metal oxide nanoparticles in healthcare

Journal Pre-proof Emerging applications of biocompatible phytosynthesized metal/metal oxide nanoparticles in healthcare Robin Augustine, Anwarul Hasan PII:

S1773-2247(19)31530-8

DOI:

https://doi.org/10.1016/j.jddst.2020.101516

Reference:

JDDST 101516

To appear in:

Journal of Drug Delivery Science and Technology

Received Date: 9 October 2019 Revised Date:

15 December 2019

Accepted Date: 9 January 2020

Please cite this article as: R. Augustine, A. Hasan, Emerging applications of biocompatible phytosynthesized metal/metal oxide nanoparticles in healthcare, Journal of Drug Delivery Science and Technology (2020), doi: https://doi.org/10.1016/j.jddst.2020.101516. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier B.V.

Graphical abstract

Emerging applications of biocompatible phytosynthesized metal/metal oxide nanoparticles in healthcare Robin Augustine,1,2* Anwarul Hasan1,2* 1

Department of Mechanical and Industrial Engineering, College of Engineering, Qatar University, Doha, Qatar 2 Biomedical Research Center (BRC), Qatar University, Doha, Qatar *Corresponding authors Email Anwarul Hasan: [email protected] Robin Augustine, [email protected]

Abstract Various applications of nanotechnology in healthcare, agriculture, environmental and other technological fields have considerably transformed human life. However, harmful effects of nanomaterials synthesized by traditional methods reduce the potential of the instantaneous application of nanotechnology-based products in healthcare field. Application of plant extracts as reducing agents minimizes the use of hazardous chemicals to produce nanomaterials. Phytonanoparticles are relatively biocompatible for biological applications due to the lack of traces of harmful chemicals in them. The specific plant or plant part used for the synthesis process plays pivotal role as it influences the properties of resultant nanoparticles. Phytonanoparticles can generally be used as antimicrobial agents in blood bags, wound dressings, dental implants and other biomedical devices. They are also extensively studied for their potential applications in cancer detection and therapy. In this review, we discuss about various biomedical applications of phytonanoparticles which are synthesized using plant parts such as shoots, leaves, fruits and roots of different plant species. Key words: Nanoparticles, phytosynthesis, silver nanoparticles, gold nanoparticles, copper nanoparticle, antimicrobial agents

1

1. Introduction Various inorganic nanoparticles such as silver, gold, copper, platinum and their oxides are used in many applications including healthcare. Physicochemical methods of nanoparticle synthesize are widely used for the commercial production of metallic and metal oxide nanoparticles due to the long-term stability and the ability to generate monodispersed nanoparticles. However, many of such methods involve the use of potentially hazardous chemicals which are harmful to both the human beings and the environment [1]. In addition, the presence of the traces of hazardous chemicals on the synthesized nanoparticles make them less suitable for medical applications [2]. Some studies compared the toxicity and biological performance of nanoparticles synthesized by chemical and green routes [3]. For instance, when chemically and phytosynthesized nickel nanoparticles

with

relatively

similar

physicochemical

properties

were

compared,

phytosynthesized ones showed higher free radical scavenging activity, antibacterial activity and superior biocompatibility [3]. Various types of nanoparticles are extensively used in several biomedical applications including antibacterial dressings, anticancer agents, image contrast agents, and biosensors. Improving the biocompatibility of metallic nanoparticles is highly important due to their wide range of potential applications in several biomedical, diagnostics and cosmetics products. A considerably large amount of research data can be found in recent past literature regarding the use of several biosynthesis approaches for the production of metal and metal oxide nanoparticles such as silver, copper, gold, and platinum [4,5]. Nanoparticle synthesized by biological methods are relatively safe for medical applications because of the use of biologically derived and nontoxic components as reducing as well as stabilizing agents. Plant mediated synthesis otherwise called “phytosynthesis” of nanoparticles is the most widely used and easiest biosynthesis approach. Many plant species and plant derivatives such as whole plant extract, fruit extract, leaf extract and seed extract were demonstrated for their potential to generate various metallic nanoparticles [6–8]. Bioactive compounds present in plant body such as polyphenolic compounds, alkaloids, terpenes, flavonoids, ascorbic acid, citric acid, and several reductase enzymes can act as reducing agents of metal salts and generate nanoparticles [9]. During the formation of nanoparticles, biomolecules present in the plant extracts can act as capping agents and stabilize the formed nanoparticles [10]. Presence of such molecules can be detected by techniques such as Fourier transform infrared spectroscopy (FTIR), Proton nuclear 2

