INTRODUCTION:

Herbal medicines have been used from years throughout the world; especially in India, herbal medicines are in high demand. The use of herbal medicines has increased because of their ability to treat different diseases with fewer side effects^1. since ancient time, herbal remedies and natural products (NPs) are being used to cure the diseases. In the ancient time, before the arrival of high throughput screening concerned to drug discovery, 90–95% drug materials were NPs. Information on the source of new drugs nearby 1981–2007 specifies that approximately half of the drugs are based on the NPs^3.Herbal medicines were not considered for development of novel formulations due to lack of scientific justification and processing difficulties.

The modern phyto-pharmaceutical research can solve the scientific needs of herbal medicines in developing novel drug delivery systems, such as nanoparticles, micro emulsion, matrix system, solid dispersion, liposomes and solid lipid nanoparticles^1.In most of the conventional dosage forms, only a limited amount of administered dose reaches the targeted site, while the majority of the drugs get distributed throughout the body depending on physicochemical and biochemical properties resulting in low therapeutic effect. The main advantage of novel drug delivery systems (NDDS) includes targeted drug delivery, which reduces dosage frequency, increases the solubility and absorption whereas decreases elimination². Nanoparticles refer to colloidal systems with particle size ranging from 10 to 1000 nm. Nanoparticles have several advantages including solubility enhancement, bioavailability enhancement, efficacy enhancement, dose reduction and improved absorption of herbal medicines compared to traditional herbal dosage forms^5.

Cancer Cell targeting:⁴

Cancer is a term used to describe a broad group of diseases in which abnormal cells have undergone unregulated growth to form a mass of tissue (tumor) and are able to invade other tissues. Cancer cells can spread to other parts of the body through the blood and lymphatic system. There are different types of cancers, identified by the name of the organ in which they start. For example, the cancers that begin in the colon, liver, and breast are called colon, liver, and breast cancers, respectively. The development of all types of cancers starts in the cells. To maintain a healthy body, different cells grow and divide in a controlled manner to produce more cells. After the damaged cells undergo apoptosis (programmed cell death) they are replaced by new ones. However, sometimes this systematic process goes wrong. Mutation (changes in genetic material) affects normal cell growth and division. When this happens, instead of dying, new cells form, although the body does not need them. These extra cells may further form a mass of tissue called a tumor. Tumors can be benign or malignant.

Benign tumors (non-cancerous):

A benign tumor is a mass of cells that lacks the ability to invade neighboring tissue or metastasize. The cells in benign tumors do not spread to other parts of the body.

Malignant tumors (cancerous):

The cells in these tumors can invade nearby tissues and spread to other parts of the body.

Singh (2004), described the liposomal formulation of digitalis glycosides like oleandrin, digoxin, and digitoxin for the protein-stabilized nanoparticle (PSL) formulation, used for treating cell proliferation and reducing toxicity, the high drug to lipid ratio, and long circulating time in the blood stream, and also, it has the ability to deliver drugs to tumor sites. They also described a method for preparation of a variety of liposomal digitalis glycoside compositions used for treating cell proliferative diseases in humans and mammals. PSL are formed by the uniform coating of protein onto liposomes to overcome the problems of drugs like toxicity, low bioavailability, and low plasma distribution. It is also used to treat cancer, acquired immunodeficiency syndrome (AIDS) and other diseases such as diabetes and cardiac disorders, in humans and mammals. This invention provides an effective method to reduce the growth of cancer or reduce the incidence of metastasis, inflammation, and arthritis in animals^4.

