Metal Nano Delivery Systems For Improved Efficacy of Herbal Drugs

1Department of Molecular Biology and Genetic Engineering, College of Basic Sciences and Humanities, GB Pant University of Agriculture and Technology, Pantnagar 263145, Uttarakhand, India. 2Department of Chemistry, Bareilly College, MJP Rohilkhand University, Bareilly, Uttar Pradesh, India. 3Department of Veterinary Physiology and Biochemistry, College of Veterinary and Animal Sciences, GB Pant University of Agriculture and Technology, Pantnagar 263145, Uttarakhand, India.

From past two decades, nanotechnology is exploited for efficacious drug delivery and tissue-specific targeting of drug (Kumar et al., 2015).Improved drug delivery techniques help in minimizing toxic effects and achieving enhanced effectiveness which is beneficial for the patients.In recent past, there has been a renewed public interest in natural remedies both in developing and developed countries.As per World Health Organization (WHO) "herbal medicines as finished, labeled medicinal products that contain active ingredients, aerial or underground parts of the plant or other plant material or combinations".According to WHO reports, 80% of the populations from developing countries exploit herbal medicines for their primary health care needs (Yadav et al., 2014).Herbal 'renaissance' is happening all over the world due to rising concern over the safety of modern allopathic medicines.Even the genesis of modern medicine is from traditional therapeutic systems (Patwardhan et al., 2004).Plants and natural products have been used since long for curative/ healing purposes in different cultures like China, Egypt, Africa, America and India.Herbal medicine, also known as "herbalism" or "botanical medicine" is a medical system based on the use of plants or plant extracts that may be taken orally or applied to the skin (Griggs, 1982).In spite of criticisms regarding certain features of herbal medicine, many pharmacologists today, recognize the potential scientific rationale of biological effects produced by these phytomedicines (Sharma et al., 2011).
Though herbal medicines are considered as dependable and affordable therapeutics, however, some problems are associated with them viz.rapid release of the herbal drug, unknown toxicity, low solubility, poor bioavailability and oral absorption, etc. (Thillaivanan & Samraj, 2014).Besides the general notion that "the herbal drugs are safe", many pharmaco-vigilance studies have suggested that these natural drugs have frequently unknown active ingredients and thus their standardization and quality control are not an easy task (Ekor, 2013;Mathur, 2016).Delivery of herbal medicines also requires an improved delivery system for their sustained release and targeted delivery for enhanced patient compliance (Goyal et al., 2011).NDS is a new concept of drug delivery that helpsto overcome the limitation of traditional drug delivery systems.NDS, when employed for herbal medicine, may be helpful in enhancing the efficacy and lowering their side effects (Ansari et al., 2012).In novel phytoformulations, various nano-delivery vehicles, viz., liposomes, polymeric nanoparticles, nanoemulsion, nanospheres, solid lipid nanoparticles (SLNs), are used in which phytoconstituents can be incorporated and these nanosized herbal formulations not only help in sustained release of the drug but can also eliminate the inadequacies of conventional herbal formulations (Elmowafy et al., 2013;Priprem et al., 2015).Present communication explicates upon various metal nano delivery systems that could be used for herbal formulations and thus could be helpful in improving therapeutic efficacy of phytomedicines.

Herbal drugs
Herbal drugs based curative system is one of the oldestforms of health care system.Plant based formulations may proveexceedingly important for the healthcare of a person (Mathur, 2016).A vast increase in global human population, inadequateaccessibility of expensive allopathic drugs coupledwith unwanted side effects and problems like multidrug resistance indangerous pathogens have led way to the development of alternative plant-based natural medicines for a broad range of diseases (Greenwell& Rahman, 2015).Phytomedicine or phytopharmaceutical, is a complex mixture derived from plant sources that is used as a medicine or drug.Approximately 50% of the functional drugs are prepared from natural resources (Kingston, 2011).