magnetic resonance (1H-NMR) spectroscopy and other spectroscopic approaches. For instance, nickel oxide nanoparticles synthesized using Eucalyptus globulus leaf extract, revealed the presence of various functional moieties like C–N, C–H, C=C and O–H which indicate the role of phytobiomolecules in capping and stabilization of formed nanoparticles [11]. Depending upon the plant species used, such anchored or conjugated biomolecules on the phytonanoparticles can vary and thus the resulting biological properties too. Such information can be obtained from an interesting review article by Rajeshkumar et al. [12]. Phytonanoparticles synthesis can be performed by exploiting either intracellular or extracellular mechanisms. Recent reports indicated that some plants growing in metal-rich conditions can intracellularly synthesize metallic nanoparticles [13]. However, isolation of formed nanoparticles from the plant body without the contamination of plant tissues and possible plant pathogens is a difficult to achieve task. On the other hand, extracellular routes of nanoparticles synthesis involve the addition of plant extracts to a hot metal salt precursor solution and enabling the reduction of metal ions [4,14]. Instead of the whole plant extract, purified forms of plant compounds such as enzymes, antioxidants and alkaloids can also be used to synthesize metallic nanoparticles [15]. Many of the plants which are used for the phytosynthesis of nanoparticles have high medicinal value [4,8,14,16–21]. Synthesized nanoparticles using the extracts of such medicinal plants contains biomolecules with medicinal values. Therefore, eco and biofriendly nanoparticles synthesized using plants and plant derivatives can find several applications in the pharmaceutical, cosmeceutical and medical products. 2. Biomedical applications of phytonanoparticles Phytonanoparticles have been applied in many fields such as agriculture, medicine, and several industrial applications. Owing to their excellent biocompatibility and medicinal value, phytonanoparticles are recommended for several applications such as antimicrobial agents, anticancer agents, image contrast agents, fluorescent probes and drug delivery systems [22]. Emerging biomedical applications of phytonanoparticles are summarized in Figure 1. Phytosynthesized silver nanoparticles (AgNPs) are mostly utilized in biomedical sector due to their outstanding antimicrobial activity. For instance, silver, zinc, and other metal nanoparticles are also used in wound dressings, food packaging, and catheters due to the excellent antimicrobial property. Another important application of phytonanoparticles is the development 3

of sensors for the recognition of various analytes related to agriculture, diagnostics and environmental sectors. Moreover, phytonanoparticles are suggested for the use in drug delivery and cell labeling. Some of the highly promising applications of metal and metal oxide nanoparticles are yet to be fully explored, such as photothermal therapy, photoimaging and magnetically induced drug delivery. In the following sections, biomedical applications of phytosynthesized nanoparticles such as silver, gold, copper etc. are discussed in detail.

Figure 1: Synthesis of metal nanoparticles through plant extracts and their possible biomedical applications. Adapted from [23]. 2.1. Antimicrobial applications Many healthcare and biomedical products such as biomaterial implants, wound dressings, catheters, stents and blood bags require antimicrobial property to avoid infections and biofouling [24]. Nanoparticles such as silver, gold, copper and zinc oxide can be used in such biomaterials 4

to provide them antimicrobial property [25]. Studies showed that the phytochemicals present on the phytonanoparticles can improve the natural antimicrobial activity of metallic nanoparticles [4]. Several types of terrestrial and marine plants are being used for the production of antimicrobial nanoparticles [26]. For example, an AgNPs synthesized using an Asteraceae member, Artemisia nilagirica were highly effective against many microorganisms [27]. Similarly, AgNPs produced from the extract of marine seaweed Sargassum wightii were also effective against multiple bacteria such as K. pneumoniae, S. aureus, and S. typhi [28]. Moreover, AgNPs generated using various plant parts/extracts such as Coptidis rhizome [29], Tulsi (Ocimum sanctum) [30], Carissa carandas (Karonda) [31], Origanum vulgare (Oregano) [32], and Salicornia bigelovii [33], showed antibacterial activity against multiple types of bacteria. AgNPs synthesized using Biophytum sensitivum was incorporated in nano-micro dual-porous calcium pectinate scaffolds to generate antibacterial wound dressing (Figure 2) [20]. Obtained nanoparticles showed pale yellow to brick red colour when dispersed in water depending on the concentration of silver nitrate used for the synthesis (Figure 2A). UV-visible spectra (Figure 2B) and XRD analysis (Figure 2C) showed the characteristic absorption maxima and diffraction patterns of AgNPs, respectively. Particles where almost spherical in morphology (Figure 2D). Developed AgNP loaded pectinate wound dressings were highly porous (Figure 2E). XRD patterns of AgNPs loaded pectin hydrogels confirmed the presence of AgNPs in the pectinate (Figure 2F). Fibroblast cells cultured in the presence of biosilver incorporated pectin hydrogels showed their intact morphology (Figure 2G). Promising antibacterial activity shown by the membranes against Gram negative (E. coli) and Gram positive (S. aureus) bacteria help to protect the wound by effectively fight off the invading microbes (Figure 2H). Antimicrobial nanohybrids of AgNPs loaded chitosan (CHNF), cellulose (CNF) and lignocellulose (LCNF) nanofibers were developed and characterized by Mohammadalinejhad et al. [34]. They have used Lythrum salicaria extract as both reducing agent as well as a capping agent for the synthesis of spherical AgNPs with diameters ranging between 45 and 65 nm. LCNF substrate showed slow release of AgNPs than other nanofibers. However, the growth inhibition of E. coli and S. aureus due to the activity of nanohybrids was CHNF ˃ LCNF ˃ CNF.

