Recent advances in nanoparticles-based strategies for cancer therapeutics and antibacterial applications

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Recent advances in nanoparticles-based strategies for cancer therapeutics and antibacterial applications

11

Surendra Gullaa, Dakshayani Lomadab, Vadali V.S.S. Srikanthc, Muthukonda Venkatakrishnan Shankard, Kakarla Raghava Reddye, Sarvesh Sonif, Madhava C. Reddya,* a

Department of Biotechnology and Bioinformatics, Yogi Vemana University, Kadapa, India b Department of Genetics and Genomics, Yogi Vemana University, Kadapa, India c School of Engineering Sciences and Technology, University of Hyderabad, Hyderabad, India d Department of Materials Science & Nanotechnology, Yogi Vemana University, Kadapa, India e School of Chemical and Biomolecular Engineering, The University of Sydney, Sydney, NSW, Australia f School of Science, College of Science Engineering and Health, RMIT University, Melbourne, VIC, Australia *Corresponding author: e-mail address: [email protected]

Abbreviations DMBA DOX MSN PCL PEG ROS SPIONS TGF TNF USPIONS VEGF

dimethyl benz(a) anthracene doxorubicin mesoporous silica polycaprolactone polyethylene glycol reactive oxygen species superparamagnetic iron oxide nanoparticles transforming growth factor tumour necrotic factor ultra superparamagnetic iron oxide nanoparticles vascular endothelial growth factor

Methods in Microbiology, Volume 46, ISSN 0580-9517, https://doi.org/10.1016/bs.mim.2019.03.003 © 2019 Elsevier Ltd. All rights reserved.

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1 Introduction Cancer is a complex, malignant, widespread disease around the world. It is a term used to describe a large group of diseases that are characterized by cellular malfunction. Healthy cells are programmed to “know what to do and when to do”. Cancerous cells do not have this programming and therefore grow and replicate out of control. They also serve no physiological function. These cells are termed as neoplasia. The neoplasmic mass often forms a clump of cells known as a tumour. Cancer arises from the loss of normal growth control. In normal tissues, the rate of new cell growth and that of the old cell death are kept in balance. In the case of cancer, this balance is disrupted. This disruption can result from uncontrolled cell growth or loss of a cell’s ability to undergocell suicide by a process called apoptosis. The major cause of cancer is the mutations, which are primarily caused by UV rays, smoking, and consumption of alcohol and infectious agents like the hepatitis virus. Mutations change the DNA base pairs and the proto-oncogenes are converted into oncogenes that in turn lead to the malfunction of the genes and cause the failures of cell cycle regulation and uncontrolled cell growth and finally leading to the tumour formation. There are more than 100 types of cancers, which are named based either on the site or type of the cell in which cancer grows. For example, cancer that begins in the colon is called colon cancer while the one that begins in melanocytes of the skin is called melanoma. Most common cancers in males are prostate (19%), lung and bronchus (14%), colon and rectum (9%). In females, most common cancers are breast (30%), lung and bronchus (13%) and colon and rectum (7%) (Siegel, Miller, et al., 2018). According to cancer research in the UK, the major types of cancers are carcinoma (begins in skin or tissue), sarcoma (begins at connective tissue), lymphoma (through the bloodstream) and leukaemia (begins through cells of the immune system). In women breast cancer is the second most common cause of death and it occupies first place in women cancer according to 2017 cancer statistics (Siegel, Miller, et al., 2016). Ovarian cancer is the next leading cancer cause of death in women (Latha, Panati, et al., 2014). Cancer has become a major public health problem throughout the world. It was estimated in 2018 that 1,735,350 new cases of cancer will be diagnosed in the United States and that about 609,640 people will die. As per NICPR, India, 2.5 million people are living with cancer in India and each year 0.7 million new cancer patients are registered while many people die every year due to cancer-related issues. In India, for every 8 min, one woman died due to cervical cancer. 5–10% of breast cancer cases can be attributed to inherited factors and most popular hereditary susceptible genes in breast cancer are BRCA1 and BRCA2. Key biomarker for recognition of breast cancer is human epidermal growth factor receptor-2 (HER-2). Normal-immune system and physiological conditions protect the body from tumours, auto-immunity and tissue damage while responding to pathogens by expressing the immune checkpoints such as CTLA4 and PD1 (Pardoll, 2012). Immune response against cancer is a balance between immune activating and immune suppressive mechanisms. To induce tumour immunity, sufficient numbers of functional dendritic cells (DCs) must be generated in situ, capture, and process tumour-

1 Introduction

associated antigen (TAA), migrate to secondary lymphoid organs and stimulate TAA-specific T cells. TAA-specific T cells must then provide a home to a tumour, recognize TAA and eradicate tumour cells. Defects in any of these processes will cause sub-optimal or no immune responses. By secretion of cytokines such as IL-6, IL-10, Macrophage colony stimulating factor (MCSF) and vascular endothelial growth factor (VEGF), tumours prevent DC differentiation and function. Decreased expression of DC accessory molecules and inefficient lymphoid homing are also related to tumour immunopathogenesis. The understanding of how cancer escapes from the normal immune system is crucial. Once the normal cells are converted into cancer cells, the genetic changes in the cancer cells hinder the process of the normal immune system through the outgrowth of poorly immunogenic tumour variants (Block & Markovic, 2009) and they continuously grow and suppress the immune system (Fujimoto, Greene, et al., 1976). Though the immune cells present in the tumour microenvironment are able to identify the tumour cells and promote the apoptosis of the cells, the tumour cells escape from apoptosis by expressing proteins like ARP—Fas and Fas ligand, BCL-2, p53 (Ben-Hur, Gurevich, et al., 2000) or inhibiting the NK cell activity by expressing HLA-G (Paul, Rouas-Freiss, et al., 1998). Cancer cells have the ability to escape from the immune system by creating a highly immunosuppressive network because of the pathological interactions between tumour cells and host immune cells in the tumour microenvironment (Latha et al., 2014). There are complex interactions among various immune cells and their role in creating the immunosuppressive tumour microenvironment. There are many ways to treat cancer. The types of treatment (namely, surgery with chemotherapy and/or radiation therapy, immunotherapy, targeted therapy, hormone therapy, stem cell transplantation, precision medicine and anti-angiogenesis therapy) depend on the type of cancer and how advanced it is. A combination of treatments is also used. Of late, use of “nanoparticles” in different cancer treatment strategies has gained prominence due to the advances in “Nanoscience and technology”, which involves design, synthesis, characterization, and application of nanomaterialsprimarily aiming to improve life. Nanomaterials exhibit properties that are distinctively different from their bulk counterparts owing to a characteristic dimension (at the nanoscale in the concerned nanomaterial) that is either comparable or smaller than a length scale that is critical to a phenomenon associated with the concerned material. Among various nanomaterials, nanoparticles (NPs)a have gained prominence owing to the ease in their synthesis and handling. More importantly, NPs are used in a variety of applications including biological applications. A wide range of nanoparticles have been found to exhibit characteristics that are useful in treating cancers (Silva, 2004). Nanoparticles conjugated with chemotherapeutic agents overcome drug resistance (Hu & Zhang, 2009). FDA approval has been granted to some of the nanoparticle-based products like PEGylated liposomal doxorubicin, liposomal a

Nanoparticle is an agglomerate of atoms, molecules, ions, etc. It can be either amorphous or crystalline. Crystalline nanoparticle is an agglomerate of crystallites of same material or crystallites of two or more different materials whereas amorphous nanoparticle is an agglomerate of atoms, molecules, ions, etc., without any crystal structural ordering.

