Anti-cancer green bionanomaterials: present status and future prospects

ABSTRACT

Cancer is one of the most common health problems responsible for outnumbered deaths worldwide. Nanomedicine plays an important role in developing alternative and more effective treatment strategies for cancer theranostics. However, the toxicity, high cost and nanoparticles (NPs) production complexity are some of the major issues that obstruct the use of existing nanomedicine. Recently, the green synthesis of biogenic NPs from plants and microbial sources has become an emerging field due to their safer, eco-friendly, simple, fast, energy efficient, low-cost and less toxic nature. Interestingly, NPs play a key role in diagnosis of tumor at the initial stage by allowing cellular visualization. Furthermore, prospective applications of green NPs include magnetically responsive drug delivery, anti-cancer activity, photo-thermal therapy and bio-imaging. The present review provides perspective on the use of anti-cancer green bionanomaterials with a focus on their present status and future prospects in the theranostics of cancer.

GRAPHICAL ABSTRACT

KEYWORDS:

• Bionanomaterials
• cancer theranostics
• green nanoparticles
• phytosynthesis
• microbial synthesis

1. Cancer: a global menace

According to the National Cancer Institute (NCI), United States (U.S), cancer contains over more than 100 types Institute (1). Besides, it is anticipated that the incidence of cancer by 2030 will reach around 21.7 million and there would be about 13 million deaths owing to aging and population growth. The latest report published in June 2016 by iMShealth (Institute for Healthcare Informatics) anticipates the global cancer treatment market to reach $150 Billion by 2020 Informatics (2). Nevertheless, the tumor load in the future is likely to be considerably larger due to lifestyle adoption, leading to an increased risk of developing tumor, such as physical inactivity, cigarette smoking and unhealthy diet in the economically developing countries’ society (3). Notably, cancer causes one in seven deaths globally, causing more deaths than malaria, tuberculosis and AIDS Society (3 , 4). Impressively, the largest proportion of cancer cases is in developing countries, accounting for around 57% of new cases and 65% of cancer-related deaths. In 2012, cancer caused premature deaths of about 4.3 million people and the number of premature cancer deaths are presumed to increase by 44% between 2012 and 2030 Organization (5). By 2025, it is estimated that in the industrialized world only 20–25% of the people will be aged over 65 years, and of those 50–60% who die of tumor will be aged over 75 years (6). On 1 January 2016, over 15.5 million of the population of the United States had a previous history of cancer disease. By 1 January, 2026, this number is estimated to increase to 20.3 million. Moreover, the high prevalent cancers in 2016 that affects women are uterine corpus (757,190), breast (3,560,570), and colon and rectum cancer (727,350). For men, prostate (3,306,760), melanoma (614,460), and colon and rectum (724,690) cancers are most common (7). Additionally, nearly 189,910 new cancer patients and about 69,410 cancer-related deaths were estimated among black people in 2016 in the United States, involving 95,920 cases among women and 93,990 cases in men. Although black people have higher death rates due to cancer than whites, the discrepancy has lessened for all types of cancer combined and for prostate and lung cancers (in males only).

Radiotherapy, chemotherapy and surgery are some of the cancer treatments which are used to improve a patient’s life. Besides, one of the major problems in the cancer treatment process is the side-effects owing to conventional treatment strategies (8–10). Recent cancer research findings have enhanced understanding about carcinogenesis, the metastatic cascade and genetic factors that influence tumor growth and development. Overall, despite some progress in cancer control, incidence and death rates are increasing for cancer types. Recently, the applications of nanobiotechnology have revealed novel strategies for the treatment and diagnosis of cancer. Thereby, the current review article aims to highlight significant applications of biosynthesized green nanomaterials in cancer theranostics and the hurdles in their way to clinical trials.

2. Green bionanomaterials: an insight

Green bionanomaterials involving metals such as gold, silver, copper, titanium, zinc and iron prepared from different bio-sources, and have been reported for various biomedical applications (11). In addition, metal NPs are used in drug delivery, gene delivery, medicine, cell labeling, sensors, food packaging, wound dressings, etc. However, some applications of metal NPs are still under development such as magnetically responsive drug delivery, photo-thermal therapy and photo-imaging (Figure 1) (12–14). Although fabrication of NPs has attracted great interest for various physical and chemical processes, but there is an urgent need to explore alternative routes owing to some unsatisfying conditions of these methods such as the need for high temperature in the thermo-reductive process or intensive energy in the laser ablation process (15). Moreover, the fabrication of NPs by a chemical process may require toxic substrates, generates harmful wastes or requires large amounts of energy and even has low productivity (16). Hence, natural products and resources may ultimately prove to be more efficient and cost-effective. Remarkably, many plant extracts, algae and an extensive range of microorganisms containing bacteria, actinomycetes, fungi and yeast are reported to be proficient in synthesizing bionanomaterials, Priester et al. (17), Barabadi et al. (18), Honary et al. (19), Rahimi et al. (20), Salunke et al. (11), Ovais et al. (21), Mukherjee et al. (22), Patra et al. (23) and Ovais et al. (24). Interestingly, isolated chloroplasts were reported to be able to catalyze the biosynthesis of bionanomaterials. More interestingly, microalgae were designed for ecofriendly, scalable and permanent photobioreactors for sustainable and continuous fabrication of valuable bionanomaterials (15). Notably, the exact mechanism of biosynthesis of metal NPs is not well understood yet (25). However, it is believed that some enzymes play a role in bio-reducing metal ions to form metal NPs (26, 27). Figure 2 shows the schematic mechanism of microbial-mediated synthesis of metal NPs (11). The negatively charged bacterial cell wall interacts electrostatically with metal ions having positive charge. In addition, the bioreduction process may be catalyzed by enzymes inside the cells or on the cell surface. Salunke et al. (28) suggested the role of Saccharomyces cerevisiae cell wall components, some proteins and alcoholic compounds in the synthesis and stabilization of MnO₂ NPs (28). The mechanism of extracellular microbial-mediated biofabrication of metal NPs is basically due to microbial nitrate reductase responsible for reduction of metal ions into metallic NPs (11). All the mentioned mechanisms lead to extracellular or intracellular fabrication of metal NPs. In case of phytosynthesis of metal NPs, it is believed that phytochemicals such as proteins, flavonoids, polyphenols, alkaloids, saponins, phenols, essential oils and polyols which are present in the plants extract play a main role in bio-reducing the metal ions, converting them to metal NPs and also capping of the synthesized NPs for stabilization (13, 29–31). The plant-mediated mechanism of biogenic silver NPs’ (AgNPs’) production is illustrated in Figure 3.

Figure 1. Biological synthesis and applications of metal NPs in biomedical and environmental fields (Adapted with permission from Singh et al. (12)).

Figure 2. Schematic mechanism of microbial-mediated synthesis of metal nanoparticles (Adapted with permission from Salunke et al. (11)).

Figure 3. Plant-mediated mechanism of biogenic silver nanoparticles’ (AgNPs’) production: a step forward for cancer nanomedicine (Adapted with permission from Ovais et al. (21)).

2.1. Anti-cancer activity of green nanomaterials: A mechanistic approach

In vitro anti-cancer activity of metal bionanoparticles has been confirmed against different cancer cell lines, i.e. MDA-MB-231 and MCF-7 (human breast adenocarcinoma) (32, 33), A549 (human lung adenocarcinoma) (34, 35), HCT116 (human colon colorectal carcinoma) (36), HeLa (human cervical cancer) (37, 10, 38), NCI-H460 (non-small cell lung cancer) (39), U87 (glioblastoma multiforme cell) (40), PANC-1 (pancreatic adenocarcinoma) (41), MG-63 (osteosarcoma cell) (42, 43), AGS (human gastric carcinoma) (44, 45), SMMC-7721 (human hepatoma cells) (46), LS174T (human colon adenocarcinoma cell) (46), HT-29 (human colorectal adenocarcinoma) (47), Varsha B (48), Caco-2 (human epithelial colorectal adenocarcinoma) (47, 49), HCT 15 (human colon adenocarcinoma) (50, 51), PC-3 (human prostate carcinoma) (52, 53), U937 (human histiocytic lymphoma cell) (54), COLO205 (human colon adenocarcinoma) (41, 54), B16F10 (mouse melanoma) (54, 55), 4T1 (mouse breast cancer) (56), CRL-1451 (mouse lung adenocarcinoma) (56), EAC (ehrlich ascites carcinoma) (57), CT-26 (mouse colon adenocarcinoma) (56), WEHI-3B (mouse leukemia) (56), CEM-ss (human T acute lymphoblastic leukemia) (58), CaOV-3 (ovarian adenocarcinoma) (41), Jurkat (human T acute lymphoblastic leukemia) (58, 59), HL-60 (human acute myeloid leukemia) (41, 60), K562 (human chronic myelogenous leukemia) (58, 61), A431 (human vulvar squamous cell carcinoma) (62), HNGC-2 (human adult glioma tissue) (55), ECV-304 (human urinary bladder carcinoma) (55), RAW254.7 (mouse leukemia) (49), SiHa (human cervical squamous cell carcinoma) (63), DL (dalton’s lymphoma) (64), HepG2 (hepatic cancer) (65–67), HEp-2 (human larynx carcinoma) (68, 69), ZR-75-1 (human caucasian breast carcinoma) (70), DAUDI (human burkitt’s lymphoma) (70), T47D (human breast cancer) (71), KB (human oral cancer) (72, 73), C26 (murine colon carcinoma) (74), LoVo (human colon adenocarcinoma) (75), LoVo/DX (multidrug resistance human colon adenocarcinoma sub-line) (75). The anti-cancer activity of various metal bionanoparticles from different bio-sources has been listed in Tables 1 and 2 from studies conducted in recent years by several research groups. Based on the enlisted studies, metal NPs exhibit a dose-dependent cytotoxic activity on various cancer cell lines. Moreover, biocompatibility testing of metal NPs has been done on different normal cell lines such as HaCaT (human keratinocyte) (76, 77), HMEC (human mammary epithelial cell) (33), HDFa (human normal skin dermal fibroblast) (39), HEK 293 (normal human embryonic kidney cell) (40, 78), Vero (african green monkey kidney cell) (79, 80), RWPE-1 (non-malignant human prostate epithelial cell) (81), PBMC (human peripheral blood mononuclear cell) (82), HL-7702 (normal human liver cell) (46), 3T3 (normal mice fibroblast cell) (83, 84), HUVEC (human umbilical vein endothelial cell) (55), Rat L6 (rat skeletal muscle cell) (85), MDCK (canine cocker spaniel kidney cell) (86), CV-1 (monkey African green kidney fibroblast) (87), WI-38 (human caucasian fetal lung) (87), HEK-293 (human embryo kidney) (88), BHK21 (hamster syrian kidney) (89), MRC-5 (normal human lung fibroblast cell) (41, 45), Raw 264.7 (Murine macrophage cell lines) (35), 3T3-L1 (mouse embryo) (90), PLs (human normal peripheral lymphocytes) (34), hFOB (human fetal osteoblast progenitor cell) (91), MCF10A (human breast epithelial cell) (71), H9c2 (rat cardiac myoblast) (92), NIH3T3 (mouse fibroblast) (93) and C2C12 (mouse muscle myoblast) (94).