Desai et al., (2007, 2010, 2010) provided a method to treat proliferative diseases such as cancer by providing a combination therapy comprising of an effective amount of taxane in a nanoparticle form, with albumin as a carrier, as first therapy, and use of radiation, surgery, administration of chemotherapeutic agents or a combination as second therapy. They also described a method of administering an individual taxane in a nanoparticle form based on the metronomic dosing regimen, which includes, treatment of cancer by administering an effective amount of a nanoparticles consisting of taxane and carrier protein

albumin, or an effective amount of chemotherapeutic agent, or administering an effective amount of nanoparticle consisting of paclitaxel and carrier protein albumin or administering nanoparticles and the chemotherapeutic agent simultaneously. A combination of paclitaxel and albumin nanoparticles called Abraxane were found to be effective for various cancers such as metastatic breast cancer, prostate

cancer, malignant melanoma, carcinoma of the cervix, ovarian cancer, and so on^4.

ursolic acid nanoparticles showed inhibitory role in cervical cancer progression, while no toxicity was observed to cells 293T and L02, suggesting that ursolic acid nanoparticles indeed inhibit cervical cancer development, which could be a potential therapeutic strategy for patients in future. Furthermore, the colony formation assay indicated that ursolic acid nanoparticles suppressed cervical cancer cell proliferation significantly. In addition, the migration and invasion analysis also suggested that ursolic acid nanoparticles showed inhibitory role in cervical cancer cell lines. ursolic acid nanoparticles targeted caspases and p53 with downregulation of Bcl-2 and cIAP, inducing apoptosis and leading to cervical cancer cell death. Thus, ursolic acid nanoparticles can be used as a class of antitumor drug development and treatment of cervical cancer for its potential value^42.

Sambandam et al., (2007) described the preparation of oligosaccharide bionanoparticles from the Moringa oleifera Lam gum, with a particle size between 60 nm and 100 nm.They protected plasmid DNA and RNA from degradation, along with inhibition of the growth of onion roots and induced membrane blebbing (the cavity containing gas) leading to apoptosis and death of human epidermoid carcinoma HEp2 cells^4.

Liang et al., (2009) disclosed the making of nano-micellar vinca alkaloids (vincristine and vinblastine), which are a class of effective broad spectrum anti-tumor agents entrapped in polyethylene glycolylated phospholipids, for intravenous injection. The composition contains vinca alkaloid phosphatides derivatized with polyethylene glycol (PEG), with a pharmaceutical adjuvant. The PEG molecules provide a hydrophilic protective layer for the hydrophobic core of the encapsulated medicament. This hydrophilic protective layer gives protection for medicament against enzymes and other protein molecules in the blood and they are not recognized and phagocytozed by the reticuloendothelial system in the body, hence, their circulation time in vivo is prolonged. On account of its good stability, the nano-micellar preparation improves drug distribution in the tumor tissue, increases effectiveness, and decreases toxicity. It is an effective broad spectrum anti-tumor agent used in the clinical treatment of various cancers, such as, leukemia, lymphoma, breast cancer, lung cancer, liver cancer, and many other tumors^4.

Liu et al., (2013), invented a herbal composition comprising of a therapeutically effective amount of Scutellaria baicalensis, Glycyrrhiza uralensis, Ziziphus jujuba, and Paeonia lactiflora with a chemotherapeutic compound used to treat cancer in mammals. It is useful to increase the therapeutic index of chemotherapeutic compounds, by administering the herbal composition PHY906 to mammals undergoing chemotherapy, in a nanoparticle formulation, by the oral or intravenous route, to improve the treatment of disease^4.

Withania somnifera extract/Gadolinium III oxide nanocomposite: the anticancer and radio-sensitizing efficacy of a Withania somnifera extract/Gadolinium III oxide nanocomposite (WSGNC) in mice. WSGNC was injected to solid Ehrlich carcinoma-bearing mice via i.p. (227 mg/kg body weight) 3 times/week during 3 weeks. Irradiation was performed by whole body fractionated exposure to 6Gy, applied in 3 doses of 2 Gy/week over 3 weeks. Biochemical analyses as well as DNA fragmentation were performed. Treatment of solid Ehrlich carcinoma bearing mice with WSGNC combined with γ-radiation led to a significant decrease in the tumor size and weight associated with a significant decrease in mitochondrial enzyme activities, GSH content and SOD activity as well as a significant increase in caspase-3 activity, MDA concentration and DNA fragmentation in cancer tissues. Combined treatment of WSGNC and low dose of γ-radiation showed great amelioration in lipid peroxidation and antioxidant status (GSH content and SOD activity) in liver tissues in animals bearing tumors. It is concluded that WSGNC can be considered as a radio-sensitizer and anticancer modulator, suggesting a possible role in reducing the radiation exposure dose during radiotherapy^6.