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Figure 2: Photographs displaying the color difference of biosynthesized AgNPs with different concentrations of silver nitrate solutions and whole plant extracts of B. sensitivum (A). UV visible spectra of AgNPs synthesized using different concentrations of silver nitrate and B. sensitivum extract (B). XRD patterns of AgNPs generated with different concentrations of silver nitrate and B. sensitivum extract (C). Representative TEM image of AgNPs (D). Representative SEM image of pectin hydrogel loaded with AgNPs (E). XRD patterns of AgNPs loaded pectin hydrogels (F). Proliferation of L929 fibroblast cells treated with AgNPs loaded pectin hydrogels (G). Photographs of culture plates displaying the antibacterial activity of the nanocomposite pectin hydrogels (H). Bare CaP, Cap-AgNP-0.25, Cap-AgNP-0.5, Cap-AgNP-1 are 0% w/w, 0.25% w/w, 0.5% w/w and 1% w/w biosilver loaded pectinate, respectively. Reproduced with Creative Commons Attribution License from [20].

6

Copper oxide nanoparticles synthesized using Brown alga (Bifurcaria bifurcata) with dimensions 5–45 nm exhibited high antibacterial activity against two different strains of bacteria Enterobacter aerogenes (Gram negative) and S. aureus (Gram positive) [35]. Hassanien et al synthesized copper nanoparticles using Tilia plant and studied the antibacterial activity

against

Pseudomonas

aeruginosa,

Escherichia

coli,

Bacillus

subtilis

and

Staphylococcus aureus [36]. Results of this study showed that synthesized copper nanoparticles can effectively inhibit the proliferation of these bacteria.

Mitragyna parvifolia plant bark

extract was also used for the synthesis of copper nanoparticles [37]. Phytosynthesized copper nanoparticles showed excellent antibacterial activity against Escherichia coli and Bacillus subtilis. Copper nanoparticles synthesized by Capparis spinosa showed higher inhibitory effect on Gram-positive bacteria (Staphylococcus aureus and Bacillus cereus) compared to Gramnegative bacteria (Klebsiella pneumoniae, and Escherichia coli) [38]. Copper nanoparticles synthesized using leaf extract of Nerium oleander also proved to be excellent candidates for antibacterial application due to their inhibitory effect against Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus, Salmonella typhi and Bacillus subtilis [39]. Platinum nanoparticles synthesized using Taraxacum laevigatum showed excellent antibacterial activity against gram positive bacteria (Bacillus subtilis) and gram negative bacteria (Pseudomonas aeruginosa) [40]. Platinum nanoparticles synthesized using the leaf extract of Xanthium strumarium showed antibacterial activity against

E. coli (inhibitory zone: 20 ± 0.5 mm),

Staphylococcus aureus (inhibitory zone: 22 ± 0.5 mm), Klebsiella pneumonia (inhibitory zone: 19 ± 0.5 mm), Bacillus subtilis (inhibitory zone: 19 ± 0.5 mm) and Pseudomonas aeruginosa (inhibitory zone: 18 ± 0.5 mm) at the concentration of 100 µg/well [41]. Nishanthi et al. synthesized

silver, gold and platinum nanoparticles using the rind extract of the fruit of

Garcinia mangostana [42]. Results of this study indicated that conjugation of antibiotics with nanoparticles can significantly enhance the antibacterial activity of nanoparticles. Nickel oxide nanoparticles have been synthesized using Eucalyptus globulus leaf extract and assessed for their bactericidal activity [11]. Nanoparticles possessed antibacterial and anti-biofilm activity against Pseudomonas aeruginosa, Escherichia coli and Staphylococcus aureus. Along with bacteria, fungal pathogens such as Candida species can also cause several fatal diseases [43]. Candida albicans is an opportunistic pathogenic yeast that is found in the human gut. Candida can result in severe nosocomial infection with an accompanying death rate about 7

40% [44]. AgNPs show effectiveness against several fungal pathogens including candida [45] AgNPs synthesized using Tulsi (O. sanctum) exhibited promising antifungal activity [46]. AgNPs synthesized using extracts of Shoreatum buggaia, Boswelliao valifoliolata,

and

Svensonia hyderobadensis showed antifungal activity against A. niger, A. flavus, Curvularia sp., Fusarium sp. and Rhizopus sp [47]. In a similar manner, copper nanoparticles synthesized using Tilia plant extract showed antifungal activity toward Candida albican [36]. However, the precise mechanism of antifungal action of phytonanoparticles has not been fully understood yet. One of the possible mechanism might be by damaging fungal cell wall and intercellular components [48]. AgNPs possess inhibitory effect against several viral pathogens and offer an excellent opportunity to formulate novel antiviral agents [49]. Phytosynthesized nanoparticles can act as effective broad-spectrum antiviral agents against several pathogenic viruses [50]. Several metallic nanoparticles are reported for their antiviral effectiveness against multiple types of viruses such as hepatitis B virus, herpes simplex virus type 1, HIV-1, influenza virus, respiratory syncytial virus, monkeypox virus and Tacaribe virus [49]. The antiviral property of metallic nanoparticles can be due to multiple mechanisms such as inhibition of virus binding to the plasma membrane, interference with viral attachment and inactivation of virus particles prior to entry or Interaction with double-stranded DNA and/or binding with viral particles [49,51]. Detailed information on the interaction between nanoparticles and viruses can be obtained from a comprehensive review by Galdiero et al. [49]. Phytosynthesized AgNPs using Phyllanthus niruri, Andrographis paniculata, and Tinospora cordifolia were evaluated for their effectiveness against chikungunya virus [52]. In vitro antiviral tests demonstrated that the nanoparticles synthesized from A. paniculata were most effective, followed by T. cordifolia and P. niruri based ones. Viability of cells infected with chikungunya virus increased 3 to 4 fold, upon treatment with A. paniculata based nanoparticles. Similarly, AgNPs were synthesized using the extract of an alga, C. clavulatum and tested their antiviral potential against Dengue fever virus [53]. Cellular viral uptake studies demonstrated that untreated viral infected cells possessed high intensity of fluorescence emission, which represents high level of viral uptake. However, AgNPtreated infected cells possessed low levels of fluorescence which indicate the low viral load. In another study, AgNPs generated using M. oleifera seed extract was used also tested against the dengue serotype DEN-2 [54]. AgNP showed in vitro antiviral activity against DEN-2 infecting 8