Table 1. Phyto-sources for synthesis of bionanoparticles and their anticancer activity in various cell lines for the past 5 years.

Plant	Part used	Nanoparticle type	Size (nm)	Morphology	Anticancer activity (In vitro model)^a	Dose (µg/well)	Exposure time	Major outcome	Reference
Acalypha indica	Leaf	CuO	26–30 nm	Spherical	MCF-7	6.5–100 μg/mL	48 h	IC50: 56.16 μg/mL	Sivaraj and colleagues (32)
Achillea biebersteinii	Leaf	Ag	10–40 nm	Spherical and pentagonal	MCF-7	15–100 µg/mL	24 h	IC50: 20 µg/mL	Baharara et al. (153)
Adenium obesum	Leaf	Ag	10–30 nm	Spherical	MCF-7	100–600 µg/mL	24 h	IC50: 217 µg/mL	Farah et al. (154)
Ailanthus excelsa	Leaf	Ag	22–30 nm	Spherical	MCF-7	50–150 µg/mL	24 h	IC50:265.579 µg/mL	Vinmathi and JACOB (155)
Albizia adianthifolia	Leaf	Ag	4–35 nm	Spherical	A549 and PLs	10 and 50 μg/mL	6 h	Low toxicity at 10μl/mL, but significant toxicity at 50μl/mL in A549 No toxicity in PLs	Gengan and colleagues (34)
Aloe vera	Leaf	Ag	70.7–192.02 nm	Spherical	PBMCs	0.0025–0.04 mg/mL	48 h	IC50: ≤0.0025 mg/mL	Tippayawat and colleagues (82)
Alternanthera sessilis	Leaf	Ag	30–50 nm	Spherical	PC3	1.56- 25μl/mL	48 h	IC50: 6.85 μg/mL	Firdhouse and Lalitha (156)
Alternathera tenella	Leaf	Ag	∼48 nm	Spherical	MCF-7	25–100 µg/mL	24 h	IC50: 42.5 µg/mL	Sathishkumar et al. (157)
Andean Mora (Rubus glaucus Benth.)	Leaf	Ag	12–50 nm	Quasi-spherical	HepG2	0.01–1.0 µM	2 h	No toxicity observed	Kumar and colleagues (65)
Annona squamosa	Peel	SnO2	Average size:27.5 nm	Spherical	HepG2	1–500 μg/mL	2 h	IC50:148 μg/mL	Roopan and colleagues (66)
Antigonon letopus Hook. and Arn.	Aerial part	Au	13–28 nm	Spherical with few triangular shapes	MCF-7	31.25–1000 µg/mL	48 h	IC50: 257.8 µg/mL	Balasubramani et al. (158)
Apple (Malus domestica)	Fruit	Ag	10–40 nm	Spherical	MCF-7	10–100 µg/mL	24 and 48 h	No toxicity at ≤ 70 µg/mL after 24 h of incubation Significant toxicity at ≥10 µg/mL after 48 h of incubation	Lokina and colleagues (9)
Areca catechu	Nut	Au	22.2 nm	Spherical	HeLa	6.25–100 µg/mL	24 h	IC50: 25.17 µg/mL	Rajan and colleagues (37)
Argemon maxcana	Leaf	Ag	2–6 nm	Spherical	SiHa	25–100 µg/mL	72 h	IC50:>50 µg/mL Significant toxicity at 100 µg/mL	Jha and Prasad (63)
Artemisia marschalliana Sprengel	Aerial part	Ag	5–50 nm	Spherical	AGS	3.125–100 µg/mL	24 h	IC50: 21.05 µg/mL in AGS	Salehi and colleagues (44)
Azadirachta indica	Leaf	Au	≤121.7 nm	Spherical, hexagonal and triangular	HeLa and MDCK	0.1–0.25mM	48 h	No toxicity	Dharmatti and colleagues (86)
Azadirachta indica (neem)	Leaf	Ag	94 nm	Spherical	HDFa and NCI-H460	0–240ppm	24 h	Very high toxicity at 240 ppm in NCI-H460, but no toxicity in normal HDFa	Kummara and colleagues (39)
Bambusa arubdinacea (Ba) and Bambusa nutans (Bn)	Leaf	Ag	30–90 nm	Spherical	PC3 and Vero cells	10–100 µg/mL	48 h	IC50: 73.57 µg/mL for BaAgNP in PC3 IC50: 84.88 µg/mL for BnAgNP in PC3 IC50: 93.58 µg/mL for BaAgNP in Vero IC50: 96.41 µg/mL for BnAgNP in Vero	Kalaiarasi et al. (159)
Borago officinalis	Leaf	Ag	30–80 nm	Spherical, hexagonal, and irregular	RAW 264.7, A549 and HeLa	1–10 µg/mL	24 h	No significant toxicity in RAW 264.7, Significant toxicity in A549 at 10 µg/mL and HeLa at 5 µg/mL	Singh and colleagues (35)
Broccoli	Whole plant	Cu	∼4.8 nm	Spherical	PC-3	0.5–1.5µM	2 h	No toxicity	Prasad and colleagues (52)
Broccoli florets (Brassica Oleracea L.var. Italica)	Aerial part	Ag	40- 50 nm	Spherical	MCF-7	50–150 µg/mL	24 h	IC50: 121.56μg/mL	Caroling et al. (160)
Bruguiera cylindrica	Leaf	Ag	9–24 nm	Hexagonal	MCF-7	50, 100 µg/mL	12, 24, 36 h	IC50: 100 µg/mL after 12 h of incubation 90% toxicity at 100 µg/mL after 36 h of incubation	Bhuvaneswari et al. (161)
Butea monosperma	Leaf	Ag and Au	20–80 nm	Mainly spherical but few rods, irregular and hexagonal	B16F10, MCF-7, HNGC2, A549, HUVEC and ECV-304	0.3–2.5µM	24, 48 h	No toxicity	Patra and colleagues (55)
Cajanus cajan	Seed coat	Au	9–41 nm	Spherical	HepG2 and vero cells	2–10 µg/mL in HepG2 10–320 µg/mL in vero cells	24 h	IC50:6 µg/mL in HepG2
IC50:246 µg/mL in vero cells	Ashokkumar et al. (162)
Calotropis procera L.	Latex	Cu	5–30 nm	Spherical	HeLa, A549 and BHK21	20–160 μM	24 h	No toxicity	Harne and colleagues (89)
Cassia fistula	Flower	Ag	21–30 nm	Spherical	MCF-7 and Vero cells	7.8–1000 µg/mL	24 h	IC50: 7.19 µg/mL in MCF-7 IC50: 66.34 µg/mL in Vero cell line	Remya et al. (163)
Cassytha filiformis	Whole plant	Ag	16–66 nm	Spherical	HCT116	0.1–10 μg/mL	24 h	IC50:0.5 mg/mL	Jena and colleagues (36)
Cauliflower floret (Brassica Oleracea. var. botrytis. l)	Aerial part	Ag	40–50 nm	Spherical	MCF-7	50–150 μg/mL	24 h	Moderate (40.24%) toxicity at 150 μg/mL IC50: 190.501 µg/mL	Ranjitham et al. (164)
Chlorella vulgaris (Algae)	Whole cell	Ag	6.5–13.5 nm (Average size: 9 nm)	Spherical	HepG2	2.35- 300 µg/mL	24 and 48 h	≥4.7 µg/mL significant toxicity after 24 h and 48h	Ebrahiminezhad et al. (165)
chrysanthemum indicum	Flower	Ag	37.71–71.99 nm	Spherical	3T3	25 and 50 µg/mL	24 h	No toxicity at 25 µg/mL, but toxic at 50 µg/mL	Arokiyaraj and colleagues (83)
Chrysophyllum oliviforme (Satin leaf)	Leaf	Ag	25 nm	Flower	HeLa	6.25–100 µg/mL	48 h	IC50: 40.365 µg/mL	Anju Varghese R (166)
Cissus quadrangularis	Stem	Ag	5–30 nm	Spherical	HEp 2 and Vero cells	20–160 μg	4 h	IC50:64μg in HEp 2 IC50:90μg in Vero	Renugadevi and colleagues (68)
Clerodendron serratum	Leaf	Ag	5–30 nm	Spherical	EAC	5–60 µg/mL	24 h	IC50∼40 µg/mL	Raman and colleagues (57)
Cucurbita maxima, Moringa oleifera and Acorus calamus	C. maxima (petal), M. oleifera (leaf) and A. calamus (rhizome)	Ag	30–70 nm	Spherical and cuboidal	A431	10–150 µg/mL	24 h	IC50:82.39 ± 3.1 µg/mL in AgNPs synthesized from C. maxima IC50: 83.57 ± 3.9 µg/mL in AgNPs synthesized from M. oleifera IC50: 78.58 ± 2.7 µg/mL in AgNPs synthesized from A. calamus	Nayak and colleagues (62)
Cymodocea serrulata	Aerial part	Ag	17–29 nm	Spherical	HeLa and Vero cells	10–100 µg/mL	48 h	IC50: 34.5 µg/mL in Hela IC50:61.24 µg/mL in Vero cell	Chanthini et al. (167)
Cymodocea serrulata	Leaf	Ag	5–25 nm	Spherical	A549	10–250 µg/mL	36 h	IC50: 100 µg/mL	Palaniappan et al. (168)
Datura inoxia	Leaf	Ag	30–60 nm	–	MCF-7	10–80 µg/mL	24 h	IC50: 20 μg/mL	Gajendran et al. (169)
Delonix regia	Petal	ZnO	65–184 nm	Spherical	A549	5–20 µg/mL	1–5 days	Very low toxicity after 1 day IC50∼20 µg/mL after 2 day Low toxicity at ≤10 µg/mL after 5 days	Abbasi et al. (170)
Dendropanax morbifera	Leaf	Ag and Au	Ag:100–150 nm Au: 10–20 nm	Polygon and hexagon	HaCaT and A549	1–100 µg/mL	48 h	No toxicity of AuNPs at 100 µg/mL in HaCaT and A549, Low toxicity of AgNPs at 100 µg/mL in HaCaT, No toxicity of AgNPs at 10 µg/mL, but significant toxicity at 100 µg/mL in A549	Wang and colleagues (77)
Dimocarpus Longan Lour.	Peel	Ag	9–32 nm	Spherical	PC-3	2–30 μg/mL	72 h	IC50: 5–10 µg/mL	He and colleagues (53)
Dioscorea bulbifera	Tuber	Pt, Pd, Pt–Pd	PtNPs:2–5 nm PdNPs:10–20 nm Pt–PdNPs:20–25 nm	PtNPs: spherical PdNPs: spherical and blunt ended cubes Pt–PdNPs: irregular	HeLa	10 µg/mL	48 h	Cytotoxic effect at 10 µg/mL: PtNPs (12.6%), PdNPs (33.15%), and Pt–PdNPs (74.25%)	Ghosh et al. (171)
Dracocephalum kotschyi	Leaf	Au	11 nm	Spherical	K562 and HeLa	62.5–500 µg/mL	24, 48 and 72 h	IC50: 196.32 µg/mL in K562 and IC50: 152.16 µg/mL in Hela	Dorosti and Jamshidi (61)
Ecklonia cava (marine brown alga)	Seaweed	Au	20–50 nm	Spherical and triangular	HaCaT	10–50 µg/mL	24,48, 72 h	No toxicity	Venkatesan and colleagues (76)
Eclipta alba	Leaf	Ag	310–400 nm	Cubic	RAW254.7, MCF-7 and Caco-2	0.5–50 µM	48 h	IC50: 5 µM in MCF-7 IC50:7 µM in RAW254.7 IC50: 10 µM in Caco-2	Premasudha and colleagues (49)
Erythrina indica lam	Root	Ag	20–118 nm	Spherical	MCF-7 and HepG2	0.625–25 µg/mL	24 h	IC50: 2.5 µg/mL in HEP G2 IC50∼8 µg/mL in MCF-7	Sre et al. (172)
Eucalyptus	Leaf	Ag	30–70 nm	–	AGS, MRC-5	3–100 µg/mL	24,48,72 h	IC50: 9.01, 6.31, 3.99 µg/mL in AGS after 24, 48 and 72 h of incubation, respectively. IC50: 35.44, 30.13, 21.28 µg/mL in MRC-5 after 24, 48 and 72 h of incubation, respectively.	Rashmezad and colleagues (45)
Ficus benghalensis Azadirachta indica	Bark	Ag	∼40 nm and ∼50 nm	Spherical	MG-63	20–200 μg/mL	48 h	IC50: 81.8 ± 2.6 μg/mL for Ag from A. indica IC50:75.5 ± 2.4 μg/mL for Ag from F. benghalensis	Nayak and colleagues (42)
Ficus religiosa	Bark	Au	20–30 nm	Spherical	HEK 293	10–200 μM	24 h	No toxicity	Wani K (78)
Genipa americana L.	Fruit	Au	30.4 ± 14.9 nm	Spherical	A-549 and Hela	0.01–20µM	48 h	No toxicity observed	Kumar et al. (173)
Haliclona exigua (marine sponge)	Sponge	Ag	0.078–5 μg/mL	Flower like	KB	100 to 120 nm	48 h	IC50: 0.6 µg/mL	Inbakandan and colleagues (72)
Helianthus Annuus L.	Sunflower oil	Ag	Spherical: ∼10 nm Hexagonal:40–50 nm	Spherical and hexagonal	A549	10–100 µg/mL	24 h	IC50∼65 µg/mL	Thakore et al. (174)
Helicteres isora	Stem bark	Ag	16–95 nm	Spherical	KB	0–200 µg/mL	24 h	IC50: 70 µg/mL	Bhakya and colleagues (73)
Hibiscus sabdariffa	leaf and stem	Au	10–60 nm	Near spherical	U87 and HEK 293	0–2.5 ng/mL	48 h	IC50∼1.5 ng/mL and high toxicity at 2 ng/mL in U87 and little toxicity in HEK 293	Mishra and colleagues (40)