Curcuma longa:

Curcumin, one of the most studied chemopreventive agents, is a natural compound extracted from Curcuma longa L. Extensive research over the last half century has revealed that curcumin can inhibit the proliferation of various tumor cells in culture, prevent carcinogen induced cancers in rodents and inhibit the growth of human tumors in xenotransplant or orthotransplant animal models. Several phase I and phase II clinical trials indicated that curcumin is quite safe and may exhibit therapeutic efficacy. The utility of curcumin is limited by its lack of water solubility and relatively low in vivo bioavailability. Multiple approaches including nanoparticles, liposomes, micelles and phospholipid complexes are being sought to overcome these limitations. This review describes the general properties of curcumin and its potential effect against cancer including evidences of its antitumor action in vitro, in vivo, clinically and the strategies to overcome its low bioavailability^7.

Azadirachta indica:

Nanoparticles functionalized with anticancer phytochemicals, molecular and genetic analysis would help to treat cancer more preciously. Hao et al. have reported neem components as potential agents for cancer prevention and treatment. Preliminary experiments with neem synthesized silver nanoparticles (Ag-Np) were performed against gastric cancer cells AGS in vitro to study the toxicity and efficiency. Silver nanoparticles functionalized with anticancer neem phytochemicals would help to treat cancer more preciously in addition to the bactericidal effect, their unique physical, chemical properties, and ease of synthesis and surface modification, biodistribution and biosafety. Ag Nps hold the most promise for achieving optimal targeting all cancers including brain cancer as they can bypass the BBB and improve the distribution within a brain. Multifunctional therapeutics where a nanoparticle serves as a platform to T. A. Sironmani 103 facilitate its specific targeting to cancer cells and delivery of a potent treatment, minimizing the risk to normal tissues over coming all problems of cancer therapy^8.

Syzygium aromaticum:

Both nanoparticles and cloves (Syzygium aromaticum) possess anticancer properties, but they do not elicit a signifcant response on cancer cells when treated alone. In the present study, we have tested fuorescent magnetic submicronic polymer nanoparticles (FMSP-nanoparticles) in combination with crude clove extracts on human breast cancer cells (MCF-7) to examine whether the combination approach enhance the cancer cell death. Te MCF-7 cells were treated with diferent concentrations (1.25g/mL, 12.5µg/mL, 50µg/mL, 75 µg/mL, and 100µg/mL) of FMSP-nanoparticles alone and in combination with 50 µg/mL crude clove extracts. Te efects of FMSP-nanoparticles alone and combined with clove extracts were observed afer 24hrs and 48hrs intervals. Te response of FMSP-nanoparticles-treated cells was evaluated by Trypan Blue, 4 ,6-diamidino-2-phenylindole (DAPI), and 3- (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays, respectively. We have demonstrated that cancer cell viability was decreased to 55.40% when treated with FMSP-nanoparticles alone, whereas when cancer cells were treated with FMSP-nanoparticles along with crude clove extracts, the cell viability was drastically decreased to 8.50%. Both morphological and quantitative data suggest that the combination of FMSP-nanoparticles plus crude clove extracts are more efective in treating cancer cells and we suggest that the combination treatment of nanoparticles along with clove extracts hold a great promise for the cancer treatments^9.

Origanum vulgare:

In vitro, the antiproliferative effect of essential oil [EO] of Origanum vulgare against human breast adenocarcinoma [MCF-7], and human colon adenocarcinoma [HT-29] was evaluated. The results show that the EO is composed mostly of 4-terpineol and induces a high cytotoxicity effect in HT-29. In the MCF-7 cell line, the EO was less effective. This study showed that O. vulgare main component is 4-terpineol and was effective in inducing cancer cell growth inhibition^[10]. In a human study, anti- lung cancer effect of aqueous extract of Origanum vulgare was investigated and it showed that the biosynthesized nanoparticles were found to be impressive in inhibiting human pathogens in a dose -dependent manner^[11]. Antiproliferative activity of some spices were investigated to assess their anticarcinoma activity against breast cell line. The major constituent of O vulgare was trans-sabinene hydrate [27.19%]. None of the hydro distilled essential oils of the tested plant species or their aqueous extracts demonstrated cytotoxic activity^[12]. The effect of Origanum vulgare ethanolic extracts on redox balance, cell proliferation, and cell death in colon adenocarcinoma Caco2 cells was investigated. Oregano extract leads to growth arrest and cell death in a dose- and time-dependent manner. Findings suggest that oregano can exert proapoptotic effects. Besides, whole extract can be responsible for the observed cytotoxic effects^13.