Advantages and Disadvantages of Herbal drugs
Herbal formulations are prepared from natural ingredients and are available at affordable cost.Herbal drugs are time tested, recognized for their therapeuticpotential with little or no side effects as compared to allopathicmedicines (Mahima et al., 2012).Herbal drugs can be exploited for treating differentpathological conditions.The therapeutic potential of herbal drugs are due to the presence of various secondary metabolites like phenolics, terpenoids (sapogenin), alkaloids, steroids etc., in them (Mathur, 2016).
Most of the traditional herbal preparations are crude formulations with low solubility because of the presence of hydrophobic phytochemicals.Major constraint that limits the use of herbal drugs is their low efficacy because of theirpoor solubility, bioavailability and oral administration (Jantarat, 2013; Figure 1).Traditional herbal preparations are not favored for development of newdrug formulations due to lack of chemical characterization, standardization, validationand scientific rationalization of their medicinal potential (Ekor, 2013;Thillaivanan & Samraj, 2014).Mostly, traditional herbal preparations are given through oral route and thus a low quantity of drug reaches to the site resulting in low therapeutic value as large amount of these drugs get wasted due to their distribution throughout the body depending on physicochemical and biochemical properties.Many herbal constituents may get degraded in the stomach due to the acidic environment while some others may be metabolized by liver and thusinsufficient amount of the phyto-compounds reach the blood (Yadav et al., 2011;Ansari et al., 2012).Either poor or no therapeutic impactmay be observed if insufficient quantity of the drug is administered instead of the optimal quantity/ dose (minimum effective dose level).Some phytochemicals have low solubility and bioavailability and thus exhibit narrow therapeutic index.Researchers are constantly trying to enhance the therapeutic efficacy andbetter patient compliance byspecific targeting ofthe drug and its controlled release (Park, 2014).
Due to variouslimitationsof herbal drugsand low efficacy of the treatment of relentless diseases, multidisciplinary strategies are put forwardfor targeted delivery to improve their pharmacokinetics, pharmacodynamics, biorecognition and efficacy.Suchinnovative delivery methods require interdisciplinary inputs of polymer chemistry, pharmacology, nanotechnology, bioconjugate chemistry, etc (Charman et al., 1999).