Impatiens balsamina	Flower	Ag	Average size: 15 nm	Spherical	U937, COLO205, B16F10, HepG2, HeLa	25–200 µg/mL	24 h	IC50:84.17 ± 2.13 µg/mL in U-87 IC50:65.40 ± 2.41 µg/mL in COLO205 IC50:196.5 ± 4.19 µg/mL in B16F10 IC50:95.52 ± 4.08 µg/mL in HepG2 IC50:93.27 ± 2.53 µg/mL in HeLa	Nalavothula R (54)
Iresine herbstii	Leaf	Ag	44–64 nm	Cubical	HeLa	25–300 μg/mL	3 h	IC50:51 μg/mL	Dipankar and Murugan (175)
Justicia adhatoda	Leaf	Ag	11–20 nm	Spherical	HeLa	10–80 µg/mL	4 h	IC50:55 µg/mL	Kudle et al. (176)
Lavandula vera	Leaf	Zn	30–80 nm	Spherical	A549, MCF-7, HT-29, and Caco-2	10–160 µg/mL	24 h	IC50: 22.3 ± 1.1 µg/mL in A549 IC50: 86 ± 3.7 µg/mL in MCF-7 IC50: 10.9 ± 0.5 µg/mL in HT-29 IC50: 56.2 ± 2.8 µg/mL in Caco-2	Salari and colleagues (47)
Mangifera indica Linn	Peel	Au	6.03 ± 2.77–18.01 ± 3.67 nm	Quasi-spherical	CV-1 and WI-38	10–160 μg/mL	24 h	No toxicity	Yang and colleagues (87)
Mimosa pudica	Leaf	Au	12 nm	Spherical	MDA-MB-231, MCF-7 and HMEC	2–10 μg/mL for MDA-MB-231 & MCF-7 5–80 μg/mL for HMEC	24 and 48 h	IC50:4 µg/mL in MDA-MB-231 after 48 h of incubation IC50:6 µg/mL in MCF-7 after 48 h of incubation IC50 did not observed after 24 h no significant toxicity in HMEC	KS and colleagues (33)
Momordica charantia	Leaf	Ag	∼91.63 nm	Spherical	MCF-7	12–100 µg/mL	24 h	IC50: not exactly mentioned in the text, but between 50–100 µg/mL	Gandhiraj V (177)
Momordica cymbalaria	Fruit	Ag	Average size: 15.5 nm	Spherical	Rat L6	20–100 µg/mL	24–48 h	IC50∼20 µg/mL	Swamy and colleagues (85)
Morinda citrifolia	Root	Ag	30–55 nm	Spherical	HeLa	0.1–100 μg/mL	24 h	Highly significant toxicity at 100 μg/mL	Suman et al. (178)
Moringa oleifera	Flower	Pd	10–50 nm and 2–18 nm	Spherical	A549 and human normal peripheral lymphocytes cells	10 μg/mL and 50 μg/mL	6 h	Significantly cytotoxic to A549 cells and no toxicity in normal peripheral lymphocytes	Anand and colleagues (95)
Musa paradisiaca (banana)	Stem of banana	Au	Average size: 30 nm	Spherical	MCF-7 and HEK-293	10–100 nM	24 h	IC50:>80 nM in MCF-7 No toxicity at 60 nM in HEK-293, but low toxicity above 60 nM	Arunkumar and colleagues (88)
Oak fruit hull (Jaft)	Fruit	Ag	Average size: 40 nm	Spherical	MCF-7 and human blood mononuclear cells	0.02–50 µg/mL	24 h	IC50: 50 µg/mL (AgNPs in purified water) in MCF-7 IC50:0.04 µg/mL (AgNPs in plant extract) in MCF-7 No toxicity in human blood mononuclear cells	Heydari and Rashidipour (99)
Origanum vulgare (Oregano)	Leaf	Ag	63–85 nm	Spherical	A549	10–500 μg/mL	36 h	IC50:100 µg/mL	Sankar et al. (179)
Padina gymnospora (marine Macroalgae)	Leaf	Au	Average size: 14.10 ± 1.5 nm	Spherical	HepG2, A549, and 3T3	5–80 nM	48 h	IC50: 51.9 nM in HepG2 IC50: 76.40 nM in A549 No toxicity in 3T3	Singh and colleagues (84)
Piper pedicellatum	Fruit	gold-reduced graphene oxide (Au-rGO) nanocomposite	8–15 nm	Pentagonal, hexagonal and spherical	PC3 and RWPE-1	10–50 µg/mL	–	IC50: 12.02 µg/mL in PC3 IC50: 25.1 µg/mL in RWPE-1	Saikia and colleagues (81)
Plumbago zeylanica, Semecarpus anacardium and Terminalia arjuna	Bark, root bark and nut, for P. zeylanica, S. anacardium and T. arjuna, respectively	Ag	80–98 nm, 60–95 nm and 34–70 nm for P. zeylanica, S. anacardium and T. arjuna, respectively	Spherical for P. zeylanica and T. arjuna Cubic for S. anacardium	HepG2, PC3 and Vero cells	1–100 μg/mL	48 h	IC50 of HepG2, PC3 and Vero cells: 70.97, 58.61, 96.41 μg/mL, respectively for P. zeylanica. IC50 of HepG2, PC3 and Vero cells: 83.86, 42.77, 10.04 μg/mL, respectively for S. anacardium. IC50 of HepG2, PC3 and Vero cells: 28.42, 41.78, 69.48 μg/mL, respectively for T. arjuna.	Prasannaraj and colleagues (79)
Potentilla fulgens	Root	Ag	10–15 nm	Spherical	MCF-7 and U-87	0–12 µg/mL	24 h	IC50:4.91 µg/mL in MCF-7 IC50:8.23 µg/mL in U-87	Mittal et al. (180)
Premna serratifolia L.	Leaf	Ag	16–32 nm, (Average size: 22.97 nm)	Cubic	Hepato-cancerous Swiss albino mice	500 mg/Kg in vivo	15 days (In vivo study in mice)	Significant anticancer effect to improve biochemical plasma factors to reach normal levels	Patra and colleagues (55)
Rheum rhabarbarum	Stem	Ag	60–80 nm	Spherical	HeLa	10–500 μg/mL	72 h	IC50: 28.5 μg/mL	Reddy et al. (181)
Rosa canina	Fruit	ZnO	≤ 50 nm	Spherical	A549	0.05–0.5 mg/mL	24 h	No significant toxic effect up to 0.1 mg/mL IC50∼0.25 mg/mL	Jafarirad et al. (182)
Rosa indica	Petal	Ag	23.52–60.83 nm	Spherical	HCT 15	5–60 µg/mL	24 h	IC50: ∼30 µg/mL	Manikandan and colleagues (50)
Rosa indica	Petal	Ag	23.52–60.83 nm	Spherical	HCT 15	5–60 µg/mL	24 h	IC50: ∼30 µg/mL	Manikandan and colleagues (50)
Rosmarinus officinalis	Leaf	Ag	Average size: 60 nm	Cubical	HL-60	1 mM, 2mM	6, 12, 24 h	No IC50 after 6h IC50: <2 mM after 12h 80% toxicity at 2 mM after 24h	Sulaiman and colleagues (60)
Sargassum Muticum (algae)	Whole cell	hyaluronan/ zinc oxide (HA/ZnO) nanocomposite	3–8 nm	Polygonal	PANC-1, CaOV-3, COLO205, and HL-60 and MRC-5	0–100 μg/mL	72 h	IC50 is 10.8 ± 0.3 μg/mL, 15.4 ± 1.2 μg/mL, 12.1 ± 0.9 μg/mL, and 6.25 ± 0.5 μg/mL for the PANC-1, CaOV-3, COLO-205, and HL-60 cells, respectively. No toxicity observed in MRC-5	Namvar and colleagues (41)
Sargassum longifolium	Seaweed	Ag	Average size: 30 nm	Cubical	HEp 2	3.9–1000 μg/mL	48 h	IC50: 62.5 µg/mL	Devi and colleagues (69)
Sargassum muticum	Seaweed	ZnO	50–100 nm	Hexagonal	4T1, CRL-1451, CT-26, WEHI-3B and 3T3	0–100 µg/mL	72 h	IC50:21.7 ± 1.3 µg/mL in 4T1 IC50:17.45 ± 1.1 µg/mL in CRL-1451, IC50:11.75 ± 0.8 µg/mL in CT-26, and IC50:5.6 ± 0.55 µg/mL in WEHI-3B, no toxicity in 3T3	Namvar and colleagues (56)
Sargassum muticum	Seaweed	Au	5.42 ± 1.18 nm	Spherical	CEM-ss, Jurkat, HL-60, K562 and normal human blood mononuclear cells	0–100 µg/mL	72 h	IC50:4.22 ± 1.12 µg/mL in K562 IC50:5.71 ± 1.4, 6 µg/mL in HL-60 IC50: 55 ± 0.9 µg/mL in Jurkat IC50: 7.29 ± 1.7 µg/mL in CEM-ss no toxicity in normal human blood mononuclear cells	Namvar and colleagues (58)
Sargassum muticum	Seaweed	Fe3O4	18 ± 4 nm	Cubic	Jurkat, MCF-7, HeLa and HepG2	–	72 h	IC50:23.83 ± 1.1 μg/mL in HepG2 IC50:18.75 ± 2.1 μg/mL in MCF-7 IC50:12.5 ± 1.7 μg/mL in HeLa IC50:6.4 ± 2.3 μg/mL in Jurkat	Namvar and colleagues (59)
Sargassum swartzii	Seaweed	Au	20–60 nm	Spherical and few hexagonal	HeLa	15.63–500 µg/mL	24 h	IC50: 41.10 µg/mL	Dhas et al. (183)
Sesbania grandiflor	Leaf	Ag	10–45 nm	Spherical	MCF-7	0–50 µg/mL	24 and 48 h	IC50: 20 µg/mL	Jeyaraj et al. (184)
Solanum muricatum	Leaf	Ag	20–80 nm	Irregular	HeLa	10–100 µg/mL	72 h	IC50: 37.5 µg/mL	Gorbe et al. (185)
Solanum trilobatum	Fruit	Ag	12.50–41.90 nm	Spherical and polygonal	MCF 7	5–50 µg/mL	24 h	IC50: >20 µg/mL	Ramar et al. (186)
star anise (Illicium verum)	Pod	Au	20–150 nm	Triangular and hexagonal	A549	10–200 nM	48 h	Low toxicity	Sathishkumar et al. (187)
star anise (Illicium verum)	Pod	Au	20–50 nm and 30–150 nm	Triangular and hexagonal	A549	10–200 nM	48 h	Low toxicity at 200 nM	Sathishkumar and colleagues (187)
Sterculia foetida L.	Seed	Ag	Average size: 6.9 ± 0.2 nm	Spherical	HeLa	1–16 µg/mL	24 h	IC50: >2 µg/mL Significant toxicity at 16 µg/mL (>90%)	Rajasekharreddy and Rani (188)
Styrax benzoin	Benzoin gum	Ag	12–38 nm	Spherical	Raw 264.7, Hela, A549 and HaCaT	1–5 µg/mL in Raw 264.7, Hela and A549. 1–10 µg/mL in HaCaT	24 h	≤2 µg/mL no significant toxicity in Raw 264.7, ≥1 µg/mL significant toxicity in Hela and A549, no significant cytotoxic up to 10 µg/mL in HaCaT	Du and colleagues (96)
Syzygium cumini	Fruit	Ag	5–20 nm	Spherical	DL	50–500 µg/mL	48 h	IC50∼100 μg/mL	Mittal and colleagues (64)
Syzygium samarangense	Leaf	Ag	–	Spherical	A549	50–200 µg/mL	24 h	IC50: 87.37 µg/mL	Thampi and Shalini (189)
Tabernaemontana divaricata	Flower	Au	100 nm	Nearly spherical	MCF-7 and Vero cells	25–75 μg/mL	24 h	75 μg/mL moderate toxicity in MCF-7 but little toxicity in Vero cell line	Raj and Khusro (80)
Taxus yunnanensis	Callus	Ag	6.4–27.2 nm	Spherical	SMMC-7721, LS174T, A549, MCF-7 and HL-7702	10–50 µg/mL	24 h	IC50: 27.75 µg/mL in SMMC-7721 IC50: 81.39 µg/mL in HL-7702 IC50: 40.3 µg/mL in A549 IC50: 42.2 µg/mL in MCF-7 IC50:27.75 µg/mL in LS174T	Xia and colleagues (46)
Torreya nucifera, Cinnamomum japonicum, and Nerium indicum	Leaf	Ag	8–42 nm, 4 35 nm, 4–38 nm	Spherical, pentagonal	3T3-L1	0.1 ng/mL–10 μg/mL	24 h	Low toxicity in AgNPs from T. nucifera and N. indicum, but moderate toxicity in AgNPs from C. japonicum	Kalpana and colleagues (90)
Turbinaria turbinata (marine algae)	Whole cell	Ag	8–16 nm	Spherical	EAC	42–98 µg/mL	–	99% toxicity at 98 µg/mL	Khalifa et al. (190)
Vigna radiata (green gram)	Seed	Lanthanum	–	Spherical	Mg-63	12.5–200 µg/mL	48 h	IC50: 200 µg/mL	Chatterjee A (43)
Vigna radiata (green gram)	Seed	Titanium dioxide	–	–	Mg-63	12.5–200 µg/mL	48 h	IC50: 200 µg/mL	Chatterjee et al. (191)
Vitex negundo L.	Leaf	Ag	5–49 nm	Spherical	HCT15	10–100 μg/mL	48 h	IC50: 20 μg/mL	Prabhu and colleagues (51)
Zataria multiflora	Leaf	Au	10–50 nm (Average size: 20.52 nm)	Different shapes; pentagon, triangular, undefined shapes	HeLa and BMSCs	0–400 µg/mL	48 h	Significant toxicity at 400 µg/mL in Hela cell line (IC50:100 µg/mL). IC50: 300 µg/mL in BMSCs:	Baharara and colleagues (101)
Zingiber zerumbet	Rhizome	ZnO–Ag nanocomposite	23 nm	Spherical	Vero cells	0–300 µg/mL	24 h	No toxicity at ≤100 µg/mL but at higher concentration toxicity gradually increased	Azizi et al. (192)

