight gain compared to other groups that underwent DOX treatment. This could be attributed to the common adverse effect from chemotherapy, but the appetite and behavior of the mice were not changed much throughout the period for all of the mice under treatment.

The anti-tumor efficacy in vivo with tumor-bearing BALB/C mice. BALB/c mice were subcutaneously implanted with CT-26 cells and were given different treatment by intravenous injection of normal saline (control), DOX, MGO-PEG-CET/DOX, MGO-PEG-CET/DOX + magnet, and MGO-PEG-CET/DOX + magnet + laser (30 mg/kg DOX). (a) The gross observation of tumor-bearing BALB/c mice on day 0 and 14, the gross view of incised tumor and the H&E staining of the incised tumor on day 14 (bar = 200 µm); The relative tumor volume (b) and body weight (c) were recorded. *p < 0.05 compared with control, DOX, and MGO-PEG-CET/DOX, # p < 0.05 as compared with MGO-PEG-CET/DOX + magnet. Reproduced with permission (Lu et al., 2018).

6 Conclusion and future perspectives

Pharmaceutical field begins to develop in recent decades and has introduced a huge number of novel drug delivery system. Most of them are still in incipient stage, including Fe₃O₄-NPs. Plenty of factors make Fe₃O₄-NPs the potential nanodrug carrier in drug delivery system. The usage of external magnetic field which guides the Fe₃O₄-NPs to the specific region shows the promising applications of Fe₃O₄-NPs in variety of biomedical related field, particularly targeted drug delivery. However, there is still no Fe₃O₄-based nanoparticles drug delivery product on the market. Many intensive researches are yet to be done to commercialize these nanoparticles as a product in medical domain. Before these Fe₃O₄-NPs to be launched as a product, several limitations need to be overcome. The methodologies in the preparation of Fe₃O₄-NPs need to be improved and the characterization is the most crucial part. The results will show the properties of the Fe₃O₄-NPs possessed which subsequently determine the potential application Fe₃O₄-NPs.

Important features that have to be taken into consideration when selecting Fe₃O₄-NPs for drug delivery are the saturation magnetization, size, shape, surface charge, colloidal stability, drug loading capacity and release behavior, biocompatibility and toxicity. However, the fettle of the Fe₃O₄-NPs in body after drug delivery is important. It is safe if they are able to eliminate from body system. But, if the Fe₃O₄ core is exposed, it can cause several problems which correlated with neurological disorders. Hence, the selection of Fe₃O₄-NPs for targeted drug delivery should be chosen carefully based on the mechanism of conjugation between polymer, drug molecules and Fe₃O₄-NPs, else the burst effect would produce toxic chemicals that is harmful to body system.

6.1

6.1 Future works

In vivo test using Fe₃O₄-NPs should be carried out and investigated thoroughly before clinical practice. This procedure can study the effectiveness of Fe₃O₄-NPs in body system and might provide useful information to improve the desirable characteristics of Fe₃O₄-NPs in targeted drug delivery study. The linkage of drug loaded Fe₃O₄-NPs and cells should also be studied to understand the mechanism of cell uptake. Hence, in this case, molecular docking simulation can be done to study the interaction between drug carrier and cells. Besides, in order to evaluate the efficacy of nanomedicine, preclinical research is required to generate data sets that depicts nanomedicine behavior, such as tumoral accumulation, intratumoral distribution, tumoral retention of the system and the additional contribution of the peripheral pharmacokinetics of the nanomedicine (Hare et al., 2017). Some key parameters that affect the nanomedicine efficacy must be confirmed in preclinical testing. There are several researches are essential to this study, for instance, characterization of the intra-tumoral carrier retention, identification of the treatment efficacy in tumors that reaches less EPR-rich sizes and evaluation the efficacy of nanomedicine with appropriate dose and schedule. The data obtained from these researches can understand how the plasma, off-target tissue and tumor pharmacokinetics of the nanomedicine are influenced by repeat dosing.

Numerous researches have been done in this study to overcome the problems of targeted drug delivery in treating cancer disease. All the experimental results so far provide a promising outcome and show the potential of Fe₃O₄-NPs in targeted drug delivery. It is believed that Fe₃O₄-based nanoparticles in clinical treatment is not far off anymore, where they can eventually be used in curing diseases rather than just research in the near future.

Declarations of interest

None.

Acknowledgements

The authors would like to extend their gratitude and appreciation to the members of Chemical Energy Conversions and Applications (ChECA) Research Laboratory, Department of Environmental Engineering and Green Technology, Malaysia-Japan International Institute of Technology, Universiti Teknologi Malaysia.

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