vero cells. After 6 h of treatment, DEN-2 yield was 5.8 log10 PFU/ml in the control, while it was 1.4 log10 PFU/ml post-treatment with AgNP (20 µl/ml) which highlight the strong potential of green-synthesized AgNP to control dengue fever. Phytonanoparticles also showed sizedependent interaction with human parainfluenza virus type 3 and with herpes simplex virus types 1 and 2 [55]. Tannic acid (TA-AgNPs) functionalized AgNPs showed good antiviral efficacy against genital herpes infection [56]. The mice treated intravaginally with TA-AgNPs showed low virus load in the vaginal tissues quickly after the treatment. Moreover, vaginal tissues treated with TA-AgNPs exhibited considerable increase in the number of activated B cells, IFNgamma+ CD8+ T-cells, and plasma cells. The spleens of treated mice possessed higher number of effector-memory CD8+ T cells and IFN-gamma+ NK cells in comparison to placebo control group. Results of several studies indicated that use of phytonanoparticles such as nanosilver as antibacterial, antifungal and antiviral agents is viable approach that deliver alternative therapeutic possibilities against several devastating pathogenic diseases. Overall, plant-mediated synthesis of inorganic nanoparticles can be employed to develop novel, relatively safe, and cheap therapeutic agents to fight against several microbial pathogens with no considerable cytotoxicity on mammalian cells. 2.2. Wound healing applications Trauma, burn, skin diseases, or removal of skin during surgery results in wounds. Such wounds can result in pathogenic invasion and related complications if not protected properly. In order to prevent wound infections, a suitable wound dressing materials with bacterial barrier property, antibacterial property, and ability to promote wound healing should be used [57]. In this regard, wound dressings holds great promises for improving the healing while acting as a mechanical, thermal and pathogen barrier [58]. Several such wound dressing loaded with nanoparticles are able to reduce the wound contraction time and reduce wound infection without considerable adverse effects [59,60]. Many biodegradable polymers such as collagen [61], gelatin [62], chitosan [63], polylactic acid (PLA) [64,65], polycaprolactone (PCL) [66–69], polyvinyl alcohol (PVA) [14,70] etc. are extensively studied for wound dressing applications. One of the most interesting and promising 9

advancement in the field of wound care is the development of biodegradable polymeric patches/membranes loaded with antimicrobial agents to inhibit pathogens and promote healing [66,71,72]. Among many other techniques, electrospinning is a robust technique used for the development of porous membranes for wound dressing applications with microbial barrier property [73–76]. P. nigrum (black pepper) leaf extract mediated biosynthesized AgNPs were incorporated in electrospun PCL membranes to provide antibacterial property [21]. In the case of PCL/silver nanocomposite membranes, fiber diameter was significantly reduced as the nanoparticle concentration increased in the composite. Incorporation of nanoparticles improved the

mechanical

properties

of

the

membranes.

Developed

membranes

containing

phytonanoparticles exhibited antibacterial activity against S. aureus and E. coli in a concentration dependent way. Electrospun PVA membranes containing phytosynthesized AgNP was suggested for wound healing applications [14]. Whole plant extract of Mimosa pudica was utilized for the phytosynthesis of AgNPs (Figure 3). Nanoparticles loaded PVA membranes possessed excellent blood compatibility, wound fluid uptake, antibacterial action, good mechanical strength and cytocompatibility. At optimum concentration, presence of AgNPs enhanced the wound healing in in vitro wound contraction model.

Figure 3: Extract of Mimosa pudica was utilized for the synthesis of biosynthesized AgNP. PVA membranes loaded with AgNP presented satisfactory exudate uptake capability, antibacterial