^aCancer and normal Cell Lines: HeLa (human cervical cancer), HepG2 (hepatic cancer), MDA-MB-231 and MCF-7 (human breast adenocarcinoma), PC-3 (human prostate carcinoma), KB (human oral cancer), A549 (human lung adenocarcinoma), HCT116 (human colon colorectal carcinoma), EAC, NCI-H460 (non-small cell lung cancer), U87 (glioblastoma multiforme cell), PANC-1 (pancreatic adenocarcinoma), CaOV-3 (ovarian adenocarcinoma), COLO205 (colonic adenocarcinoma), HL-60 (acute promyelocytic leukemia), MG-63 (osteosarcoma cell), AGS (human gastric carcinoma), SMMC-7721 (human hepatoma cells), LS174T (human colon adenocarcinoma cell), HT-29 (human colorectal adenocarcinoma), Caco-2 (human epithelial colorectal adenocarcinoma), HCT 15 (human colon adenocarcinoma), U937 (human histiocytic lymphoma cell), B16F10 (mouse melanoma), 4T1 (mouse breast cancer), CRL-1451 (mouse lung adenocarcinoma), WEHI-3B (Mouse leukemia), CEM-ss (human T acute lymphoblastic leukemia), Jurkat (human T acute lymphoblastic leukemia), K562 (human chronic myelogenous leukemia), A431 (human vulvar squamous cell carcinoma), HNGC-2 (human adult glioma tissue), ECV-304 (human urinary bladder carcinoma), RAW254.7 (mouse leukemia), SiHa (human cervical squamous cell carcinoma), DL, HaCat (aneuploid immortal keratinocyte cell line), RAW 264.7 (murine Macrophage), PBMC (peripheral blood mononuclear cell).