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doxorubicin, liposomal daunorubicin, and nanoparticle albumin (NAB) paclitaxel for breast, ovary, lung, pancreas and Kaposi’s sarcoma treatment (Zhang, Tang, et al., 2017). Metallic nanoparticles have different physical, chemical and optical properties. The key properties of nanoparticles for biomedical applications are shape, size, surface area and surface charge. The properties of nanoparticles mainly influence the enhanced cellular uptake and transport of these particles in the biological fluid. It was established that positively charged nanoparticles have more cellular uptake when compared with negatively charged ones (Chithrani & Chan, 2007; Peng, Lu, et al., 2017). Nanoparticles have become useful for targeting tumour sites once modified in chemical, surface area and charge size. Hence, nanoscale particles are the frontier of nanotechnology when applied as a biomaterial. The use of nanomedicines has increased enormously and nanomaterials have been shown to offer promising strategies to optimize and improve the treatment of numerous disorders including cancers. Also nanomedicines based therapy has the ability to overcome the limitations of current immunosuppressive and biological therapies. It has been established that in cancer therapy these NPs are used as vehicles for carrying the drugs to target regions and also fluorescent labelled NPs are used in the imaging technology (Farokhzad & Langer, 2009). NPs less than 10 nm can easily reach the target sites in our body (Davis & Shin, 2008). For instance, currently, several ongoing clinical types of research are involved in the development of anti-angiogenesis therapy. Angiogenesis is a process of formation of new blood vessels from the pre-existing vessels that transports oxygen and nutrients to cells and removes unwanted products (Carmeliet, 2003). In 1971, Folkman proposed a hypothetical theory on tumour growth and expansion (Hanahan & Folkman, 1996) stating that angiogenesis is essential (Folkman, 1971) for the release of proangiogenic factors that affect existing vessels and promote tumour growth and metastasis. Vascular endothelial growth factors (VEGF) and their receptors play a central role in the angiogenesis process. VEGF is a stimulator for angiogenesis because it provides growth factors that are required for the vascular endothelial cell growth, proliferation and formation of tubular structures (Ferrara, 2002; Prior, Yang, et al., 2004). Hanahan and Weinberg postulate that all cancers acquire the same six hallmark capabilities, namely, self-sufficiency in growth signals, evading growth suppressors, tissue invasion andmetastasis, evading apoptosis, enabling replicative potential, sustained angiogenesis (Hanahan & Weinberg, 2000). Angiogenesis, as shown in Fig. 1, is a significant event for tumourigenesis. In the absence of angiogenesis, the tumour will not grow beyond 1–2 mm3 (Naumov, Akslen, et al., 2006). For expansion of tumours, neovascularization must reach beyond 400 μm, a vascular tissue like epidermis originating tumours require a new vascular invasion. Angiogenesis is mandatory not only for the continual growth of tumours but also for metastasis. Four basic steps are essential for the tumour angiogenesis or neovascularization as shown in Fig. 1. First, nearby the basement layer is wounded causing direct damage and hypoxia. Second the action of endothelial cells due to the release of angiogenic factors and proliferation. Third stabilization of endothelial cells. Fourth the continuing influence of angiogenic factors on the angiogenic process (Spannuth, Sood, et al., 2008).

1 Introduction

FIG. 1 Mechanisms of tumour neovascularization; (A) Sprouting is an invasive process. In this process, the proteolytic activities degrade the basement membrane of endothelial cells, allowing their invasion and migration. (B) Vasculogenic mimicry is the process of generation of microvascular channels by aggressive tumour cells. (C) Vessel co-option is a mechanism in which tumours obtain a blood supply from existing mature blood vessels. (D) In the tumour neovascularization process pro-angiogenic factors (VEGF) are released by the tumour cells leading blood vessel growth and subsequent tumour expansion.

A variety of different molecules are involved in the activation of angiogenesis, including vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), plate derived growth factor (PDGF), epidermal growth factor (EGF), granulocyte stimulating growth factor (GSGF), matrix metalloproteinase’s (MMP’s), transforming growth factor (TGF), tumour necrosis factor (TNF), hepatocyte growth factor (HGF) and angiopoietins (Kitadai, 2010). Inhibition of angiogenesis stops the possibility of migration and invasion of cancer cells and reduces tumour growth. Angiostatin, endostatin, tissue inhibitors of matrix metalloproteinase’s (TIMP), interferon and interleukins act as endogenous angiogenesis inhibitors (Yadav, Puri, et al., 2015). In general proangiogenic factors and anti-angiogenic factors are tightly regulated and maintained in balance but in the tumour microenvironment the proangiogenic factors overcome the effect of anti-angiogenic factors and favour the angiogenesis process without regulation and finally lead to the progression and development of tumour growth (Risau, 1997). Therefore, tumour development must

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require angiogenesis and it has become a promising therapeutic strategy for the treatment of cancer. To date, FDA approved angiogenesis inhibitors are bevacizumab, temsirolimus, cetuximab, erlotinib hydrochloride, sorafenib, sunitinib, trastuzumab, panitumumab, thalidomide. In this review, the existing nanoparticles’-based strategies for cancer treatment will be highlighted especially from the perspective of nanoparticles’ properties. The focus will be on the use of several metal and metal oxide nanoparticles for targeting cancer and angiogenesis (Fig. 2). Further, the antibacterial characteristics of different types of nanoparticles are also discussed (Fig. 5).

FIG. 2 Influence of different nanoparticles on angiogenesis.

2 Nanoparticles for targeting angiogenesis in cancer

2 Nanoparticles for targeting angiogenesis in cancer 2.1 Titanium dioxide nanoparticles (TiO2) Titanium dioxides have a wide range of applications due to their unique physical and chemical properties. Titanium dioxide used in textiles, papers, food, and drugs. Latha, Lomada, et al. (2016) designed titanium dioxide based nanoparticles such as titanium dioxide nanotubes (TNT), TiO2 fine particles and investigated the effect of these nano compounds on collagen-induced arthritis (CIA), autoimmune encephalomyelitis (EAE) concluding that these Ti-O based nanoparticles reduced proinflammatory cytokine HMGB1. In human-human bronchial EC, titanium dioxide nanoparticles induced the oxidative stress, apoptosis and neural toxicity (Long, Tajuba, et al., 2007). TiO2 nanoparticles at 30–70nm induced apoptosis and oxidative DNA damage on human liver cells even at a very low concentrations (Shukla, Kumar, et al., 2013). Bare titanium dioxide nanoparticles suppressed the angiogenesis in vitro and in vivo they suppressed retinal neovascularization (Jo, Kim, et al., 2014). These nanoparticles are dose dependent, nontoxic, and induce apoptosis in human breast cancer cells (MCF-7) and normal breast epithelial cells (HBL-100) (Murugan, Dinesh, et al., 2016). TiO2 nanoparticles loaded with doxorubicin (DOX-TiO2) are accumulated more at tumour sites and induced apoptosis through a caspase-dependent mechanism (Chen, Wan, et al., 2011). TiO2 nanoparticles arrested the cell cycle at G0/G1 phase in the A549 cell line. TiO2 NPs block the transforming growth factorβ (TGF-β) by interacting with the TBRI/II complex (Li, Song, et al., 2018). Latha et al. developed spherical TiO2 fine particles (TFP). TiO2 nanosquars (TNS), TiO2 nano tubes (TNT) were evaluated on anti-cancer, anti-angiogenesis and gene expression of P53, MDA7 and transcription factor STAT3 concluding that these nanoparticles inhibited the proliferation of breast cancer cell line (MDA-MB-231), 3T3 fibroblast cell lines, the formation of blood vessels on CAM model and they up-regulated the tumour suppressor genes p53 and MDA7. This study concluded that titanium dioxide nanotubes have more anti-cancer and anti-angiogenic properties compared to TFP and TNS (Latha, Reddy, et al., 2017). Wright et al. compared the effect of titanium dioxide nanoparticles and TiO2 fine and ultra-fine particles on the human keratinocyte cell line (HaCaT) concluding that on keratinocytes these particles induced apoptosis in dose-depended manner and size of TiO2 does not influence apoptosis (Wright, Iyer, et al., 2017). Fluorescent titanium nanoparticles composite with DOX/ FTN induced apoptosis with great anticancer activity towards human osteosarcoma cells and MCF-7 breast cancer cells by damaging the mitochondrial membrane that leads to cytochrome C into the cytoplasm (Masoudi, Mashreghi, et al., 2018). Mesoporous titanium NPs with an average size of 190 nm had drug releasing capacity in a pH dependent manner, maximum at pH 7.4 in in-vitro (Zamani, Rostami, et al., 2018). Small sized titanium dioxide nanoparticles induced more oxidative stress and apoptosis in an LL2 cancer cell line and reduced tumour volume on subcutaneous induced LL2 tumour in BALB/c mice (Fujiwara, Luo, et al., 2015).

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2.2 Iron nanoparticles (Fe) The role of iron is to transfer oxygen to all parts of the body with the help of red blood cells. A low dose of iron ions is essential for cell replication and DNA synthesis (Crowe, Maglova, et al., 2004). Gao, Zhao, et al. (2017) demonstrated that a combination of low alcohol and high iron intake resulted in significant liver oxidative damage in mice. However, the role of iron as a nanoparticle is largely unknown. Recent data suggests that magnetic iron oxide nanoparticles can be used for celltargeted drug delivery, cell tracking and diagnostic agents. Iron oxide nanoparticles (IONP) have been produced based on the size, shape, and type of coating including starch, albumin, silicon and polyethylene glycol. Tan et al. synthesized spherical shaped dextrin IONP and citrate–IONP with the size of 50 nm. These nanoparticles significantly decreased the migration and viability of HUVECs at a concentration as low as 0.1 mM. These results showed that citrate–IONP reduced more migration of HUVECs when compared with the dextran–IONP (Wu, Tan, et al., 2010). Soares et al. synthesized anionic maghemite-Fe2O3 nanoparticles coated with (DMSA, citric acid, and lauric acid) with different iron concentrations in order to evaluate the toxicity of surface coated maghemite-Fe2O3 in human melanoma cells. Citrated surface coated maghemite NPs inhibited 50% of cell proliferation, lauric acid inhibited 10% and DMSA-coated nanoparticles did not cause any toxic effect to the human myeloma cells. Concentrations as high as (588 and 840 g iron/mL) lauric acid coated nanoparticles induced significant cell death through apoptosis and influenced the metabolic process (de Freitas, Soares, et al., 2008). By using the magnetic nanoparticles, MRI measured the VVF changes and it is a surrogate marker of angiogenesis (Guimaraes, Ross, et al., 2011). Phe-functionalized and tamoxifen loaded iron oxide nanoparticles deliver chrysin and tamoxifen to the breast cancer cell line MCF-7 and induced cytotoxicity (Nosrati, Javani, et al., 2018; Nosrati, Rashidi, et al., 2018). Qian et al. synthesized iron NPs at the size (50–600 nm) which were non-toxic to human microvascular endothelial cells at 50μg/mL and at different time periods (0–6 h) (Apopa, Qian, et al., 2009). Iron oxide nanoparticles at different concentrations (0.15, 1.5, 15 mM) reduced the viability of pc12 cells, increased cytoskeletal disruption, diminished the ability to form mature neurites in response to NGF exposure and produced more neurites at low concentration (Pisanic, Blackwell, et al., 2007). In a rabbit model, iron NPs were highly effective for the treatment of tongue cancer (Ohtake, Umemura, et al., 2017). Superparamagnetic iron oxide nanoparticles (SPIONs) carry drugs to targeted regions that can be guided. These SPIONs modified A7R reduced HUVEC cell viability at concentrations higher than 10 μg Fe/mL compared to cells that were treated with SPIONs modified with a sebacic acid or A7R peptide (Niescioruk, Nieciecka, et al., 2017). Biosynthesized SPIONs up-regulated the apoptotic proteins in HeLa cells (Shanmugasundaram, Radhakrishnan, et al., 2018). Furthermore, ultra-superparamagnetic iron oxide nanoparticles (USPIONs) at the size of 3.5 nm functionalized with c(RGDyC) peptide and labelled with 99mTc did not affect the viability of the H1299 αvβ3 integrin positive lung carcinoma cell line. In vivo studies showed USPIONs target the