10

action, blood compatibility, cytocompatibility and in vitro wound contraction. Reproduced with permission from [14]. 2.3. Applications in cancer therapy Cancer is a devastating disease that affects billions of people in the world and results in severe illness, amputations and mortality. Many types of nanomaterials are suggested for multiple types of applications in the field of cancer diagnosis and therapy [77]. Studies have demonstrated that nanoparticles can activate proapoptotic pathways mediated by the generation of reactive oxygen species (ROS) [78]. AgNPs generated using the plant extract of O. vulgare (Oregano) exhibited concentration dependent inhibitory activity against lung cancer cell line, A549 (LD50 – 100 µg/ml) [32]. Relatively low concentration of gold nanoparticles (AuNPs) are able to show apoptosis in malignant cells [79]. Green synthesized AgNPs using Morinda citrifolia exhibited a higher cytotoxic effect in HeLa cell lines compared to other chemotherapeutic drugs [80]. The cell morphology was considerably changed even at treatment with amount as low as 0.1 µg/well (Figure 4A). At 100 µg/well nanoparticle content, almost all the cells were died. Biosynthesized AgNPs by the yeast Cryptococcus laurentii exhibited excellent antitumor response in the breast cancer cell lines such as MCF7 and T47D [81]. AgNPs synthesized from the extract of Ganoderma neo-japonicum mycelia showed good cyototoxicity against breast cancer cells [82]. Low concentrations of AgNPs (1 to 10 µg/mL) successfully inhibited breast cancer cell proliferation and induced the membrane leakage. AgNPs synthesized using Syzygium cumini fruit extract showed antioxidant and anticancer activity against Dalton lymphoma cell lines under in vitro condition [83]. About 100 µg/mL nanoparticle content resulted in the substantial reduction of Dalton lymphoma cell viability. Salvadora persica extract was utilized for the production of zinc oxide nanoparticles (ZnO-NPs) to use as anticancer agents [84]. Phytosynthesized nanoparticles could reduce the viability of HT-29 cancer cell line in a concentration dependent manner. Composite hydrogels consisting of alginate, chitosan and phytosynthesized AgNPs showed good anticancer effect on breast cancer cell line MDA-MB– 231 [85]. About 5 mg/well nanoparticle content (in 24 well culture plate) of chitosan-alginateAgNPs resulted in the 50% reduction in MDA-MB–231 cells proliferation. Results of Annexin V− and PI− staining indicated that untreated control MDA-MB–231 cells remained almost viable whereas chitosan-alginate-AgNPs-treated cells undergone apoptosis (Figure 4B) (lower left 11

quadrant). Upon treatment with chitosan-alginate-AgNPs (5 and 10 mg/well treatments), population of apoptotic cells (in the upper right quadrant) was considerably increased. This suggests that anticancer activity of phytosynthesized AgNP loaded composite against MDA-MB231 cells was due to the induction of apoptosis. Unlike other studies, observed inhibitory activity of chitosan-alginate-AgNPs at relatively very high nanoparticle contents (5-10 mg/well treatment groups) might be associated with the low amount of AgNPs released from the chitosan-alginate matrix. Copper nanoparticles synthesized using Tilia plant extract exhibited good anticancer activity against tested human colon cancer Caco-2 cells, human hepatic cancer HepG2 cells and human breast cancer Mcf-7 cells [36]. Copper nanoparticles synthesized using Acalypha indica have shown potential cytotoxic effects against MCF-7 breast cancer cell lines [86]. Copper oxide nanoparticles were synthesized using the aqueous black bean extract and studied the anticancer activity [87]. Results of sulforhodamine-B assay indicated that in the presence of phytonanoparticles, mitochondria-derived ROS were increased and initiated lipid peroxidation of the liposomal membrane. Mitochondrial structure was found to be altered upon the incubation with copper nanoparticles. Proliferation of cancer cells was also significantly reduced upon treatment with phytosynthesized copper nanoparticles. Copper oxide nanoparticles synthesized using Ficus religiosa also showed ROS mediated anticancer activity against A549 adenocarcinomic human alveolar basal epithelial cells [88]. Platinum nanoparticles synthesized using the leaf extract of Xanthium strumarium showed promising anticancer activity [41]. Nanoparticles showed an IC50 value of 90 µg/ml/24 h against HeLa cancer cell lines by the MTT assay. Palladium nanoparticles were synthesized using the leaf extract of Evolvulus alsinoides and evaluated the in vitro anticancer activity of human ovarian cancer A2780 cells [89]. Exposure to phytosynthesized palladium nanoparticles resulted in the reduction in Human ovarian A2780 cancer cell viability. Furthermore, ROS generation, activation of autophagy, impairment of mitochondrial membrane potential, enhanced caspase-3 activity and DNA fragmentation were observed on palladium nanoparticles treated cells. Rokade et al. reported the phytogenic synthesis of platinum nanoparticles and palladium nanoparticles using medicinal plant Gloriosa superba tuber extract and their anticancer properties [90]. Induction of apoptosis was the most predominant mechanism of anticancer activity of these nanoparticles. Platinum– palladium bimetallic nanoparticles along with individual platinum and palladium nanoparticles 12