Table 2. Microbial sources for synthesis of bionanoparticles and their anticancer activity in various cell lines for the past 5 years.

Microbial species	Microbe type	Nanoparticle type	Size (nm)	Morphology	Anticancer activity (In vitro model)^a	Dose (µg/well)	Exposure time	Major outcome	Reference
Aspergillus deflectus and Penicillium pinophilum	Fungus	Ag/CS	15–40 nm	–	MCF 7, PC3 and A549	12.5–100 μg/mL	24 h	IC50:27.9 and 53μg/mL in MCF 7 and PC3 for AgNPs synthesized from A. deflectus under optimized conditions and no toxicity in A549 No toxicity of AgNPs synthesized from P. pinophilum under optimized conditions in MCF 7 and PC3 and low toxicity in A549	Osman et al. (193)
A. flavus	Fungus	Ag	Average size: 33.5 nm	–	HL-60	5 and 10 μg/mL	6, 12 and 24h	High toxicity at 10 μg/mL after 6 h IC50∼5μg/mL after 12 h. Very high toxicity at 10μg/mL after 12h	Sulaiman et al. (194)
A. flavus SP-3 Trichoderma gamsii SP-4 Talaromyces flavus SP-5 Aspergillus Oryzae SP- 6	Fungus	Ag	20–60 nm	Spherical	HEp2	0–1000 μg/mL	24 h	IC50: 23μg/mL for T. gamsii SP-4, 100 µg/mL for A. flavus SP-3, 39 µg/mL, for T. flavus SP-5, and 36 µg/mL for A. oryzae SP-6	Anand et al. (195)
Aspergillus foetidus	Fungus	Au	30–50 nm	Spherical	A549	10–100µM	12 h	No toxicity	Roy et al. (196)
Bacillus cereus	Bacterium	Cu	11–33 nm	Spherical	HaCat, Vero, hFOB, MCF 7, A549, CaCO2, Neuro-2a, HCT 116, RAW 264.7 and HepG2	20–60 μg/mL	48 h	IC50: ∼20, ≥20, ≥60 μg/mL in hFOB, HaCat and Vero, respectively IC50:3.27 μg/mL in A549; IC50: ≤20 μg/mL in Neuro-2a and RAW 264.7; IC50: ≥20 μg/mL in MCF 7, CaCO2 and HepG2; IC50: ∼40 μg/mL in HCT 116	Tiwari and colleagues (91)
Bacillus cereus	Bacterium	TiO2	69–140 nm	Spherical	HEp2 and Vero cells	0.008–0.5 mg/mL	4 h	IC50: 0.465 mg/mL in HEp2 Low toxicity in Vero	Sunkar et al. (197)
Bacillus cereus (ATCC 14579) and Escherichia fergusonii (ATCC 35469)	Bacterium	Ag	10–20 nm for both of bacteria	Spherical and hexagonal for both of bacteria	NIH3T3 D4	–	24 h	≤0.25 mg/100 µL is nontoxic and 1 mg/100 µL is toxic for AgNPs from B. cereus. ≤ 0.0625 mg/100 µL is nontoxic and 0.25 mg/100 µL is toxic for AgNPs from E. fergusonii	Pourali and Yahyaei (198)
Bacillus flexus	Bacterium	Au	Average size: 20 nm	Different shapes (irregular, spherical, triangular)	MCF-7	25–200 μM/mL	24h	No toxicity	Murugan et al. (199)
Bacillus sp. MSh-1	Bacterium	Se	80–220 nm	Spherical	MCF-7	0–200 μg/mL	24 h	IC50: 41.5 ± 0.9μg/mL	Forootanfar et al. (200)
Bacillus subtilis	Bacterium	Cr(III)	4–50 nm (Average size: 20 nm)	Spherical	HEK 293	0.1–50 µL (1 mM)	48 h	At 50 µL(1 mM) the viability of HEK 293 cells was 83.5 ± 1.66%	Kanakalakshmi et al. (201)
Beauveria bassiana	Fungus	Ag	20.44 – 34.16 nm	Spherical	HeLa	3.125–50 μg/mL	24 h	IC50: 28.8 ± 2.5μg/mL	Prabakaran and colleagues (38)
Cryptococcus laurentii (BNM 0525)	Yeast	Ag	35 ± 10	–	MCF-7, T47D and MCF10-A	0–5 μg/mL	12 h	Significant toxicity above 2.5 μg/mL in MCF-7 and T47D but slight toxicity in MCF10-A	Ortega and colleagues (71)
Endophytic Fungus	Fungus	Au	15–35 nm	Spherical	HEp2 and Vero cells	1.17–75 μg/mL	4 h	IC50: 23 μg/mL in Hep2 IC50: 12 μg/mL in Vero	Nachiyar et al. (202)
Enterococcus sp.	Bacterium	Au	6–13 nm	Spherical	HepG2 and A549	1–100 μg/mL	24 h	IC50: 100μg/mL	Rajeshkumar (203)
Enterococcus sp.	Bacterium	Ag	10 to 80 nm	Spherical	HepG2 and A549	1–100 μg/mL	24 h	IC50: 50μg/mL in HepG2 IC50: 100μg/mL in A549	Rajeshkumar et al. (204)
Fusarium oxysporum	Fungus	Terbium oxide (Tb2O3)	10 nm	Spherical	MG-63, Saos-2 and normal Primary osteoblast	(0.023–0.373 μg/mL	48 h	IC50: 0.102 μg/mL in MG-63 and Saos-2 ≤ 0.373μg/mL low toxicity in normal Primary osteoblast	Iram et al. (205)
Fusarium oxysporum	Fungus	Au	10–40 nm	Spherical	ZR-75-1, Daudi and PBMC	5–500 μg/mL	24 h	Moderate toxicity in ZR-75-1 and Daudi, but no toxicity in PBMC	Ahmad Siddiqui and colleagues (70)
Fusarium oxysporum	Fungus	Ag	5–13 nm	Spherical	MCF-7	0–220 μg/cm^3	–	IC50:121.23 μg/cm^3	Husseiny et al. (206)
Fusarium oxysporum (Fungus)	Fungus	Ag	10–15 nm	Quasi-spherical	C26 and HaCaT	2–16 μg/mL	24 h	No toxicity at ≤6 μg/mL in HaCaT. Significant toxicity at ≥8 μg/mL in C2 6	Potara and colleagues (74)
Halococcus salifodinae BK18	Bacterium	Se	Average size: 28 nm	Rod and hexagonal	HeLa and HaCat	10–150 μg/mL	24 h	IC50∼50 μg/mL in HeLa, No toxicity in HaCat	Srivastava et al. (207)
Humicola sp.	Fungus	Ag	5–25 nm	Spherical	NIH3T3 and MDA-MB-231	50–1000 μg/mL	24 h	Very low toxicity at 250 μg/mL in both cell line Significant toxicity at 1000 μg/mL in both cell line	Syed and colleagues (93)
Humicola spp.	Fungus	Au	18–24 nm	Spherical	NIH3T3 and MDA-MB-231	50–1000 μg/mL	24 h	No toxicity at 50 μg/mL in both cell line Significant toxicity at ≥250 μg/mL in both cell line	Syed et al. (208)
Klebsiella pneumoniae (KACC 11402)	Bacterium	Au	16–36 and 24–50 nm	Spherical	3T3L1, H9c2 and HepG2	0.01–1000 μg/mL	24 and 48 h	No toxicity	Kalpana and colleagues (92)
Moraxella osloensis	Bacterium	Titanium dioxide (TiO2)	60–150 nm	Irregular	HaCaT and HEp2	8–100 μg/mL	–	IC50: 55 μg/mL in HaCaT IC50: 172 μg/mL in HEp2	Valli Nachiyarand colleagues (103)
Nocardiopsis sp.	Marine actinobacterium	Au	Average size: 11.57 ± 1.24 nm	Spherical	HeLa	50–400 μg/mL	24 h	IC50: 300 μg/mL	Manivasagan et al. (209)
Nocardiopsis sp.	marine actinobacterium	Au	10–50 nm Average size: 39 ± 2 nm	Spherical and triangular	HeLa	50–500 μg/mL	24, 48 h	IC50:350 and 250 μg/mL after 24 h and 48 h of incubation	Manivasagan and Oh (210)
Nocardiopsis sp. MBRC-1	Bacterium	Ag	Average size: 45 ± 0.15 nm	Spherical	HeLa	50–250 μg/mL	24 h	IC50: 200 μg/mL	Manivasagan et al. (211)
Nocardiopsis valliformis OT1 strain	Alkaliphilic actinobacterium	Ag	5–50 nm	Spherical	HeLa	25–100 μg/mL	48 h	IC50: 100μg/mL	Rathod et al. (212)
Penicillium brevicompactum	Fungus	Au	10–120 nm	Spherical, triangular and hexagonal	C2C12	200–2000ng/mL	24, 48, 72 h	IC50: >1000 ng/mL after 24h IC50: >200 ng/mL after 48h Significant toxicity after 72 h at any range of concentration	Mishra and colleagues (94)
Penicillium decumbens (MTCC-2494)	Fungus	Ag	30–60 nm	Spherical	A-549 and Vero cells	20–120 μg/mL	24 and 48 h	A-549 IC50:80 and 60 μg/mL after 24 h and 48 h of incubation, respectively. Vero cell IC50: 100μg/mL after 24 h of incubation	Majeed and colleagues (100)
Pleurotus djamor var. roseus	Fungus	Ag	5–50 nm	Spherical	PC3	1–6 μg/mL	24 h	IC50: 10 μg/mL	Raman et al. (213)
Pleurotus ostreatus	Fungus	Ag	4–15 nm	Spherical	MCF-7	10–640 μg/mL	24 h	IC50∼160 μg/mL	Yehia and Al-Sheikh (214)
Pseudomonas aeruginosa (JQ989348)	Bacterium	Ag	13–76 nm	Spherical	Human carcinoma cervical cell line	5–100 μg/mL	24 h	100% toxicity at 40μg/mL	Ramalingam et al. (215)
Schizophyllum commune	Fungus	Ag	51–93 nm	Spherical	HEP -2	10–100 μg/mL	24 h	IC50:53 μg/mL	Arun et al. (216)
Stenotrophomonas maltophilia	Bacterium	Ag	Average size: ∼93 nm	Cuboidal	HeLa and Splenocyte cells	0–500 μg/mL	48 h	IC50: >31.25 μg/mL in HeLa IC50: >250 μg/mL in Splenocyte cells	Oves et al. (217)
Streptomyces naganishii (MA7)	Actinobacteria	Ag	5–50 nm	Spherical	HeLa	0.1–300 μg/mL	48 h	IC50: 1.53 μg/mL LD50:24.39 μg/mL	Shanmugasundaram et al. (218)
Streptomyces rochei MHM13	Actinomycetes	Ag	22–85 nm	Spherical	HepG2, HCT-116, MCF-7, PC-3, A-549, CACO, HEp-2 and HeLa	1.56–50 µg/well	24 h	IC50:32.90 µg/Well in HepG2 IC50:9.05 µg/Well in HCT-116 IC50:40.00 µg/Well in MCF-7 IC50: 48.50 µg/Well in PC-3 IC50: 42.10 µg/Well in A-549 IC50: >50 µg/Well in CACO IC50: >50 µg/Well in HEp-2 IC50: >50 µg/Well in HeLa	Abd-Elnaby et al. (219)
Trichoderma koningii	Fungus	Au	10–14 nm	Spherical	LoVo and LoVo/DX	1–1000 μg/mL	24 h	IC50:33.04 ± 4.9 μg/mL in LoVo IC50:28.88 ± 2.9 μg/mL in LoVo/DX	Maliszewska (75)
Trichoderma viride	Fungus	Ag	5–40 nm	–	MCF-7	1–100 µg/mL	24 h	Low toxicity ≤10 µg/mL, but toxicity gradually increased over 10 µg/mL	Kulandaivelu and Gothandam (220)
Xylorious	Fungus	Ag	–	Spherical	HT-29	7.8–1000 μg/mL	48 h	IC50:62.5 μg/mL	Varsha B (48)