2 Nanoparticles for targeting angiogenesis in cancer

αvβ3 integrin allowing molecular imaging of tumour angiogenesis (Xue, Zhang, et al., 2015). The heat generating PEG-coated iron oxide nanocubes generate heat at tumour sites and reduced the size of the tumour (Kolosnjaj-Tabi, Di Corato, et al., 2014). Dutta et al. prepared polymer grafted magnetic nanoparticles that are non-toxic and they can encapsulate the drugs and release them at the desired temperature and pH at the target position (Dutta, Parida, et al., 2016). In addition, Iron oxide nanoparticles with RGD-conjugated human ferritin extends in vivo MRI detection of vascular inflammation and in experimental carotid and AAA disease (Kitagawa, Kosuge, et al., 2017). Green synthesized iron oxide nanoparticles from Psoralea corylifolia seeds induced apoptosis in Caki-2, MDCK tumour cell line (Nagajyothi, Pandurangan, et al., 2017).

2.3 Silicon nanoparticles (Si NPs) Silicon is an essential trace element that is important for good bone formation and connective tissues, and it also effects the physiological process of skeleton tissue (Pietak, Reid, et al., 2007). Silicon is present mainly in the skin and connective tissues of the body and it causes fibrosis in lung tissue. Crystalline silicon irritates the eye and skin on contact and causes redness and watering of the eyes. Dietary intake of Si is between 20 and 50 mg Si/day (Jugdaohsingh, Tucker, et al., 2004). Multi-functional porous Si NPs are used for targeting drug delivery as these particles deliver the drug without changing drug properties. Intra-tumoural delivery of these nanoparticles-loaded with drug retained in the tumour and efficiently suppressed tumour growth when compared to the free drug. Hence, Multi-functional porous Si NPs can be used for constructing theranostic nanosystems for simultaneous studies of the in vivo behaviour of the nanocarriers and their drug delivery efficiency (Wang, Sarparanta, et al., 2015). Mesoporous silica nanoparticles have been used as drug delivery systems for hydrophobic cancer drugs (Lu, Liong, et al., 2007). Mesoporous silica NPs introduced with PEG-folic acid on the surface of polydopamine loaded with DOX delivered drug depended on pH (Cheng, Nie, et al., 2017). Another study on Quercetin loaded mesoporous silica nanoparticles (MSN) conjugated with folic acid, induced apoptosis by regulating Akt & Bax signalling pathways in breast cancer cells (MDA-MB-231), without imparting any toxicity (Sarkar, Ghosh, et al., 2016). MSN loaded with anticancer drug ruthenium complex and conjugated with folate acid are accumulated in hepatocellular carcinoma cell HepG2 showing higher anticancer activity in a size dependent manner. Small sized particles were accumulated more in HepG2 cells, and they inhibited tumour growth of HepG2 tumour-bearing nude mice (Ma, He, et al., 2018). MSN loaded with DOX delivers drug to multidrugresistant cancer cells and decreased their viability whereas MSN loaded with surviving Si-RNA complex suppressed the surviving expression and induced cytotoxicity to A549 lung cancer cell line (Dilnawaz & Sahoo, 2018; Xia, Zhang, et al., 2018). Recently, it has been demonstrated that luminescent porous Si NPs coated with dextran are potential theranostic agents for bioimaging and

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sonodynamic therapy for the treatment of cancer (Sviridov, Osminkina, et al., 2017). Multifluorescent silica nanoparticles have been prepared and used in in vitro and in vivo biological and medical applications. These multi-fluorescent silica nanoparticles had no toxicity on in vivo injection and in labelled cells (Nakamura, Shono, et al., 2007). Guarnieri et al. prepared different sized silica nanoparticles (25, 60, 115 nm) and charged the surfaces with both positive and negative charges and treated with HUVECs at different times with increasing doses. Results showed that small NPs (25, 60 nm) both positively and negatively charged had no cytotoxic effect on HUVECs. Whereas large size NPs positively charged at concentrations of 250 and 2500 pM slightly reduced the cell viability and the negatively charged NPs did not show a toxic effect on HUVECs. This study concluded that the silica nanoparticles at 25 nm had no anti-angiogenic property even at high concentrations and hence can be useful for drug delivery, molecular imaging, gene therapy and in biological applications (Guarnieri, Malvindi, et al., 2014). Silica nanoparticles exhibited cardiovascular toxicity mainly in vascular endothelium but not in cardiomyocytes. These Si NPs disrupted the cytoskeletal organization, damaged mitochondria, initiated the expression of cellular adhesion molecules and impaired angiogenesis (Duan, Yu, et al., 2014). Luminescent porous silicon nanoparticles (LPSINPs) were injected subcutaneously into BALB/C mice for morphological analysis. After 4 weeks of injection, these LPSINPs did not cause any significant toxicity to kidney, liver, and spleen of BALB/C mice (Park, Gu, et al., 2009). Silicon nanoparticles at the size of 62 nm and concentrations ranging from 25 to 100 μg/mL did not effect the viability of HUVECs between 6 and 9 h but at 12 h the higher concentration decreased the viability of HUVECs. Also, silicon nanoparticles exhibited late apoptosis in HUVECs and increased ROS levels resulting in oxidative damage in HUVECs. In zebrafish embryo in vivo studies, these nanoparticles inhibited angiogenesis and disturbed heart formation. These results concluded that silicon nanoparticles inhibited angiogenesis in a time and dose-dependent manner (Duan, Yu, et al., 2013). Porous silicon nanoparticles delivered tamoxifen (anti-oestrogen treatment of breast cancer) to the target site with drug release prolonged by weeks without any burst effect, hence it was shown to be a good tamoxifen carrier (Haidary, Mohammed, et al., 2016). Allyl isothiocyanate conjugated silicon quantum dots entered into HepG2 cells, increasing ROS generation, reducing cell viability and inhibiting migration of HepG2 cells (Liu, Behray, et al., 2018).

2.4 Zinc nanoparticles (Zn) Zinc is an important element that maintains hormone levels and acts as an antioxidant. During pregnancy, it is important for the proper development of factors (EscottStump, 2008). Zinc deficiency causes infertility in both males and females accelerating the ageing process (Fallah, Mohammad-Hasani, et al., 2018). In adults, 8 mg/ day is required, mainly found in beef, pork, and dark chicken meat (SarubinFragakis & Thomson, 2007). Zinc is present in DNA-binding proteins and is also involved in the DNA repair mechanism (Ho, 2004). Zinc oxide NPs at a size of