synthesized using Dioscorea bulbifera tuber extract showed promising anticancer activity against HeLa cells [91]. Bimetallic nanoparticles showed higher anticancer activity than individual nanoparticles. Leaf extract of medicinal plant Ocimum sanctum was used for the synthesis of nickel nanoparticles [92]. Quercetin has been conjugated with obtained nickel nanoparticles to provide higher anticancer effect on human breast cancer MCF–7 cells. Quercetin conjugated nickel nanoparticles showed dose dependent anticancer effect against MCF–7 cells. The IC50 value of quercetin conjugated nickel nanoparticles was 6.25 µg/mL whereas quercetin alone showed a much higher value (50 µg/mL). Oxidative stress due to ROS generation, subsequent loss of mitochondrial membrane potential, capsase -9, -7 activation and resulting apoptosis were the major reasons for the anticancer activity of quercetin conjugated nickel nanoparticles. Nickel oxide nanoparticles synthesized using Moringa oleifera plant extract showed better cytotoxicity against cancer cells [93]. MTT cell viability assay on HT-29 (Colon Carcinoma cell lines) cells and morphological observations indicated that the synthesized nickel oxide nanoparticles can inhibit human colon cancer cell proliferation. Nickel oxide nanoparticles synthesized using Geranium wallichianum have shown significant anticancer activity against HepG2 cancer cells (IC50 value: 37.84 µg ml−1) [94]. Nickel oxide nanoparticles synthesized using Andrographis paniculata (leaf extract) showed potential anticancer activity against MCF-7 breast cancer cell line [95]. Although not conclusive, the plausible mechanism of anticancer activity of the phytosynthesized metal/metal oxide nanoparticles include the induction of reactive oxygen species, cell membrane damage, mitochondrial damage, generation of pro-apoptotic caspases and DNA damage or fragmentation (Figure 4C).

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Figure 4: Effect of phytosynthesized nanoparticles on cancer cells. Images of HeLa cells treated with various concentration of M. citrifolia synthesized AgNPs (A). Annexin V and PI staining of MDA-MB-231 cells treated with phytosynthesized AgNPs loaded chitosan-alginate composites at different concentrations (B). Schematic representation of possible mechanisms of anticancer activity for phytosynthesized nanoparticles (C). A and B are reproduced with permission from [80] and [85], respectively. C is adapted from [96]. 14

Treatment of tumours with elevated temperatures in the range of 40-44 °C is referred as hyperthermia treatment.

Superparamagnetic nanoparticles are extensively reported for their

application in magnetic hyperthermia treatment. The medicinal plant Gardenia was used for the

synthesis of superparamagnetic α-Fe2O3 nanoparticles with non-saturating MS value of 8.5 emu/g at room temperature [97]. Hyperthermia study showed that the α-Fe2O3 nanoparticles can achieve a temperature of 40 °C and 43 °C within 6 min. Based on the heating profile of phytosynthesized α-Fe2O3 nanoparticles, the Specific absorption rate (SAR) values (167.7 Oe, 300 MHz) calculated and are found to be around 62.75 W/g and 24.38 W/g for 5 µg/mL and 10 µg/mL nanoparticle concentrations respectively which is satisfactory for hyperthermia

applications. 2.4. Bioimaging and biosensing applications Metallic and metal oxide nanoparticle have great potential in bioimaging and biosensing research due to the ability in gaining sensitive data in a noninvasive manner, in early-stage cancer diagnosis and cell tracking. Plasmonic properties of many of the metallic nanoparticles such as silver and gold are greatly depend on their physical properties such as shape, size, and dielectric medium that surrounds them [98,99]. The sensing of biomolecules relies on the binding of them on the surface of metal nanoparticles and subsequent changes in the plasmonic properties of the nanoparticles. The adherence of biomolecules on the surface of nanoparticles increases the refractive index and result in the shifting of the extinction spectrum [100]. Diverse shaped AgNPs are incorporated in biosensors for detecting different biomolecules and sensing their multiple range of interactions. Phytosynthesized nanoparticles have great potential in biosensing applications. Optical imaging is a highly promising bioimaging technique with huge potential for improving diseases identification and management. Optical imaging uses non-ionizing radiation as the object illumination source to characterize samples at both cellular and molecular level. The most commonly used optical imaging techniques for healthcare applications include bioluminescence imaging, fluorescence imaging, optical coherence tomography, Raman imaging and photoacustic imaging [101,102]. One of the major limitations of in vivo optical imaging is the limited tissue penetration [103,104]. However, this issue can be managed by the usage of near-infrared (NIR) optical imaging, due to reduction in scattering and minimal absorption within the NIR region 15

[105]. Several drawbacks of conventional imaging probes can be reduced using nanostructured probes. A possible drawback of nanomaterial based fluorescent probes is related to their composition; since they typically contain toxic heavy metal such as cadmium. In this context, low toxic metal nanoparticles such as gold and silver receiving increasing attention as fluorescent probes [106]. As AgNPs are photostable thus they can used as biological probes for the continuous monitoring of dynamic events for an extended period. Functionalization of biomolecule on the surface of AgNPs can increase the specificity for cell membrane. Phytonanoparticles have large scope in this area as they lend themselves to act as multifunctional constructs. Chen et al., demonstrated the green synthesis of AuNP/gelatin/protein hybrid nanogels exhibiting metal-enhanced luminescence or fluorescence [107]. Gelatin and protein were used as both reducing and stabilizing agents. With the assistance of luminol solutions and hydrogen peroxide, the AuNP/gelatin/lactoferrin nanogels exhibited enhancement of fluorescence (~50fold) as compared to free lactoferrin. Similarly, AuNP/gelatin/horseradish peroxidase nanogels exhibited enhanced bioluminescence (~11-fold) in a horseradish peroxidase-luminol system. Fluorescence confocal microscopic imaging in RAW 264.7 cells demonstrated the great potential of these systems for the bioimaging applications. Hybrid crystalline magnetite/gold (Fe3O4/Au) nanoparticles with ∼35 nm size were synthesized using grape seed proanthocyanidin and suggested as X-ray contrast agents [108]. Magnetization and magnetic resonance imaging experiments indicated that the Fe3O4 component of hybrid nanoparticles possess excellent superparamagnetism. They showed dark T2 contrast and high relaxivity (124.2 ± 3.02 mM–1 s–1). Phantom based computed tomographic imaging studies demonstrated good MR contrast capability of the nanohybrids which might be due to the nanogold component (Figure 5A-C). It was further observed that the relaxation rate (1/T2) varied linearly with iron content (Figure 5D). Cellular uptake study indicated their localization in the intracytoplasmic region of the cell, which is appropriate for the imaging of cells.