^aCancer and normal Cell Lines: HeLa (human cervical cancer), A549 (human lung adenocarcinoma), HepG2 (hepatic cancer), MDA-MB-231 and MCF-7 (human breast adenocarcinoma), PC-3 (human prostate carcinoma), MG-63 (osteosarcoma cell), HT-29 (human colorectal adenocarcinoma), Caco-2 (human epithelial colorectal adenocarcinoma), HL-60 (human acute myeloid leukemia), HEp-2 (human larynx carcinoma), ZR-75-1 (human caucasian breast carcinoma), DAUDI (human burkitt’s lymphoma), T47D (human breast cancer), LoVo (human colon adenocarcinoma), LoVo/DX (multidrug resistance human colon adenocarcinoma sub-line), HaCat (aneuploid immortal keratinocyte cell line), hFOB (homo sapiens bone), Neuro-2a (mus musculus brain neuroblastoma), HCT 116 (homo sapiens colon colorectal carcin), RAW 264.7 (murine Macrophage), NIH3T3 (mouse fibroblast), Saos-2 (homo sapiens bone osteosarcoma), PBMC (peripheral blood mononuclear cell).

According to the literature, several studies reported nontoxicity and biocompatibility of some metal NPs in normal cell lines, but high toxicity in cancer cell lines. For instance, Anand et al. (95) reported notable antitumor activity of phyto-synthesized palladium NPs against A549, but no toxicity was found in human normal peripheral lymphocytes cells (95). Besides, Du et al. (96) reported plant-mediated synthesis and anti-cancer activity of AgNPs against Hela and A549 in the range of 1–5 µg/mL, but no significant cytotoxic effect was observed up to 10 µg/mL in normal HaCaT and also ≤ 2 µg/mL in Raw 264.7 (96). Similarly, Uma Suganya et al. (33) reported substantial in vitro anti-cancer activity of biosynthesized AuNPs (2–10 μg/mL) against MDA-MB-231, but no significant toxicity was found in normal HMEC in the range of 5–80 μg/mL, indicating considerable biocompatibility of NPs in normal cells (33). Also, Kummara et al. (97) showed very high cytotoxicity of green synthesized AgNPs against NCI-H460 at 240 ppm, but no cytotoxicity was found in normal HDFa (97). Furthermore, Singh et al. (98) reported not only remarkable cytotoxicity of phyto-fabricated AgNPs against A549 and HeLa above 5 μg/mL, but also no significant toxicity in normal RAW 264.7 (98). Further work showed antitumor effects of bio-fabricated AgNPs (0.02–50 µg/mL) against MCF-7; however, no cytotoxic effect was found in normal human blood mononuclear cells (99). In addition, Namvar et al. (58) reported biocompatibility of biological AuNPs in normal human blood mononuclear cells up to 100 µg/mL, but substantial cytotoxicity against cancer cell lines including CEM-ss, Jurkat, HL-60 and K562 (58). Likewise, Venkatesan et al. (76) showed biocompatibility of biosynthesized AuNPs in normal HaCaT in the range of 10–50 µg/mL (76). Furthermore, Yang et al. (87) reported no cytotoxicity of plant-mediated synthesized AuNPs (10–160 μg/mL) in normal CV-1, WI-38 (87). Although these studies depicted biocompatibility of metal NPs, some studies are not in agreement. Specifically, Majeed et al. (100) reported fungus-mediated synthesis of AgNPs by using Penicillium decumbens (MTCC-2494) and assessed significant cytotoxic effects by MTT assay in the range of 20–120 μg/mL against A-549 while 50% survival was demonstrated in the normal Vero cell line (100). In other study reported by Baharara et al. (101), as evidenced by MTT assay, biosynthesized AuNPs inhibit proliferation of HeLa cells (IC50:100 µg/mL) and normal bone marrow mesenchymal stem cells (IC50:300 µg/mL). However, cytotoxicity of AuNPs in bone marrow were lower than cancerous Hela cells (101). Likewise, Xia et al. (46) affirmed stronger cytotoxic effects of biogenic AgNPs (IC50: 27.75 µg/mL) against human cancerous hepatoma SMMC-7721 cells but showed lower cytotoxic against human normal liver (HL-7702) cells (IC50: 81.39 µg/mL) (46). Furthermore, Ma et al. (102) reported that the biosynthesized AgNPs, using a cell-free filtrate of the fungus strain Penicillium aculeatum Su1 as a reducing agent, presented higher biocompatibility toward human bronchial epithelial cells and high cytotoxicity in a dose-dependent manner with an IC50 of 48.73 μg/mL toward A549 cells. Additionally, Kasithevar (13) reported a simple and rapid synthesis of AgNPs using aqueous leaf extract of Alysicarpus monilifer mostly spherical in shape with a mean size of 15 ± 2 nm. Their study showed no cytotoxicity of AgNPs against Vero cell lines at the concentration of 200 µg/mL after 72 h of incubation. In contrast, Valli Nachiyar et al. (103) reported microbial-mediated synthesis of titanium dioxide (TiO₂) NPs. In their study, TiO₂ NPs were found to be more toxic against normal HaCaT (IC50: 55 μg/mL) than cancerous HEp2 cell lines (IC50:172 μg/mL) (103). Moreover, Lima et al. (104) reported genotoxic effects of microbial biosynthesized spherical AgNPs (Average size: 40.3 ± 3.5 nm) at concentrations of 5.0 and 10.0 μg/mL (104). In a study, natural anti-cancer flavone Chrysin (ChR), (5, 7-Dihydroxyflavone ChR), was used to synthesize AgNPs and AuNPs in a greener route without toxic additives. ChR strongly reduces Ag⁺ and Au³⁺ into their nano-forms with uniform size, shape and surface chemistry. In vitro anti-cancer results revealed that the prepared NPs exhibit enhanced cytotoxicity than ChR against treated two different breast carcinoma cell lines (MDA-MB-231 and MDA-MB-468) (105). Besides, Rajendran et al. (106) reported the highly stable flavonoid apigenin conjugated to gold nanoparticles (ap-AuNPs) are formed when apigenin reacts with Au³⁺ under appropriate conditions. The ap-AuNPs are also found to exhibit toxicity toward cancerous A431 cell lines, while being nontoxic toward normal epidermoid cells (HaCat). Additionally, Sahu et al. (107) investigated the role of pure aqueous solution of plant secondary metabolites, namely hesperidin, naringin and diosmin, in the biosynthesis of AgNPs. The secondary metabolites have the polyhydroxy group which may be responsible for their role in the reduction of metal ions into NPs. In this study, the cytotoxicity of the synthesized AgNPs was investigated on the cancerous HL-60 cell line. The result represented that AgNPs synthesized using naringin as reducing agent had higher stability and better cytotoxic activity (107). Interestingly, a fish-intestine-associated bacterial strain was a potential source of exopolysaccharide (EPS) production reported with a significant ability to reduce iron-based materials and convert them to iron oxide nanoparticles (FeONPs). EPS was extracted from a spore-forming strain of Bacillus subtilis isolated from the gut microbiome of the freshwater fish Oreochromis mossambicus. In this study, the in vitro cytotoxicity effects of free EPS and EPS-stabilized FeONPs were probed in the human epidermoid carcinoma cell line A431. The IC50 values of EPS and EPS-stabilized FeONPs were found to be 350.18 and 62.946 mg/mL, respectively (108). In a study, AgNPs were biosynthesized by an aqueous leaf extract of Erythrina suberosa (Roxb.). Following that, the cytotoxicity of AgNPs was compared with plant extract and AgNO3 against the A-431 osteosarcoma cell line. The IC50 values were determined to be around 106.15, 74.02 and 136.73 μg/mL for leaf extract, AgNPs and AgNO3, respectively, indicating excellent anti-cancer activity of AgNPs among all (109). Notably, the exact mechanism of metal NPs’ anti-cancer activity is not fully understood yet. However, it is believed that reactive oxygen species (ROS) generation, Sub-G1 arrest in cell, up-regulation of p53 protein and caspase-3 expression, inhibition of VEGF-induced activities are the major proposed anti-cancer mechanisms (21, 110). Recent advances in the proposed mechanisms for anti-cancer activity shown by colloidal biogenic AgNPs are shown in Figure 4. Importantly, the ROS leads to activation of caspase-3 which is responsible for cell apoptosis by arresting the cell cycle at the G2/M phase (111). Besides, increased oxidative stress leads to oxidation of glutathione (GSH) to glutathione disulfide (GSSG) through the oxidation process. Notably, GSH is known as an antioxidant that prevents cells from ROS damages, consequently resulting in remarkably much MNPs’ cytotoxicity and loss of GSH (24). Furthermore, AgNPs were shown to downregulate the activity of a recognized enzyme involved in DNA damage repair named DNA-dependent protein kinase (112). Coccini et al. (113) showed that the AgNP-induced oxidative stress genes involved Gpx1, SOD, FMO2 and GAPDH in different organs indicating AgNP-induced toxicity. Jeyaraj et al. (114) evaluated the caspase-mediated apoptotic cell death on treatment of biosynthesized AgNPs in the HeLa cell line. AgNPs exhibited the downregulation of Bcl-2 gene and, conversely, upregulation of the Bax gene. This regulation triggered the cascade and regulates the caspases 3, 8 and 9 which are responsible for apoptotic cell death (114). More interestingly, some studies reported neither cancerous nor normal cells showed metal NPs’ mediated cytotoxicity. Specifically, Patra et al. (55) reported phytosynthesis of AuNPs and AgNPs and assessed their lack of cytotoxic effect in the range of 0.3–2.5 µM on different cancer and normal cell lines. In another study, the in vitro cytotoxicity of microbial biosynthesized AuNPs (0.01–1000 μg/mL) on normal 3T3-L1, H9c2 and cancerous HepG2 cell lines showed the nontoxic and biocompatible nature of biosynthesized AuNPs (92).