2 Nanoparticles for targeting angiogenesis in cancer

60 nm were incorporated into PCL (polycaprolactone) scaffolds and when their angiogenesis effect was studied on human dermal fibroblast cells (HDFa), ZnO nanoparticles containing scaffolds had a higher cell density at (0, 0.5, 1, 2, 3, 4, and 6 wt%) compared to controls. In chick chorioallantoic membrane CAM model, PCL scaffolds with nanoparticles at a concentration of 1 wt% increased the formation of matured blood vessels. ZnO nanoparticles with PCL scaffolds at 1 wt% are pro-angiogenic (Augustine, Dominic, et al., 2014). ZnO nanoparticles activateTcells and kill cancer cells at low concentrations (0.2–0.5 mM) (Hanley, Layne, et al., 2008). Hanley et al. prepared different sizes of ZnO nanoparticles at sizes (4, 8, 13, 20 nm) and tested them for immune cell cytotoxicity with different concentrations (0, 0.5, 1, 2, 2.5, 5 and 10 mM) with the result that monocytic cells had the greatest susceptibility, followed by NK cells, then by lymphocytes which were the most resistant and suggesting that ZnO nanoparticles produces TNF-α destroys tumour cells, small size zinc nanoparticles more toxic compared to larger ones (Hanley, Thurber, et al., 2009). ZnO NPs induced oxidative stress and activated the JNK pathway (c-Jun N-terminal kinase) which is involved in the induction of apoptosis in primary astrocytes (Wang, Deng, et al., 2014). ZnO nanoparticles with an average diameter of 196 nm have no cytotoxic effect up to 24 h. However, after 48 h, these nanoparticles decreased the viability of human colon carcinoma cells (LoVo) in adose and time dependent manner (5 μg/cm2). At higher levels (10, 20, 40 μg/cm2) induce cytotoxicity and apoptotic cell death (De Berardis, Civitelli, et al., 2010). ZnO NPs were cytotoxic to MCF-7, A549 cell lines (Selvakumari, Deepa, et al., 2015). Zinc nanoflowers with a size of 500 nm increased the proliferation of HUVECs and increased mature blood vessels in a dose-dependent manner and zinc nanoflowers had wound healing activity (Barui, Veeriah, et al., 2012). Zinc nano pellets size at 200–500 nm inhibited 50% of pc-3, MDA-MB-231 breast cancer cell lines (Gopala Krishna, Paduvarahalli Ananthaswamy, et al., 2016). Vijaykumar et al. synthesized zinc oxide NPs from Laurus nobilis leaf extract inhibiting human lung cancer cell line-A549 viability at 80μg/mL (Vijayakumar, Vaseeharan, et al., 2016). The composition of titanium dioxide and zinc oxide nanoparticles inhibited (HeLa) human cervical cancer cell line, Chinese hamster ovary cells (CHO), human breast adenocarcinoma cells (MD-231) and Mus musculus skin melanoma cells (B16F10) in a dose-depended manner (Chakra, Rajendar, et al., 2017). Zinc nanoparticles combined with polyinosinic–cytidylic acid (pIC) in-vitro induces significant cell death in human A375 melanoma and B16F10 mouse melanoma cells, and in vivo significantly inhibited B16F10 mouse melanoma tumours (Ramani, Mudge, et al., 2017). Green synthesis of zinc oxide nanoparticles from Pongamia pinnata seed extract inhibited the viability of breast cancer cell line MCF-7 (Malaikozhundan, Vaseeharan, et al., 2017). Calcium phosphate cement (CPC) incorporated into Zinc bio-glass activates odontogenic differentiation and promotes angiogenesis (Zhang, Park, et al., 2015). ZnO thin coated chips released zinc ions, induced oxidative stress, suppressed antiapoptotic molecules and showed cytotoxic to A549 lung cancer cell lines (Moon, Choi, et al., 2016). ZnO NPs down-regulated the hepatocyte integrity and oxidative stress markers in dimethyl nitrosamine-induced HCC in adult male Wister rats

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(Hassan, Mansour, et al., 2017). Green synthesized ZnO NPs from Mangifera indica leaf extract inhibited the proliferation of A549 cell line in a dose-dependent manner (Rajeshkumar, Kumar, et al., 2018). Surface functionalized ZnO NPs from N-acetyl-L-cysteine (NAC) conjugated with camptothecin reduced the proliferation of A549 lung cancer cell line by releasing camptothecin (Li, Zhang, et al., 2018). ZnO NPs from Turbinaria conoides in vitro decreased the viability of DLA cells and in in vivo at a concentration of 50 μg/kg reduced the tumour volume in Daltons lymphoma ascites (DLA) bearing Swiss albino mice (Raajshree & Brindha, 2018). ZnO NPs activated PINK1/parkin-mediated mitophagy process and increased ROS levels in CAL27 cells leading to decreased viability (Wang, Gao, et al., 2018). Doxorubicinwrapped ZnO NPs increased the cellular accumulation of DOS in the human colorectal adenocarcinoma cell line (Caco-2) leading to decreased viability (Kim, Lee, et al., 2017).

2.5 Silver nanoparticles (Si) Silver nanoparticles play an important role in our health and immunity. Deficiency of silver causes impairment in immune function. Silver is used medicinally in wound dressing creams (Atiyeh, Costagliola, et al., 2007) and as an antibiotic coating on medical devices. Inorganic salts are the best source for synthesizing silver nanoparticles and depending on the synthesizing methods silver nanoparticles are available at different structures most commonly triangular and hexagonal shapes (Besinis, De Peralta, et al., 2014). Small silver nanoparticles ranging from 1 to 100 nm are more toxic and when they aggregated inhibit immune function (Christensen, Johnston, et al., 2010). Silver nanoparticles synthesized from Saliva officinalis extract with an average size of 16.5  1.2 nm affect endothelial cells by inhibiting blood vessel formation in a dose-dependent manner (Baharara, Namvar, et al., 2014). Silver nanoparticles synthesized by using B. licheniformis at a size of 40–50 nm and a concentration of 50 ng/mL significantly blocks the VEGF-induced proliferation of bovine retinal capillary endothelial (BREC) cells and also inhibits endothelial cell migration and tube formation. It has been shown that VEGF and silver nanoparticles inhibited 80% of tube formation of BREC cells (Kalishwaralal, Banumathi, et al., 2009). Furthermore, silver nanoparticles at 500 nM strongly inhibited the formation of microvessels and vessel number in vivo using a mouse model. Hence, silver NPs can be targeted therapeutic molecules for the treatment of eye-related neovascular diseases and diabetic retino therapy (Gurunathan, Lee, et al., 2009). Silver NPs at 500 nm decreased 50% viability through apoptosis of Dalton’s lymphoma ascites (DLA) cells at a concentration of 500 nM (Sriram, Kanth, et al., 2010). Conjugated Silver nanoparticles with heparin derivative (glucose or DAPHP) at a concentration of 10μg/CAM have no lethal effects when compared to unconjugated silver nanoparticles. The data suggested that normal silver nanoparticles have 60–70% lethal effects whereas the conjugated nanoparticles improve the safety profile of the metals (Kemp, Kumar, et al., 2009). Kang et al. prepared polyvinylpyrrolidone (PVP) coated silver nanoparticles with a size of approximately 2–3 nm inducing the formation of thicker blood vessels

2 Nanoparticles for targeting angiogenesis in cancer

at concentrations of 0.5, 1, 5, 10, 20 μg/mL when compared to untreated blood vessels. Silver nanoparticles induced VEGF signalling and angiogenesis in b16F10 melanomas (Kang, Lim, et al., 2011). Silver nanoparticles at an average size of 10 5 nm and concentrations of 2.5 and 0.25ppm slightly increased the production of IL-12 in Normal Human Epidermal Keratinocytes (NHEK) and Normal Human Dermal Fibroblasts (NHDF) and supported the wound healing process (Frankova´, Pivodova, et al., 2016). Pourali et al. synthesized silver nanoparticles from Bacillus thuringiensis and Enterobacter cloacae which increased the formation of collagen bundles and decreased the rate of angiogenesis (Pourali, Razavian Zadeh, et al., 2016). Silver NPs at 50nm size influenced cytotoxicity on HeLa cells through the apoptotic pathway (Pandurangan, Enkhtaivan, et al., 2016). Silver NPs encapsulated with chitosan Nano formulations inhibited MCF-7 breast cancer cell lines in a dose-dependent manner (Nayak, Minz, et al., 2016). Silver NPs synthesized from Panax ginseng Meyer and Origanum vulgare, inhibited the viability, migration and phosphorylation of A549, MCF-7, and HepG2 cell lines. Silver NPS up-regulated the P38 MAPK/p53-mitochondrial caspase-3 pathway in lung cancer cell line A549 and induced cell apoptosis, and NPs synthesized from Melia dubia leaf were cytotoxic to human breast cancer cell line KB (Castro-Aceituno, Ahn, et al., 2016; Kathiravan, Ravi, et al., 2014; Sankar, Karthik, et al., 2013). NPs synthesized from fruit extract of Cleome viscosa induced cytotoxicity on lung A549 and PA1 ovarian cancer cell lines in a dose-dependent manner (Lakshmanan, Sathiyaseelan, et al., 2018). Silver nanoparticles embedded into a specific polysaccharide entered into the cytoplasm of HCT-116, SKBR3 and HT29 cells, inducing ROS production and up-regulating apoptosis (Buttacavoli, Albanese, et al., 2018). NPs synthesized from seaweeds had a dose dependent cytotoxicity on A549 and HEPG-2 cancer cell lines (Devi, Bhimba, et al., 2012; Maharani, Sundaramanickam, et al., 2016). NPs synthesized from Ginseng fresh leaves inhibited B16BL6 melanoma and A549 lung cancer cells at a concentration of 100 μg/mL (Singh, Singh, et al., 2016). Spherical shaped silver nanoparticles at 10nm entered into cells through diffusion or endocytosis, damaging protein and nucleic acids, and inhibiting cell proliferation of MCF-7 (human breast cancer cell line), HeLa (Human cervical carcinoma cell) and inducing apoptosis in a dose-dependent manner. Also in in-vitro, silver nanoparticles at 400 μg/mL completely inhibited the tube formation of HUVECs and also inhibited HIF-1 function (Yang, Yao, et al., 2016). Silver nanoparticles at a high 400 nm concentration decreased inflammatory cytokines (TNF-α, IL-12) and VEGF growth factors that are produced by NFDFs and NHEKs (Frankova´ et al., 2016). NPs synthesized from aqueous rhizome extract of Acorus calamus reduced the viability of Hep2, COLO205 and SH-sy5y and up-regulated apoptosis in Hep2 cell lines, and in in-vivo toxicity studies revealed that male Wistar rats treated with silver nanoparticles at 5 mg/kg did not alter any serum biochemical markers but a twofold increase in concentration alters biochemical properties of TNF-α and IL-6 cytokine levels for up to 29 days and after 84 days complete elimination of silver from the rats was observed (Nakkala, Mata, et al., 2018). NPs synthesized from dried fruit extract of Ficus carica showed cytotoxicity to MCF-7 breast cancer cell line and oral administration of these NPs were acutely toxicity safe in Swiss albino female rats (Jacob, Prasad, et al., 2017). Silver nanoparticles activated the