16

Figure 5: MRI imaging application of phytosynthesized Fe3O4/Au hybrid nanoparticles. MR phantom images (T2-weighted) of Fe3O4 and Fe3O4/Au hybrid nanoparticles with reference to untreated control (A). Signal intensity vs TE plots for Fe3O4 alone (B) and Fe3O4/Au hybrid nanoparticles (C). Plot of T2 relaxation rate (1/T2) against varying Fe concentrations (D). Reproduced with permission from [108]. 2.5. Drug delivery applications In order to enhance the uptake, circulation time in the bloodstream and biodistribution of drugs, many nanoparticles have been designed and used [109,110] in the treatment of several lifethreatening diseases such as cancer, diabetes and infectious diseases [111]. Major benefits of these approaches are the precise delivery of conjugated or loaded cargos to diseased cells and minimal adverse effects to neighboring normal cells. Metallic nanoparticles such as those based on gold are suitable for the generation of drug delivery systems because of their 17

cytocompatibility and immunocompatibility [112]. Although chemically synthesized AuNPs have been extensively studied for their potential applications in drug delivery, information regarding the drug delivery application of phytosynthesized AuNPs is rather limited [113]. Phytosynthesized AuNPs conjugated with vancomycin was found to be effective to suppress the growth of vancomycin-resistant S. aureus even at a very low concentration (8 µg/mL) [114]. Phytosynthesized gold and AgNPs can also be used for the effective delivery of anti-cancer drugs to the cancer cells. For this, Butea monosperma leaf extract was used for the production of the nanoparticles. Overall schematic representation of the phytosynthesis, nanoparticle characterization and their proposed applications in chemotherapeutic drug delivery is shown in Figure 6A. Transmission electron microscopic images (TEM) showing the morphology, size and shape of b-Au-500 and b-Ag-750 are presented in Figure 6B. TEM images of b-Au-250 and bAu-500 indicate that the nanoparticles were 50–75 nm in size and almost monodispersed and generally spherical in shape. Similarly, TEM images of b-Ag-500 and b-Ag-750 clearly indicate the presence of large spherical nanoparticles (20–80 nm). Nanoparticle based drug delivery systems conjugated with doxorubicin (DOX) [b-Au-500-DOX and b-Ag-750-DOX] showed significant inhibition of murine melanoma cancer cell (B16F10) proliferation compared to free drug (Figure 6D and Figure 6E) [115]. Result of cell cycle analysis indicated that cell cycle arrest happened at the sub-G1 phase in the cells exposed to b-Au-500-DOX and b-Ag-750-DOX as a result of the apoptotic cell death (Figure 6F). In another study, Peltophorum pterocarpum (PP) mediated green-synthesized AuNPs was used as an effective drug delivery system for the delivery of DOX [116]. Furthermore, in vitro and in vivo anticancer activities of DOX loaded drug delivery system were performed on A549 and B16F10 cancer cells and melanoma tumor mouse models, respectively. Cellular internalization and subsequent release of free DOX were marginally low compared to biosynthesized AuNP-PP-DOX conjugates. Moreover, AuNP-PPDOX conjugates exhibited superior tumor reduction potential than non-conjugated DOX.

18

Figure 6: Schematic representation of the production of drug delivery system based on phytosynthesized gold and AgNPs via Butea monosperma leaf extract and it’s in vitro and in vivo anticancer potential (A). TEM images of phytosynthesized nanoparticles (B). Cellular uptake of DOX, b-Au-500-DOX and b-Ag-750-DOX by fluorescence microscopy (C). In vitro anticancer efficacy of b-Au-500-DOX (D) and b-Ag-750-DOX (E) on B16F10 cells. In vitro cell cycle analysis in B16F10 cells treated with b-Au-500-DOX and b-Ag-750-DOX (F). Reproduced with permission from [115]. 2.6. Dental applications

19

The immense interest in the dental applications of nanomaterials resulted in the emergence of a separate field of nanomedicine referred as nanodentistry. Incorporation of phytosynthesized nanoparticles to the dental acrylic resin can provide excellent antimicrobial property to dental composite. AgNPs with 10–20 nm in dimensions were synthesized using the leaf extract of Justicia glauca and tested against dental microorganisms [117]. The phytosynthesized AgNPs were tested against the microbial pathogens causing dental caries and periodontal diseases such as Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, Streptococcus mutans, Micrococcus luteus, Lactobacillus acidophilus, Bacillus subtilis and Candida albicans. Phytonanoparticles showed a considerable antimicrobial activity against the tested dental pathogens with a minimum inhibitory concentration (MIC) ranging from 25 to 75 µg/mL. In