Figure 4. Recent advances in proposed mechanisms for anticancer activity shown by colloidal biogenic silver nanoparticles (AgNPs) (Adapted with permission from Ovais et al. (21)).

The cytotoxicity of NPs may depend on parameters such as particle size, surface area and surface reactivity (115). Upon understanding the mechanism of metallic NPs’ synthesis from plants and microbes, strategies can be designed for optimum synthesis of NPs of the desired shape and size. Eventually, based on heterogeneity of bio-sources, various factors such as temperature, synthesis conditions, reaction time, substrate concentrations and pH can have significant impacts on the rate of synthesis reaction.

2.2. Biocompatible nanomaterials for cancer diagnosis

Recent nano-medical developments helped the progress of NPs for diagnostic and therapeutic (theranostics) applications. Notably, NPs can play a vital role in cancer diagnosis at an early stage by allowing visualization of cancer cells. Cancer diagnostic instruments used routinely in preclinical research and clinical practice involve MRI, CT, ultrasound, optical imaging, positron emission tomography, photo-acoustic imaging and single-photon emission CT (SPECT). In this regard, these instruments differ based on their underlying physical principles, sensitivity and specificity to contrast agents, tissue contrast, spatial resolution, quantitativeness and tissue penetration (116). Remarkably, alpha fetal protein (AFP) is a cancer biomarker in clinical diagnosis associated with the disease progression and therapeutic responses of liver cancer. Xuan et al. (117) reported a plasmonic ELISA strategy by means of alkaline phosphatase-mediated growth of AgNPs for the colorimetric detection of serum AFP. This plasmonic ELISA provided high sensitivity displaying high performance in cancer diagnosis and therapeutic monitoring. This plasmonic assay is based on the in situ generation of AgNPs, leading to rapid color with various degrees of yellow, which can be easily performed on currently available instruments in clinical laboratories. Surprisingly, cancer detection has been widely investigated by applying metal NPs for marking tumor cells to find tumor-target fluorescence bio-imaging as an excellent fluorescent probe (118). Specifically, Ge et al., (118) reported biosynthesis of fluorescent Au/Ce nanoclusters (NCs) (1.2–2.2 nm) as highly sensitive bio-imaging agents. As demonstrated in Figure 5, the Au/Ce NCs show significant fluorescence in the HeLa cancer cells (Figure 5A–C). Moreover, Figure 5D depicted the variations of fluorescence intensity between cancerous and normal cell types. Besides, the same results were obtained in HepG2 in the same situation. In contrast, the control group including L02 cells showed almost no intracellular fluorescence. Furthermore, according to the acceptable in vitro results, Au/Ce NCs were also investigated for in vivo bio-imaging in a tumor mice model of cervical carcinoma. As shown in Figure 6, fluorescence was observed around the tumor after 24 h of subcutaneous Au/Ce NCs injection (118). This is in agreement with the study of Wang et al., 2013, which demonstrated green synthesis of silver NCs employing glutathione and showed in vivo fluorescent tumor imaging through living animal tumors (119). Furthermore, Mukherjee et al. (120) reported green synthesis of monodispersed AgNPs (20–60 nm) by using Olax scandens leaf extract, with spherical shape and high stability for several days. In this study the fluorescence properties of biogenic AgNPs were observed through two cell lines (A549 & B16F10) employing a fluorescence microscopy. The untreated cells used as control and those treated with chemically fabricated AgNPs did not exhibit fluorescence, while those cancerous cells that were treated with biological synthesized AgNPs exhibited very strong fluorescence indicating the internalization of AgNPs by A549 & B16F10 cells (120). Overall, based on the aforementioned, the use of nanotechnology will be the best strategy for cancer diagnosis due to their self-fluorescence ability. One of the major drawbacks of current cancer treatment strategies is the lack of targeted drug delivery, resulting in systemic toxicity (8 , 121). Recently, magnetically targeted NPs have overcome this significant disadvantage of non-specificity as carriers for FDA-approved anti-cancer drugs. The basic principle is the loading of a particular anti-cancer drug on to a magnetic NP carrier like biocompatible super-paramagnetic iron oxide nanoparticles followed by injecting into the blood stream. Thereupon, with the application of external magnetic fields (high-gradient), the particular drug delivery system (DDS) is targeted specifically at cancerous cells via changes in physiological conditions (osmolality, enzymatic activity and temperature). Indeed, by applying this strategy the associated side-effects along with the amount of the drug delivered are reduced, ultimately leading to reduced systemic toxicity (122 , 123). Seo et al. (124). have reported a novel study of biosynthesizing AuNPs via employing heavy metal binding proteins (HMBPs) of genetically engineered Escherichia coli acting as reducing, stabilizing and capping agent. The synthesized NPs were spherical in nature having a size of 5–20 nm in diameter. Furthermore, the group loaded doxorubicin (Dox) on the AuNPs@HMBPs DDS for treating the cancerous HeLa cells. The process of AuNPs@HMBPs’ preparation along with Dox-loaded AuNPs@HMBPs’ cytotoxic evaluation are illustrated in Figure 7 (124).

Figure 5. Fluorescence images of HeLa cancer cells which were incubated in the absence of Au/Ce NCs (A), in the presence of 50 μmol/L (B) and 150 μmol/L (C) Au/Ce NCs solutions for 24 h. (D) The fluorescence intensity variations along cross-sections a (in A), b (in B) or c (in C). Fluorescence images were collected by applying fluorescence excitation wavelength at 488 nm (Adapted with permission from Ge et al. (118)).

Figure 6. Tumor nude mice models of cervical carcinoma in vivo imaging. (A) In vivo fluorescence imaging 24 h after a subcutaneous injection of 5 mmol/L Au/Ce NCs solution near the tumor. (B) In vivo fluorescence imaging 24 h after an intravenous injection of 5 mmol/L Au/Ce NCs solution through the tail. (C) Control nude mice without tumor after intravenous injection equivalent to PBS through the tail. Fluorescent Au/Ce NCs were observed inside the tumors using a 455 nm excitation wavelength (Adapted with permission from Ge et al. (118)).

Figure 7. Biosynthesis of AuNPs by employing heavy metal binding proteins (HMBPs) in recombinant E. coli and subsequent conjugation of doxorubicin. Doxorubicin-loaded AuNPs complexes can be easily fragmented to release doxorubicin from AuNPs to defuse through the cancer cell (Adapted with permission from Seo et al. (124)).