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ASK1/JNK, P38-caspase 3 pathway in human adenocarcinoma A549 cells, inhibiting growth and inducing apoptosis (Ma, Zhao, et al., 2017). Silver nanoparticles activated PtdIns3K signalling, inducing cytoprotective autophagy in B16F10 melanoma cells and reducing tumour growth in a subcutaneous tumour model (Lin, Huang, et al., 2014).

2.6 Copper nanoparticles (Cu) Copper is an essential trace element to all living organisms. In humans, copper is required for the functioning of different metabolic process (Sigel, Sigel, et al., 2013). Copper is involved in the formation of red blood cells and also stimulates the immune system to fight against infections and injured tissues (Klevay, 1997). Furthermore, copper is essential in the aerobic respiration of all eukaryotes. However, an excess amount of copper in-take causes toxicity. Copper ions increased the proliferation and migration of endothelial cells and activated some pro-angiogenic factors like VEGF, fibroblast growth factors (FGF), tumour necrosis factor alpha α (TNFα) and interleukins (Goodman, Brewer, et al., 2004; Nasulewicz, Mazur, et al., 2004). Copper nanoparticles at higher concentrations are toxic (40–100 μm) to dorsal root ganglion (DRG) neurons and toxicity is observed depending on the size and concentration. Larger nanoparticles of 80nm are less toxic when compared to smaller nanoparticles of size 40 and 60nm (Prabhu, Ali, et al., 2010). Copper nanoparticles at 50ppm concentration have no effect on blood vessels and embryo development, and also at the molecular level copper nanoparticles affect mRNA expression (Mroczek-Sosnowska, Sawosz, et al., 2015). Curcumin capped copper nanoparticles at a size of 178 nm slightly inhibit blood vessel formation, proliferation of breast cancer cell line MDA-MB-231 in a dose-dependent manner suggesting that the carbonyl group is an important factor for the manifestation of the tested biological activity of curcumin (Kamble, Utage, et al., 2015). Copper oxide nanoparticles at a size of 75 nm inhibited HUVEC cell migration, proliferation and tube formation in a dosedependent manner. Results from this study showed that CO-NP inhibited angiogenesis in vivo and suggested that this CO-NP may be a potential therapeutic agent to suppresses tumour angiogenesis (Song, Wang, et al., 2014). Copper oxide nanorods at sizes of 200–400 nm induced apoptosis in human cervical carcinoma cells (Pandurangan, Nagajyothi, et al., 2016). Copper nanoparticles at 10 nm embedded in calcium alginate and polypropylene decreased the viability of CNh and SaOS cell lines in a dose-dependent manner (Palza et al., 2017). Green synthesized copper nanoparticles from Eclipta prostrata leaves were cytotoxic to HepG2 cancer cell line (Chung et al., 2017). Biosynthesized copper nanoparticles from C. chinense leaves are toxic to human colon cancer cell line HCT-116 at IC50 40 μg/mL (Gnanavel, Palanichamy, et al., 2017). When compared to copper nanoparticles alone, copper nanoparticles embedded with chitin were more cytotoxic to MCF-7 breast cancer cell line inducing apoptosis (Solairaj et al., 2017). Green synthesized copper nanoparticles from medicinally important plant extracts inhibited MCF-7 breast cancer, A549 lung cancer, HeLa cervical,

2 Nanoparticles for targeting angiogenesis in cancer

Table 1 Copper oxide nanoparticles effect HUVECs. CO-NP concentration

HUVEC proliferation (% of cells)

HUVEC migration (% of cells)

Tube formation (loop number)

Matrigel assay (CD3% staining)

Control 1.25 μg/mL 2.5 μg/mL 5.0 μg/mL

50 35 30 10

100 35 25 10

100 35 25 10

100 65 50 30

Hep-2 epithelioma cells in the dose-dependent manner and nontoxic to normal cells (Rehana, Mahendiran, et al., 2017). Metallic copper nanoparticles decreased the viability of human skin melanoma A375, A549 and C6G cells at lower concentration 1.71 μg/mL. These nanoparticles arrested the cell cycle at G2 phase and induced apoptosis, but were nontoxic to white blood cells (Chakraborty & Basu, 2017). Green synthesized copper oxide NPs up-regulated tumour suppressor protein expression in A549 lung cancer cells and induced apoptosis (Kalaiarasi, Sankar, et al., 2018). CUNPs synthesized from Ole europaea leaf extract were much less cytotoxic to normal dermal fibroblast cells, and induced apoptosis in AMJ-13 (human breast), SKOV-3 (ovarian) cancer cells, and toxicity studies revealed that mice treated with these NPs inhibited the expression of ADA enzyme activity in blood, thymus and spleen (Sulaiman et al., 2018). NPs synthesized from Ormocarpum cochinchinense leaf extracts arrested the growth of human colon cancer cell line HCT-116 (Gnanavel et al., 2017) (Table 1).

2.7 Gold nanoparticles (Au) There are different types of gold nanoparticles based on size, shape and properties. Most studies have found that gold nanoparticles play a key role in targeting drugs. Rotello et al. successfully delivered drugs in vitro by using gold nanoparticles. Spherical gold nanoparticles with a size of 50 nm internalize the best of all nanoparticles sizes (Agasti, Chompoosor, et al., 2009; Kim, Ghosh, et al., 2009). GNPs inhibited VEGF signalling in 3T3 and HUVECs cells in size and dose-dependent manner (Arvizo, Rana, et al., 2011). Kodiha et al. suggested that the toxicity GNPs correlated with changes in nuclear organization and function (Kodiha, Hutter, et al., 2014). Gold nanoparticles combined with glucose kill human cancer cells (HeLa, MCF-7) in a dose-dependent manner (Song, Xu, et al., 2013). When compared to naked GNP the combination of GLU-GNP resulted in an approximate 31% increase in nanoparticle uptake (Puvanakrishnan, Park, et al., 2012). Gold nanoparticles coated with Avastin or a beyacizu MAB (anti-VEGF) antibody increase the level of apoptosis in CLL-B cancer cells. The non-coated gold nanoparticles alone were able to induce some levels of apoptosis in CLL-B cells (Mukherjee, Bhattacharya, et al., 2007). Gold nanoparticles