Polygala senega: Ethanolic extract of Polygala senega (EEPS) had little or no cytotoxic effects on normal lung cells, but caused cell death and apoptosis to lung cancer cell line A549. In the present paper, ethanolic root extract of P. senega (EEPS) was nanoencapsulated (size: 147.7 nm) by deploying a biodegradable poly-(lactic-co-glycolic) acid (PLGA). The small size of the NEEPS resulted in an enhanced cellular entry and greater bioavailability. The growth of cancer cells was inhibited better by NEEPS than EEPS. Both EEPS and NEEPS induced apoptosis of A549 cells, which was associated with decreased expression of survivin, PCNA mRNA, and increased expression of caspase-3, p53 mRNAs of A549 cells. The results show that the anticancer potential of the formulation of EEPS-loaded PLGA nanoparticles was more effective than EEPS per se, probably due to more aqueous dispersion after nanoencapsulation. Therefore, nanoencapsulated ethanolic root extract of P. senega may serve as a potential chemopreventive agent against lung cancer^14.

Panax ginseng:

The pharmaceutical role of silver nanoparticles has been increased over the last decades, especially those synthesized through herbal medicinal plants, due to their variety of pharmacological importance. Panax ginseng Meyer (P. ginseng) has been widely used as a therapeutic herbal medicine for a long time in cancer treatment. In this study, the cytotoxic and oxidative effect of a novel silver nanoparticles synthesized from P. ginseng fresh leaves (P.g AgNPs) were evaluated in different human cancer cell lines. In addition, the effect of P.g AgNPs on cell migration, apoptosis and the determination of the mechanism involve was determinate by the use of A549 lung cancer cell line. It was found that P.g AgNPs treatment inhibited cell viability and induced oxidative stress in A549, MCF7 and HepG2 cancer cell lines. Likewise, P.g AgNPs treatment inhibited the epidermal growth factor (EGF)-enhanced migration, as well as decreased the mRNA levels and phosphorylation of EGF receptors in A549 cells. Moreover, P.g AgNPs modified the morphology of the cell nucleus and increase apoptosis percentage; this effect was linked to the stimulation of p38 MAPK/p53 pathway. Taken together, our results showed that P.g AgNPs exhibited anticancer activity in A549 and the regulation of EGFR/p38 MAPK/p53 pathway might be the possible mechanism of its anti-activity. Further experiments are suggested to determinate the mechanism by which P.g AgNPs induce cytotoxicity and ROS generation in MCF-7 and HepG2 cells^15.

Resveratrol:

Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a naturally occurring phenol that can act as a phytoalexin, used by several plants to help fight and then repair attacks by external photogens like bacteria and fungi. Resveratrol is also a well-known antioxidant. Resveratrol can work through many of the intracellular signaling pathways, including cell survival and apoptosis modulator tumor angiogenesis and metastatic switches¹⁶. Thus, it has tremendous potential to be used as an anticancer drug. The anticancer activity of resveratrol was first demonstrated by Jang etal. in 1996¹⁷ for the prevention of skin cancer development in mice. Since then there has been tremendous effort to use resveratrol as an anticancer agent in various cancer models, including skin cancer^18-20, breast cancer^21-23, fibrosarcoma^24,25, lung cancer^26,27, gastric and colorectal cancer²⁸, prostate cancer^29,30,hepatoma^31-32, neuroblastoma^[33], pancreatic cancer^34,35, and leukemia^36-37. However, most of these studies’ results have failed to be replicated in humans, mainly due to resveratrol’s very short half-life. It is rapidly glucoronated and sulfonated, and is a lipophilic agent, and thus it has failed when tested in the clinic. Nanotechnology-based approaches are currently being tried to enhance the bioavailability of resveratrol; significant progress has been made. The first nanoformulation of resveratrol was performed with chitosan nanoparticles. That study suggested that chitosan nanoformulations have a sustained release in vitro. The rate of release was slowed down with the increase of solidification agents^38.In another study, resveratrol-loaded nanoparticles at lower concentration led to significantly higher cell death as compared to an equivalent dose of free resveratrol, and this difference of cytotoxicity was not found to be abrogated by the inclusion of Vitamin E.³⁹Another study’s results suggested that 12 hour pre-incubation of resveratrol-loaded nanoparticles protects cells from beta-amyloid peptide (Abeta)-induced damage in a dose-dependent manner by attenuating intracellular oxidative stress and caspase-3 activity^40.Shao et al.^[39] showed the feasibility of incorporating resveratrol in mPEG-poly(epsiloncaprolactone)-based nanoparticles with high entrapment efficiency. They found that even a low concentration of encapsulated resveratrol can lead to significantly higher cell death compared to an equivalent dose of free resveratrol. It was speculated that the differential cytotoxicity between resveratrol and resvertrol-loaded nanoparticles may be mediated by the discrepancy of intracellular reactive oxygen species (ROS) levels. The results suggest that resveratrol-loaded nanoparticles could be a potentially useful chemotherapeutic formulation for malignant glioma therapy, and may have clinical relevance in the near future^40.

Nepeta deflersiana:

Silver nanoparticles (AgNPs) were synthesized using aqueous extract of Nepeta deflersiana plant. -e prepared AgNPs (ND-AgNPs) were examined by ultraviolet-visible spectroscopy, Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD), transmission electron microscopy (TEM), scanning electron microscope (SEM), and energy dispersive spectroscopy (EDX). -e results obtained from various characterizations revealed that average size of synthesized AgNPs was 33 nm and in face-centered-cubic structure. -e anticancer potential of ND-AgNPs was investigated against human cervical cancer cells (HeLa). -e cytotoxic response was assessed by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT), neutral red uptake (NRU) assays, and morphological changes. Further, the influence of cytotoxic concentrations of NDAgNPs on oxidative stress markers, reactive oxygen species (ROS) generation, mitochondrial membrane potential (MMP), cell cycle arrest and apoptosis/necrosis was studied. -e cytotoxic response observed was in a concentration-dependent manner. Furthermore, the results also showed a significant increase in ROS and lipid peroxidation (LPO), along with a decrease in MMP and glutathione (GSH) levels. -e cell cycle analysis and apoptosis/necrosis assay data exhibited ND-AgNPs-induced SubG1 arrest and apoptotic/necrotic cell death. -e biosynthesized AgNPs-induced cell death in HeLA cells suggested the anticancer potential of ND-AgNPs^41.

CONCLUSION:

Herbal drugs have been recently getting more attention because of their potential to treat almost all diseases. However, several problems such as poor solubility, poor bioavailability, low oral absorption, instability and unpredictable toxicity of herbal medicines limit their use. In order to overcome such problems, nanoparticles can play a vital role.

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41. Ebtesam S. Al-Sheddi,1 Nida N. Farshori , 1 Mai M. Al-Oqail,1 Shaza M. Al-Massarani , 1 Quaiser Saquib,2,3 Rizwan Wahab,2,3 Javed Musarrat,2,3 Abdulaziz A. Al-Khedhairy,2 and Maqsood A. Siddiqui2,3. Anticancer Potential of Green Synthesized Silver Nanoparticles Using Extract of Nepeta deflersiana against Human Cervical Cancer Cells (HeLA), Hindawi Bioinorganic Chemistry and Applications Volume 2018, Article ID 9390784, 12 pages https://doi.org/10.1155/2018/9390784.

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Received on 23.08.2019 Modified on 30.09.2019

Res. J. Pharma. Dosage Forms and Tech.2019; 11(4):247-252.

DOI: 10.5958/0975-4377.2019.00041.7