3. Hurdles for green nanomaterials as future cancer nanomedicine

A wide range of applications of metal nanoparticle therapeutics in the future is doubtless though there are still many challenges to be overcome and eventually routine clinical practice. If we talk about phytosynthesis, many amino acids, polysaccharides, flavonoids, alkaloids, vitamins, etc. exist in the metal NPs’ medium method, which play a role in NPs’ function, even if their surfaces are washed and purified since the residuals would stick to the NPs’ surface. Likewise, in microbial synthesis, there are a number of microorganisms involving saprophytes and even pathogenic microbes such as E. coli introduced as a bio-source for preparation of metal NPs which would cause some hazards according to clinical studies. As an example, Aspergillus niger, Aspergillus flavus, Fusarium solani, etc. have been employed to biosynthesize metal NPs (26, 125^{126 127 128}–129). Importantly, another limitation is the protein corona effect, which occurs via adsorption of proteins on the colloidal NPs’ surfaces when the nanoparticle enters the biological system (130). This adsorption actually compromises the ultimate dependability of NPs in the in vivo system (131). Overall, nanotechnology-based products are highly expensive probably due to difficulties in the manufacturing and preserving process; thereby its progress would cost a high amount of money. The key hurdles faced by researchers for entrance of biosynthesized NPs into the clinical phase have been graphically illustrated in Figure 8 (132^{133 135} – 134).

Figure 8. Major challenges for scientists before biosynthesized nanomaterials enter clinical trials for cancer theranostics.

By and large, many challenges and issues came in the way of scaling up nanoparticles/nanoconjugates’ production to industrial scale. NPs produced using routine top-down or bottom-up approaches in the lab vary greatly from those obtained from commercial producers. These approaches include sonication, emulsification, organic solvents evaporation and use, homogenization, centrifugation, elevated temperature, crosslinking and lyophilization (35). Practically, a slight change in the optimized conditions of NPs’ synthesis can render the NPs biologically inactive, less stable and highly impure. Hence, a robust production process should be used at the lab-scale for NPs with an extraordinary reproducibility rate to be viable for large-scale commercial production.

3.1. Diffusion and penetration

In general, diffusive resistance of various tissues (intestine, vagina, nose mucosal membranes and lungs) poses a major barrier in nanomedicine delivery. Researchers have scientifically proved that the sedimentation and diffusion velocities of NPs highly affect their penetration and cellular uptake. Specifically, it is also reported that the cellular uptake and penetration are independent of surface coating, size, density, initial dose concentration and morphology of NPs (136). In addition, Cho et al. (137) reported that the shape dependency of AuNPs for their penetration through the cells could vary depending on their surface functional group. Wang et al. (138) studied endocytosis of AuNPs with different sizes (45, 70 and 110 nm) in the human cancerous cell lines (CL1-0 and HeLa). This study revealed that the optimal size for the penetration into cells was around 45 nm. Interestingly, Chithrani et al. (139) evaluated the effect of spherical and rod-shaped AuNPs on cellular uptake in the HeLa cell line. This study depicted that spherical-shaped AuNPs had a higher cellular uptake in comparison to rod-shaped AuNPs because of variable biophysical properties such receptor diffusion kinetics. More interestingly, it was suggested that the surface coating of NPs impact on rate of uptake (140). For instance, Sur et al. (141) investigated cytotoxicity and cellular penetration of modified AgNPs with glucose, lactose, etc. in normal (L929) and cancerous (A549) cell lines. In this study, no differences were revealed in the cellular penetration of lactose- and glucose-modified AgNPs in L929, though there was a substantial growth in the cellular internalization of lactose-modified AgNPs into the A549, could be explained by the role of the chemical nature of the ligand in cellular uptake.

3.2. Toxicological and immunological aspect

Mukherjee and coworkers experimentally proved the nontoxic nature of these biogenic NPs in C57BL6/J female mice via various biochemical parameters along with a histopathology study of different organs. Even after successive injections of biogenic AuNPs (1 or 10 mg/kg/day) for seven days in healthy mice, no toxicity was observed (142). Moreover, it is interesting to note that in another study the same group reported that mice treated with chemically synthesized AuNPs showed broken alveolar walls with hyperplasic sinusoids as compared to the untreated or green synthesized AuNPs-treated mice (143). On the other hand, various chronic and acute toxicities of liver and nephrons were reported to be associated with zinc, platinum and cerium oxide NPs (144 ¹⁴⁵ –146). Hence, it is very crucial to screen the potential nanoparticles/nanomaterials for various toxicity studies including their pharmacokinetics, pharmacodynamics and responses to immune system before moving on to clinical trials (147 –¹⁴⁸ 149 ¹⁵⁰ ).

3.3. Biodegradability, metabolic kinetics and clearance

Biodegradability is very vital aspect to be considered before exploiting AuNPs in vivo. Polymeric NPs are naturally biodegradable and are cleared form the body. However, in case of metallic NPs biodegradability is slow and poses serious challenges in terms of toxicity (50 , 147, 151). Although detailed knowledge regarding the mechanism of metallic NPs’ biodegradability and clearance is still unclear, few recent studies validate the gradual excretion of metal NPs in feces and urine even up to 14 days (147 , 152). Furthermore, the studies shed light on the positively charged AuNPs, which may encounter a negative charge repulsion from the glomerular basement membrane in nephrons and pass out via urine. In another study reported by Rengan and coworkers, liposomal AuNPs were demonstrated for their biodegradability and as a potential DDS for cancer therapy. Moreover, metabolic degradation of the delivery system was noticed in liver and hepatocytes followed by its easy excretion via the renal route (147). All the studies discussed in detail that in vivo biodistribution, metabolic kinetics, clearance and ultimate dependability of NPs are determined by their shape, size and morphology.

4. Conclusions and future prospects

Green nanomaterials are currently in a highly investigative phase for the treatment and diagnosis of cancer but the ultimate dependability is yet to be decided in clinical trials. A number of new possibilities have come into account in relation to the use of green nanomaterials, owing to their biocompatibility and effectiveness. Moreover, many types of cancers that do not have cures today may be cured by these green nanomaterials in the future. Additionally, thorough understanding of key physiological barriers in vivo is the key to effectively deliver NPs into the tumor. Furthermore, the knowledge regarding the safety of nanomaterials is not sufficient and comprehensive acute and chronic toxicity in clinical studies should be observed to identify the hazards associated with the use of NPs. Considering the above discussion, it is expected that green nanomaterials could emerge as future cancer therapeutics and diagnostics agents in the near future.

Acknowledgements

We gratefully acknowledge Dr Sudip Mukherjee (Post.doc Researcher, Department of Bioengineering, Rice University, Houston, TX, USA) for his valuable suggestions and comments over the content of the manuscript.

Disclosure statement

No potential conflict of interest was reported by the authors.

Notes on contributors

Mr. Hamed Barabadi graduated as a Doctor of Pharmacy from Mazandaran University of Medical Sciences, Sari, Iran, 2014. He is currently working on his Ph.D. in Pharmaceutical Biotechnology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran. His main research interests are in nanobiotechnology with an emphasis on nanomedicine, nanobiomaterials and bioprocessing.

Mr. Muhammad Ovais is pursuing a Ph.D. degree in Nanomedicine from CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety & CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, People’s Republic of China. He has completed his MPhil-Biotechnology degree in 2017 from Quaid-i-Azam University, Pakistan and earned his BS-Biotechnology degree in 2015 with distinction from the University of Peshawar, Pakistan. His research interest lies in the development novel nano-delivery systems for cancer theranostics. He owns to his credit 19 original research and review articles in prestigious journals with a cumulative impact factor of above 50.

Prof. Dr. Zabta khan Shinwari is a Tenured Professor at Department of Biotechnology, Quaid-i-Azam University and Secretary General of Pakistan Academy of Sciences. He did his Post-doc from Japan International Research Center for Agricultural Sciences and Ph.D. from Kyoto University. His research interest lies in Medicinal plants, Molecular Systematics, Cancer Nanomedicine, and dual-use education. He is UNESCO Laureate and Avicenna Gold Medalist for Ethics in Science, 2015. Dr. Zabta owns to his credit 355 scientific publications with cumulative citations of 5842, having h-index of 37 and i10-index of 129. Moreover, he remained Vice Chancellor of many Universities in Pakistan and has won numerous national and international scientific projects. He also has to his credit highest National Civil Awarded, “Tamgha-e-Imtiaz”.

Dr. Muthupandian Saravanan graduated in Microbiology from Madurai Kamaraj University and earned his doctorate with specialization in Medical Microbiology and Nanomedicine from Sathyabama University, India. Thereafter, He did his Post Doctoral Research through Israel Government research fellowship (2011–2012) in Institute of Drug research, Faculty of Medicine, Hebrew University of Jerusalem, Israel, focusing his research on Nano-biomaterials & their Biomedical Applications. Prior to post-doc, he worked as an Assistant Professor, Department of Biotechnology, SRM University, Chennai, India. Presently, he is an Associate Professor (under UNDP) at Department of Medical Microbiology and Immunology, Institute of Bio-medical Sciences, College of Health Science, Mekelle University, Ethiopia. Dr. Saravanan owns to his credit 60 publications with cumulative citations of 1045, having h-index of 16 and i10-index of 17. He has participated in more than 40 national and international conferences and also published in more than 30 international peer-reviewed journals. He was a recipient of many fellowships and awards – notably, DST-SERC Young Scientist Award in 2012, International Fellowship “Advanced Course on Diagnostics” Sponsored by LSH&TM & Fondation Mérieux, in France 2013, International Fellowship “Pertussis: biology, epidemiology and prevention” meeting Sponsored by Fondation Mérieux & WHO in France 2014, International Union of Microbiological Societies (IUMS) travel grant in 2015 to Canada, International Fellowship “Advanced Course on Antibiotics” (AdCAb) Sponsored by Institute of Pasteur and Fondation Mérieux France, 2016. His research interest lies in Microbial Drug Resistance, Nano-biotechnology, and Nanomedicine to combat Antimicrobial resistance (AMR) and Cancer.

ORCID

Muthupandian Saravanan http://orcid.org/0000-0002-1480-3555