another study, AgNPs were synthesized in situ in orthodontic elastomeric modules (OEM) using the extract of Hetheroteca inuloides (H. inuloides) [118]. The potential of OEM with phytonanoparticles to inhibit dental microbes was tested against the clinical isolates such as Staphylococcus aureus, Streptococcus mutans, Escherichia coli and Lactobacillus casei. Phytonanoparticles loaded OEM could effectively inhibit microbial proliferation which suggest its potential to inhibit dental biofilm formation in patients with orthodontic treatment. In addition to the antibacterial performance, incorporation of phytosynthesized AgNPs can improve the mechanical bonding and hardness of the dental cements [119]. In an interesting study, AgNPs were synthesized using Mangifera indica (Mango leaves) extracts and the obtained phytonanoparticles were loaded in dental cement (in 2% weight ratio). The results of this study indicated a significant increase in the hardness of the cement reinforced with AgNPs compared to the conventional dental cement. In another study, polymethyl methacrylate (PMMA) thin films incorporated with phytosynthesized AgNPs were fabricated and tested for the antimicrobial and antibiofilm properties against the dental bacterium Streptococcus mutans. Here, Curcuma aromatica rhizome was used for the synthesis of phytonanoparticles [120]. This study suggests that PMMA/phytonanocomposite thin films can inhibit the colonization of cariogenic bacteria in dental restorative materials. 3. Future prospective and challenges The phytosynthesized nanoparticles has many benefits such as the steady production of nanoparticles without sophisticated equipment, simplicity of the synthesis process, the lack of toxic contaminants, and the possibility for rapid synthesis using numerous edible/medicinal 20

plants. Recent developments on phytosynthesized nanoparticles invariably demonstrated their potential biomedical applications such as antimicrobial agents, cancer theranostics agents, drug delivery systems, image contrast agents and in biosensors. However, scalable industrial production of such nanoparticles without batch to batch variation is yet to be addressed. Achieving a tight control of nanoparticle size and shape without compromising yield at largescale is a difficult to achieve strategy which is mandatory for the commercialization of phytonanoparticles. Moreover, new downstream processing and separation techniques need to be implemented to deal with large quantity of obtained nanoparticles. Stable production of monodispersed nanoparticles with high yield could be accomplished by adjusting several process parameters such as plant species used, amount of extract, concentration of metal salt, temperature, pH, contact time and mixing ratio. Another challenge yet to be solved is the controlled production of nanoparticles conjugated with specific plant derived biomolecules. Although it is possible to generate plant biomolecules anchored nanoparticles, further investigation regarding the specific conjugation of desired biomolecules by phytosynthesis approaches is still required. The phytosynthesized nanoparticles are demonstrated as relatively safe for healthcare applications compared to their chemically synthesized counterparts due to the lack of toxic contaminants in them. However, the safety issue owing to the metal itself, nano size and subsequent penetration and, or permeation through the tissues are still to be considered while applying in healthcare products. There are many studies to demonstrate the in vitro cytocompatibility of phytonanoparticles [121–123]. However, information regarding the in vivo acute and chronic toxicity, immunogenicity, uptake, biodistribution, excretion, clearance and pharmacodynamics of them need to be extensively studied. Rigorous research is needed in these directions before going to the clinical trials. Although plant mediated nanoparticle synthesis route is considered as ecofriendly approach, the direct or indirect ecological impact of phytosynthesized nanoparticles is still lacking. Several studies reported the possible applications of metallic nanoparticles for drug and gene delivery applications. However, information regarding the application of phytonanoparticles in the field is rather limited. It will be interesting for the researchers those who are working in the drug or gene delivery applications to explore the potential uses of phytonanoparticles. 21

Phytonanoparticles bear plant derived biomolecules on them and avoids self-agglomeration [124].

Conjugation of target specific antibodies to the plant derived molecules present on the

phytonanoparticles would be an interesting topic of research. Our literature survey shows that there is a huge scope for the phytosynthesized nanoparticles and hence considerable attention must be given to in-depth study on healthcare applications of phytosynthesized nanoparticles especially in the unexplored areas. 4. Conclusions Biomedical applications of nanoparticles synthesized from plant derived materials having various physicochemical properties and composition were widely discussed in the scientific literature. Biochemicals present in the extracts of plants such as alkaloids, can play active role in the formation as well as stabilization of phytonanoparticles. The major benefits of the phytonanoparticles are their biocompatibility and bioactivity due to the presence of plant derived biomolecules.

Owing

to

the

superior

properties

and

ecofriendly

synthesis

route,

phytonanoparticles have a lot of potential in various healthcare applications. A major challenge in phytosynthesis is the difficulty to control the size and shape of the nanoparticles. Effective utilization of phytosynthesized nanoparticles with various chemical composition, size/shapes and surface properties can be a novel, ecofriendly and economically viable approach in healthcare field that can minimize toxic chemicals used in the conventional nanoparticle synthesis routes. Conflicts of interest The authors declare that they have no conflict of interest to disclose. Acknowledgements This article was made possible by the NPRP9-144-3-021 grant funded by Qatar National Research Fund (a part of Qatar Foundation). Financial support from Qatar University through internal grant (GCC-2017-005) also gratefully acknowledged. The statements made here are the sole responsibility of authors. References [1]

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Conflicts of interest The authors declare that they have no conflict of interest to disclose.