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inhibit the tumour growth and metastasis in a preclinical mouse model of ovarian cancer (Arvizo, Saha, et al., 2013). The oligo-ethylene glycol-capped gold nanoparticles at a size of 13  2 nm and a concentration of 0.01 pmol/μL increases the formation of new arterioles (Roma-Rodrigues, Heuer-Jungemann, et al., 2016). Gold nanoparticles at a size of 100 nm and concentrations of 1, 2, and 4 nmol/L reduces the level of VEGF in HUVECs proliferation and also disturbs the morphology and membrane ultrastructure of HUVECs (Pan et al., 2014). Gold nanoparticles at 10 nm inhibited the angiogenesis of liver tumour growth in BALB/c mice at a concentration of 1 mg/kg (Pan et al., 2013). Gold nanoparticles at greater than 500 nM caused significant cell death in BREC endothelial cells and inhibited VEGF, Src and VEGFR2 induced phosphorylation, inhibited 80% tube formation in BRECs on Matrigel and also suggested that in diabetic retinopathway and other neovascular diseases gold nanoparticles are useful as therapeutic molecules (Kalishwaralal et al., 2011). Gold nanoparticles conjugated with Quercetin inhibited breast cancer cell lines (MCF-7 and MDA-MB-231), HUVECs and blood vessel formation (Balakrishnan, et al., 2016). Curcumin conjugated with fluorescent gold NPs induced apoptosis in MCF-7 and MDA-MB-231 cell lines which were non-toxic to normal (NIH3T3) cells and decreased the tumour volume in subcutaneous MDA-MB-231 tumour-bearing BALB/c mice (Khandelwal et al., 2018). Gold nanoparticles at the mean particle size of 7.2  2 nm, are toxic to colorectal cancer cell line (HT-29) at the concentration of 40 μm (de Araujo et al., 2017). Platinum coated gold Nanorods at 0.1 μg/mL are more cytotoxic to human breast cancer cell line MCF-7 (Ahamed et al., 2016). Gold nanoparticles at an average range of 100 nm inhibited the HT29 colonic cancer cell line and induced apoptosis (Bai Aswathanarayan, Vittal, et al., 2017). Gold nanoparticles from Euphrasia officinalis leaf inhibited the human lung-A549 and cervical cancer cell lineHeLa even at very low concentration, i.e., 10μg (Singh, Du, et al., 2017). Bimetallic gold nanoparticles inhibited tumour growth and lung metastasis (Shmarakov, Mukha, et al., 2017). Gold nanoparticles from Musa paradisiacal peel extract inhibited the human lung cancer cells-A549 in a dose-dependent manner (Vijayakumar, Vaseeharan, et al., 2017). Gold nanoparticles conjugated with quercetin inhibited the proliferation of HUVECs ex vivo and decreased tumour growth in DBMA induced carcinoma in vivo (Balakrishnan et al., 2016). Gold NPs loaded with linalool and conjugated with CALNN peptide arrested growth and induced apoptosis in MCF-7 breast cancer cell lines, without toxicity to mice (Jabir, Taha, et al., 2019). Gold NPs functionalized from hydroxylated tetraterpenoid deionoxanthin that were accumulated in the cytoplasm down-regulated the FOXM1 and NR4A1 inducing ROS production and autophagy in MCF-7 breast cancer cell line (Tian, Li, et al., 2018). Gold NPs capped with modified para-aminobenzoic acid-quat188-pullulan (PABA-QP) had great intracellular uptake and delivered doxorubicin, that were non-cytotoxic to normal cells and arrested the cell cycle at S and G2-M phases on chago cells (Laksee, Puthong, et al., 2018). Green synthesized gold NPs from stem bark extract of Nerium oleander inhibited MCF-7 breast cancer cell line proliferation in a dose-dependent manner (Barai et al., 2018) (Fig. 3).

2 Nanoparticles for targeting angiogenesis in cancer

FIG. 3 Factors effecting the toxicity of carbon nanotubes.

2.8 Carbon nanotubes (CNTs) Carbon nanotubes have a unique atomic configuration. Due to this property carbon nanotubes are used for diagnostic and treatment purposes (Tang, Tang, et al., 2012). The toxicity of carbon nanotubes depends on various factors like purity, functionalization, size, length and surface chemistry (Horie, Kato, et al., 2011). Recent studies have shown that nanoparticles exposed to the circulatory system result in blood clotting and heart diseases (Buzea, Pacheco, et al., 2007). Carbon nanotubes are harmful to the cells of humans and other living organisms (Alazzam, Mfoumou, et al., 2010). Researchers clearly found that CNT is harmful to the development of the embryo (Roman et al., 2013). Roman et al. concluded that singlewalled carbon nanotubes inhibit angiogenesis at low concentrations. Pulskamp et al. found that there was no toxicity in NR8383 rat alveolar macrophages and A459 lung epithelial cells exposed to SWCNT or MWCNT (5–100 μg/mL) for 24 h (Pulskamp et al., 2007). Shvedova et al. demonstrated that SWCNT was a potent inducer of TGF-β production in association with macrophage recruitment and leads to lung inflammation (Shvedova, Kisin, et al., 2005). Both SWCNT and MWCNT increases endothelial tube formation (Wang et al., 2011). SWCNT and MWCNT induce proinflammatory cytokines, such as IL-8 in HEK keratinocytes (Witzmann & Monteiro-Riviere, 2006; Zhang, Zeng, et al., 2007). Masotti et al. demonstrated that the use of polyamine-functionalized CNTs was used to regulate angiogenesis (Masotti, Miller, et al., 2016). SWCNT at a concentration of 25 μg inhibited the angiogenesis of chorioallantoic membrane and in chicken embryo mainly effected the brain and liver (Roman et al., 2013). MWCNT inhibited blood vessel formation in the CAM model (Ma et al., 2015). Polymer coated CNT transfers micro RNA, targets gene expression and regulates the proliferation of HUVECs (Masotti et al., 2016). MWCNT functionalized with lentinan delivered tamoxifen to tumour regions and induced apoptosis on MCF-7 breast cancer cell line (Yi, Zhang,

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FIG. 4 Overview of nanoparticles effect on angiogenesis.

et al., 2018). DOX-CNT incorporated with PLGA nanofibers released DOX on HeLa cells in a prolonged manner and induced cytotoxicity (Yu, Kong, et al., 2015). Singlewalled carbon nanohorns (SWCH) accumulated in the HepG2 cells entered through endocytosis, damaged mitochondrial function and activated SIRT3 that leads to the release of BAX and P53 into the cytoplasm, induced apoptosis and reduced tumour growth in subcutaneous HepG2 tumour mice (Li, Chen, et al., 2018). SWCNT functionalized with alginate and chitosan conjugated with curcumin, inhibited the proliferation of A549 lung cancer cell line (Singh et al., 2018). SWCNT conjugated with hyaluronic (HA) acid generated heat at tumour sites and reduced tumour volume on MCF-7 tumour-bearingmice; in vitro studies also showed that SWCNT-HA increased ROS expression and induced apoptosis on MCF-7 cells, and the authors conclude that these complexes may be used as targeted therapy for different types of tumours (Hou, Yuan, et al., 2017) (Table 2) (Fig. 4).

3 Metal oxide nanoparticles for antibacterial applications Hospital acquired infections have become a serious issue in biomedical fields in the last few years due to various clinical antibiotic-resistant bacterial strains such as S. aureus, E. coli, B. subtilis, P. aeruginosa, S. marcescens, M. varians, A. flavus

Table 2 Anticancer activity of different metal oxide nanoparticles. Target

Nanoparticle/ extracted from

MDA-MB-231

Tumour suppressor genes EAE and CIA (Mice) HEPG2 cells

Size (nm)

Concentration

Assays used

Major outcomes

Reference

TNP, TFP, TNT

24.5, 82, 12.8

0–100 μg/mL

MTT and CAM

Latha, Reddy, et al. (2017)

TNT

12.8

0–100 μg/mL

RT PCR

TNT nanoparticles more inhibited the proliferation of MDA-MB-231 cell line and blood vessels formation when compared to TFP and TNP TNT nanoparticles up-regulated the tumour suppressor genes

TNT and TFP

12.8, 82

50 μg/mL

30–70

0–100 μg/mL

MCF-7 cell line and HBL 100

TiO2

70.88

0–100 μg/mL

MTT and apoptosis

LL2 cancer cell line and subcutaneous tumour HUVECs

TiO2

10–70

0–200 μg/mL

Apoptosis and tumour model

These nanoparticles reduced the proinflammatory cytokines Inhibited the proliferation even at low concentrations and also caused DNA damage and induced the apoptosis These nanoparticles inhibited the proliferation of MCF-7 breast cancer cell line and induced apoptosis and these are less toxic to normal HBL100 cells Small sized nanoparticles have more cytotoxicity. Reduced the tumour volume and induced apoptosis

Shukla et al. (2013)

TiO2

HMGB1 analysis MTT and apoptosis

Iron oxide nanoparticles

38  8.14

0.1mM–1mM

Migration & invasion

Wu et al. (2010)

Maghemite Fe2O3 coated with citric acid/DMSA, lauric acid

633

588–840 g-iron/ mL

Proliferation

Iron oxide nanoparticles decreased the migration and of HUVEC in a dose-depended manner Surface coated maghemite nanoparticles inhibited 50% of human melanoma cells

Human melanoma cells

Latha et al. (2016)

Murugan et al. (2016)

Wu et al. (2010)

Fujiwara et al. (2015)

de Freitas et al. (2008)

Continued

Table 2 Anticancer activity of different metal oxide nanoparticles.—cont’d Target

Nanoparticle/ extracted from

Size (nm)

Concentration

Assays used

Major outcomes

Reference

Iron oxide nanoparticles disturb the cytoskeleton and inhibited PC12 cell growth These nanoparticles generate heat at the tumour site and reduced the size of the tumour Up-regulated apoptosis proteins that lead to decreased viability Induced the apoptosis on the dosedepended manner

Pisanic et al. (2007)

Pc12 cells

Iron oxide nanoparticles

12

0.15, 1.5, 15 mM

Proliferation

Mice/tumour

PEG-coated iron oxide

19

0.7–7 mg

Tumour growth

HeLa cells

15–30

0–100 μg

MDCK, Caki-2 renal tumour cells HUVECs

Biosynthesized SPIONs Green synthesized iron oxide nanoparticles Silica

39

0–0.4 mg/mL

MTT, apoptosis Apoptosis assay

25–115

2500 pM

Matrigel

HUVECs

Silica

62

100 μg/mL

Proliferation

MDA-MB-231

Silica loaded with quercetin

200

2.5–10 μg/mL

MTT & migration

HUVECs, Zebrafish embryo

Silica

62

25–100 μg/mL

MTT & apoptosis, mortality

Small nanoparticles (25 nm) did not show any effect. Big nanoparticles (75 nm) effectively inhibited in vitro VEGF-induced angiogenesis at 5–10 μg/mL Si NPs disturbs cytoskeleton organization and causes mitochondrial damage and inhibited HUVECs Silica NPs are cytotoxic to breast cancer cells. And also, these NPs inhibited the migration of MDA-MB231 at low concentration of 2.5 μg/ mL level After 24 h silica NPs at 50 μg/mL decreased 85.4% viability of HUVECs. And also, these NPs increases the apoptosis rate when compared to controls, these NPs induced mortality in embryos on the dose-depended manner

Kolosnjaj-Tabi et al. (2014) Shanmugasundaram et al. (2018) Nagajyothi, Pandurangan et al. (2017) Guarnieri et al. (2014)

Duan et al. (2014)

Sarkar et al. (2016)

Duan et al. (2013)

MSNp with ruthenium complex and folate acid

20–80

0–100 μg/mL

MTT, ROS, toxicity in in vivo

Zinc polycaprolactone (PCL)

60

0.5, 1, 2, 4 wt%

CAM

Human colon carcinoma LoVo cells

Zinc

196

1–40 μg/cm2

WST-1 colorimetric

MDA-MB-231, PC-3

Zinc oxide nanopellets

250–500

0–300 μg/mL

MTT

A549 cell line

Nobilis leaf extract zinc oxide NPs

50

10–80 μg/ mL

MTT

Human A375 mice B16F10

ZNO–pIC complex

50

0–100 μg/mL

MTT

MCF-7 breast cancer

Pongamia pinnata seed extract ZNO

380

5–50 μg/mL

MTT

A549 cell line

ZnO NPs from Mangifera indica leaves ZnO conjugated with camptothecin

45–60

0–100 μg/mL

MTT

70

0–100 μg/mL

MTT

HepG2, tumourbearing nude mice Blood vessels

A549 cells

Small sized nano drugs have more anticancer activity. Low toxicity towards HepG2 tumour-bearing nude mice ZnO nanoparticles at low concentration increased the matured vascular sprouting up to 1 wt% and higher concentrations do not increase the angiogenesis Lower than 5 μg/cm2 it has no cytotoxicity up to 72 h at higher doses it induces the cytotoxicity with cell survival lower than 5% Zinc oxide nanopellets inhibited 50% of the growth of PC-3 and MDA-MB231 cells At very low concentration also these green synthesized ZnO NPs inhibited human A549 lung cancer cells Zinc oxide NPs combined with pIC induced significant cell death of B16F10 melanoma, Human A375 cells Pongamia pinnata seed extract ZnO NPs decreased the viability of MCF-7 breast cancer cell line at IC50 32.8 μg/mL These NPs induced cytotoxicity on dose-depended manner on lung cancer cell line Released camptothecin into A549 lung cancer cell lines and induced the cytotoxicity

Ma et al. (2018)

Augustine et al. (2014)

De Berardis et al. (2010)

Krishna, Ananthaswamy, et al. (2016) Vijayakumar et al. (2016) Ramani et al. (2017)

Malaikozhundan et al. (2017)

Rajeshkumar et al. (2018) Li, Zhang, et al. (2018)

Continued

Table 2 Anticancer activity of different metal oxide nanoparticles.—cont’d Target

Nanoparticle/ extracted from

Size (nm)

Concentration

Assays used

Major outcomes

Reference

CAL27 cells

ZnO

500.8

0–100 μg/mL

MTT, ROS

Wang et al. (2018)

BRECs

Silver

50

50 ng/mL

Blood vessels

Silver NPs from Saliva officinalis

1–30

50–200 mg

Cell proliferation, tube formation, Matrigel plug assay CAM

Induced parkin-mediatedmitophagy, decreased the cell viability on a dosedepended manner Reduced 50% of cell viability, inhibited 80% of tube formation and VEGF-induced proliferation is blocked, inhibited the formation of microvessels

Baharara et al. (2014)

DLA cells, DLA tumourbearing mice

Silver

50

500 nM

MTT, tumour growth

Mice

Silver coated with polyvinylpyrrolidone Silver

2–3

0–10 μg/mL

Matrigel

10

0–0.16 mg/mL

SRB & apoptosis

Silver NPs encapsulated in chitosan Silver NPs from Panax ginseng leaves

160  10

0–63 μg/mL

MTT

Green synthesized silver nanoparticles inhibited the formation of matured blood vessels on the dose-depended manner Decreased the viability of DLA cells on dose and time depended on the manner, reduced the tumour volume in DLA-tumour bearing mice Silver nanoparticles increase the vessel formation in vivo Higher concentrations are toxic to human cervical carcinoma cells and it induces apoptosis Dose depended on toxic to MCF-7 cells

50

1–20 μg/mL

MTT & proliferation and migration

Silver NPs from Panax ginseng leaves

10–20

0–20 μg/mL

MTT

HeLa cells

MCF-7 cells

A549 and MCF-7

A549 and B16BL6

Decreases the viability and migration of lung cancer A549 and breast cancer MCF-7 cells and induces the apoptosis Even at low concentration2 μg/mL also decreases the viability of A549 and B16BL6 melanoma cells

Gurunathan et al. (2009)

Sriram et al. (2010)

Kang et al. (2011) Pandurangan, Enkhtaivan, et al. (2016) Nayak et al. (2016)

Castro-Aceituno et al. (2016)

Singh et al. (2016)

MCF-7 and HeLa, HUVECs HCT116, SKBR3, HT29

Silver

10

400 μg/mL

Proliferation & tube formation

Silver with EPS

11  5

0–50 μg/mL

HeLa cells, B16F10 tumour model A549, PA1 cell lines

Silver

26.5  8.4

0–800 ng/mL, 1.5 mg/kg

Silver NPs from fruit extract of Cleome viscosa Silver NPs from Acorus calamus

20–50

0–100 μg/mL

MTT, colony formation, apoptosis MTT, annexin V, tumour growth MTT

31.83

0–150 μg/mL, 5–10 mg/kg

MTT, ROS, apoptosis, biochemical analysis

CO NPs from Olia europaea leaf extract

20

0–400 μg/mL/ 100–800 mg/kg

MTT, ROS, toxicity

Copper

178

5, 15, 25 μM

CAM, migration & MTT

Cuprous oxide

70

1.25, 2.5, 5.0 mg/mL

Cell proliferation, tube formation, Matrigel

Hep2, Wistar rats

AMJ-13, SKOV-3, normal fibroblast dendritic cells, mice Blood vessels, MDA-MB-231

HUVECs, Mice

Inhibited the proliferation of MCF-7. HeLa and HUVECs and induces apoptosis Entered into the cells and increased ROS production and induced the apoptosis Induced the autophagy and apoptosis and reduced tumour volume Decreased the viability based on the dose-depended manner

Frankova´ et al. (2016)

Increased the ROS, apoptotic protein expression on Hep2 cells, serum biochemical markers like glucose, LDH, ALP, SGOT and inflammatory cytokines altered up to 29 days when rat treated at 10 mg/kg concentration Slightly affected the normal fibroblast dendritic cells and dose depended induced apoptosis on AMJ-13, SKOV-3 and higher concentration altered ADA expression in blood

Nakkala et al. (2018)

Slightly inhibited the formation of blood vessels, it has no influence on the migration of breast cancer cells even at high concentration. And these NPs increases the proliferation of time depended manner CuO-NPs inhibit HUVECs proliferation. And increased the late and early apoptosis and inhibited the formation of loop numbers, suppressed angiogenesis in vivo

Kamble et al. (2015)

Buttacavoli et al. (2018) Lin et al. (2014)

Lakshmanan et al. (2018)

Sulaiman, Tawfeeq, et al. (2018)

Song et al. (2014)

Continued

Table 2 Anticancer activity of different metal oxide nanoparticles.—cont’d Target

Nanoparticle/ extracted from

Size (nm)

Concentration

Assays used

Major outcomes

Reference

Copper oxide nanorods

200–400

0.02, 0.04 mg/ mL

Caspase

Copper NPs embedded with hydrogels Copper NPs from Eclipta prostrata leaves Copper embedded chiton NPs

10

0–20 wt%

MTT

Pandurangan, Nagajyothi, et al. (2016) Palza, Galarce, et al. (2017)

23–57

1–500 μg/mL

MTT

20  51

0–100 μg

MTT & apoptosis

HUVECs

Gold

100

1, 2, and 4 nmol/L

MTT

BALB/c mice

Gold

10

1 mg/kg via the tail vein

Proliferation

BRECs

Gold

500

100–500 nM

Tube formation

MCF-7 and MDA-MB-231, HUVECs

Gold conjugated with quercetin

3.5

25, 50, 75 μm

Migration & tube formation, CAM

HCT116

Gold

5 nm

40 μm

Proliferation & Caspase-3

Induced apoptosis in human cervical carcinoma cells on dose depended manner Alginate-based copper NPs are toxic to the CNh and SaOS cell lines on a dose-depended manner These green synthesized NPs are dose depended toxic to HepG2 cell line Cytotoxic to human breast cancer cell line MCF-7 and induced apoptosis GNPs inhibits HUVECs proliferation induced by HepG2-CM significantly, but could not inhibit alone Au NPs may specifically inhibit liver tumour angiogenesis tumour growth and ascites formation in mice. Compared with the control group, the inhibition rate of tumour growth was 28.87% VEGF-induced proliferation is blocked and inhibited 80% of tube formation of BRECs on Matrigel Significantly decreased the migration in MCF-7 and MDA-MB-231, HUVECs and also inhibited tube formation of HUVECs, inhibited the blood vessel formation Decreased proliferation and induced apoptosis

Human carcinoma cells CNh and SaOS HepG2

MCF-7

Chung, Abdul Rahuman, et al. (2017) Solairaj, Rameshthangam, et al. (2017) Pan, Wu, et al. (2014)

Pan, Ding, et al. (2013)

Kalishwaralal, Sheikpranbabu, et al. (2011) Balakrishnan, Bhat, et al. (2016)

de Araujo, de Araujo, et al. (2017)

MCF-7

A549 cell line

MDA-MB-231, NIH3T3, tumourbearing mice

Gold nanorods coated with platinum Gold NPs from Pleuroptrus multiflorus Curcumin conjugated fluorescent gold NPS

45–50

0.025, 0.05, 0.1 μg/mL

MTT

7.71

0–125 μg/mL

MTT

15

0–25 μg/mL, 20 mg/kg

MTT, apoptosis, tumour volume

MCF-7 cell line

Gold NPs from Nerium oleander

100–300

0–150 μg/mL

MTT

A549 cell line

48–50

0–20 μg/mL

MTT, apoptosis

Blood vessels

SWCNT functionalized and conjugated with curcumin MWCN

100

500 mg/L

CAM

Blood vessels

SWCNT

2

25 μg

CAM

BEAS-2B human lung epithelial cells

SWCNT

0.8–1.2

0–50 μg/mL

HeLa, A549, H1299 and HaCaT cells

SWCNT

40

0–20 μg/mL

Proliferation and in vivo xenograft mice model MTT and NF-KB pathway

A549 and Nr8383 cells

SWCNT

14

0–100 μg/mL

MTT, WST, and apoptosis

Low concentration is effectively inhibited when compared to the high concentration These NPs activates Caspase-3 and induced apoptosis A549 lung cancer cell line Non-toxic to normal cells and induced apoptosis on breast cancer cell line MDA-MB-231, and inhibited the growth of tumour in BALB/C and SCID mice Inhibited the proliferation based on dose-depended manner, non-toxic to normal cells Delivered curcumin on A549 cell lines and induced apoptosis

Branch number was significantly decreased in MWCNT group compare to control Inhibited the blood vessels formation SWCNT cause the malignant transformation of epithelial cells and cause the carcinoma and induced apoptosis SWCNT increased the oxidative stress and activates NF-kB pathway that leads to the cytotoxicity to keratinocytes No toxicity to pulmonary epithelial and macrophage cells

Ahamed, Akhtar, et al. (2016) Castro-Aceituno, Abbai, et al. (2017) Khandelwal, Alam, et al. (2018)

Barai, Paul, et al. (2018) Singh, Sachdev, et al. (2018)

Ma, Liu, et al. (2015)

Roman, Yasmeen, et al. (2013) Wang, Luanpitpong, et al. (2011)

Manna, Sarkar, et al. (2005)

, Pulskamp, Diabate et al. (2007)

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and C. albicans. Therefore, it is necessary to develop efficient antibacterial agents that are non-toxic and biocompatible. Jung, Kim, et al. (2019) synthesized Ag-doped bioactive glass/mesoporous SiO2 nanohybrid particles using a alkali-mediated sol-gel method, and investigated their antibacterial properties against Lactobacillus casei. It was found that as the % of Ag in the hybrid is increased from 1% to 5%, bacterial growth was inhibited. Another novel antibacterial material, Ag-functionalized SiO2 nanoparticles (Wysocka-Kro´l, Olszty nska-Janus, et al., 2018) was prepared through Tollen’s method, in which SiO2 NPs react with Ag-ammonia complex [Ag(NH3)+2 ] in the presence of formaldehyde as reducing agent. Ag/SiO2 hybrid particles showed excellent antibacterial properties against P. aeruginosa. Arshad, Abbas, et al. (2019) developed a new type of antibacterial material, SiO2-doped magnetic Fe2O3 NPs, through a chemical co-precipitation process at 70 °C in the presence of three different types of organic solvents (n-hexane, acetonitrile and isoamyl alcohol). These nanoparticles have a diameter in the range of 5.89–19.89 nm. These NPs were investigated for their antimicrobial properties against different bacterial and fungal species such as Escherichia coli, Aspergillus niger, Candida parapsilosis and Bacillus subtilis. They found that the solvent used in the synthesis process of SiO2-doped magnetic Fe2O3 NPs affected both antibacterial and antifungal activity. NPs synthesized in the presence of acetonitrile solvent revealed maximum antibacterial and antifungal efficiency, and the MIC values were determined to be 0.31 and 0.21 mg/L when acetonitrile solvent was used, 0.24 and 0.18 mg/L for isoamyl alcohol for Candida parapsilosis, and Aspergillus niger. NPs synthesized in n-hexane solvent resulted in an MIC value of 0.19 mg/L. Mesoporous structured bioactive Ag NPs (composition of SiO2-CaO-P2O5) were fabricated through the evaporation-induced self-assembling process, and their antibacterial activity against Enterococcus faecalis studied using the time-killing curve test and the colony-forming capacity assay (Kung, Chen, et al., 2018). It was found that the antibacterial properties of NPs are dependent on the position of Ag NPs in the bioactive materials, and the minimum inhibitory concentration (MIC) values of the NPs against the bacteria were in the range of 2.5 and 5 mg/mL. The minimum bactericidal concentrations (MBC) of the NPs against bacteria were in the range of 10 and 20mg/ mL. In another study, Ag-coated apatite nanosheet-modified SiO2 nanofibres showed superior antibacterial activity to inhibit the growth of S. aureus and E. coli (Wei, Yao, et al., 2018). Palla-Rubio, Arau´jo-Gomes, et al. (2019) developed a new type of SiO2functionalized chitosan used as antibacterial coating materials for the titanium implants to avoid dental-related infections and to stimulate the osseointegration of implants. The results showed that the hybrid materials were not only non-cytotoxic, but also enhanced cell proliferation, with outstanding antibacterial activity. In another study, Wang, Wang, et al. (2019) investigated the influence of morphological structures (smooth spheres, wrinkle dendritic porous spheres and hollow spheres) of SiO2 on the antibacterial properties of Ag NPs. They found that both wrinkle dendritic and hollow structured SiO2/Ag hybrids showed an effective inhibition of bacterial survival of S. aureus and E. coli at low particle concentrations of 125 μg/mL, in

FIG. 5 Antibacterial activity of metal oxide nanoparticles. Metal oxide nanoparticles breakdown the cell wall of bacteria by interacted with bacterial cell and inhibited the growth of both Gram positive and negative bacteria.

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comparison with smooth spherical structured particles. This indicates that they have potential for utilization as efficient antibacterial agents. Chanhom, Charoenlap, et al. (2019) developed a novel structured ternary hybrid, metalloporphyrins-sensitized TiO2-SiO2-Fe3O4 hybrid as an antibacterial agent to kill E. coli. Very recently, mesoporous SiO2 supported with maleamato-copper (II) complex was synthesized and tested against E. coli bacteria (Dı´az-Garcı´a, Ardiles, et al., 2019). The biological results revealed that they have capability of oxidative stress generation in the bacterial walls. Likewise, various strategies were developed to synthesize various types of SPIONs, zinc, Ag, TiO2, and graphene-based hybrid materials as efficient antibacterial agents (Chai, Lam, et al., 2019; Ji, Li, et al., 2019; Khanam & Hasan, 2019; Namazi, Hasani, et al., 2019; Satheeshkumar, Kumar, et al., 2019; Suo, Peng, et al., 2019) (Fig. 5).

4 Conclusions Currently nanotechnology plays an important role in cancer diagnosis and delivering drugs to specific cancer sites because nanoparticles are very small in size and they reach target sites easily. This review is based on the effect of different nanoparticles on cancer-related studies. Researchers synthesized different nanoparticles with different methods, but most of the researchers used bare nanoparticles on different cell lines and tumour models. The major disadvantages of using bare nanoparticles are incorrectly finding where these nanoparticles will bind to the cells or tumours and the high complexity of studying the mechanism of action of nanoparticles. If nanoparticles are conjugated with known targeted drug compounds and fluorescent probes, the mechanism and target drug delivery properties of nanoparticles can easily be identified. There is a need to conjugate (bio-conjugate and synthetic conjugate) and conjugate with antibodies to target the receptors that are overexpressed in cancer cells and to study cellular targets.

Acknowledgement This work was partially supported by the grant from the Science and Engineering Research Board (No: EMR/2016/007208).

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