Nano Delivery Systems for herbal drugs
Mostly "Novel Drug Delivery Systems" (NDDS) are employedin case of allopathic medicinesespecially for cancer theranostics.However, NDDS can be effectively used for herbal drugsas well which are fast becoming an important form of alternative or complementary therapy.Salient aspects of herbal therapythat need attention and improvement are-enhanced component solubility, better bioavailability, enhanced absorbency, reduction in doses and overall better compliance (Ansari et al., 2012; Figure 2).Suitable routes of drug delivery are employed to cross physical barriers, viz.bloodbrain barrier (BBB) (Kumar et al., 2015).
Process of administering pharmaceutical molecules by an appropriate route in the patient can affect the therapeutic efficacy of the drug as well.Some of the common routes of drug delivery are per-oral (through the mouth), topical (skin), transmucosal (nasal, buccal, sublingual, vaginal, ocular and rectal) and inhalation routes.Nano delivery systems (NDS) includes differentapproaches for the delivery of pharmaceuticals in the body which may either require its specific targeting or it might require systemic pharmacokineticsto get desired therapeutic efficacy of the drug.NDS are advance delivery approaches to enhance drug effectiveness by targeting the drug to the desired site, by controlling drug release to provide sustained curative effect and offer better safety (Nagavarma et al., 2012).NDS includes carrier based drug delivery system (liposomes, niosomes, microspheres, resealed erythrocytes as drug carriers), trans-dermal Delivery Systems (sonophoresis), mucoadhesive delivery systems, supramolecular delivery systems and variable release delivery systems (osmotic pump, nanoencapsulation), etc (Figure 3).Development of NDS for herbal formulations is a tricky task because of the presence of chemically diverse phytoconstituents in herbal formulations (Nagavarma et al., 2012).
To enhance selectivity, solubility, safetyand effectiveness of herbal drugsNDS can be used.Nanosized herbal drug has enhanced surface area and thushasfaster distribution in the blood and reduced toxicity with better therapeutic efficacy.Improved permeation and retention of nanoparticles (NPs) can also help to cross BBB (Kumar et  Many studies have shown that during the processing of ayurvedic metal based formulations, size of the metal particles come down to nanometer range (Pavani et al., 2013).Gold is used as Swarna Bhasma (gold ash) in different conventional Indian ayurvedic preparations and has been characterized to possess 56-57 nm size and spherical shape.Mercury-based ayurvedic preparations have crystalline mercuric sulfide of 25-50 nm size range (Pal et al., 2014).Pavani et al. (2013) reported a modified method of 'bhasmikaran' (method of preparing bhasmas) for preparation of iron oxide nanoparticles which was based on green synthesis.X-ray diffraction and transmission electron microscopy (TEM) analyses demonstrated that during ayurvedic 'bhasmikaran' method MNPs are formed.MNPs along with different phytochemicalsshow enhanced absorption and even tissue-specific targeting of therapeutic ingredients inside the body.Because of their small size, these preparations are said to be more effective.More over these naturally synthesized MNPs do not cause toxicity in the body (Paul and Chugh, 2011).Mukundan et al. (2015) reported green synthesis of silver nanoparticles using leaves extract of Bauhinia tomentosa Linn and explored its in vitro anticancer potential.
Green  (Makarov et al., 2014).However, there isneed to address certain problems associated with MNPs and ensure their biosafety before proposing their biomedical usage and their commercialization.Though many reports are available underlining usage of MNPs for different theranostic and biomedical applications, however, their potential side effects in the patients and environment are yet to be thoroughly explored (Krug & Wick, 2011).Contradictory biosafety considerations are reported pertaining to MNPs in different studies (Tsoi et al., 2012;Edmundson et al., 2014;Ambwani et al., 2015).

Nanoshells
Nanoshells are also known as coreshells which are few nanometers (1-20 nm) in size.Nanoshells have sphere-shaped cores (concentric particles) prepared of a particular compound which is surrounded by an outer coating or shell made up of a different compound (Kalele et al., 2006).By changing core-to-shell ratio or constituent compounds of nanoshells,the properties of these core shells can be changed.Semiconductor materials, insulators or metalsmay be used for the preparation of core shells.Dielectric compoundslike silica and polystyrene with high stability are typically employed for the preparation of cores (Ansari et al., 2012;Sachan & Gupta, 2015).A noveltype of sphere shaped composite metal nanoshells has been prepared in which dielectric material is used for core preparationthat is surrounded by a thin metallic shell usually made up of gold.Nanoshells have numeroususages in the biomedical area especially in drug delivery and in vivo imaging-based diagnostic strategiesas they possess unique optical and chemical attributes.Nanoshells can absorb heat and when it is illuminated by suitable wavelength thenit can transmit the heat to the local environment that leads to discharge of the cargo compound by breaking down the core-shell assembly (Kalele et al., 2006).IN core shell delivery systems, drug molecules can either be encapsulated by the shell or can be adsorbed on the surface of the shell with the help of specific functional group or could be stabilized by electrostatic bonding in the nanoshell based drug delivery systems.Upon coming in contact with the biological systems, these drugloaded nanoshells release the drug.Monoclonal antibodies specific for a diseased tissues or tumors can be attached on the surface of nanoshells in case of targeted drug delivery and in vivo diagnostic (imaging) approaches which make these core shells to be efficacious for cancer theranostics (Mamillapalli et al., 2016;Singhana et al., 2014).
G o l d n a n o s h e l l s ( A u N S s ) a r e widelyinvestigated as targeted nanovehicles for drugcarriers that could be exploited for theranostic purposes.These have potential applicability in the field of oncology including photothermal ablation, hyperthermia, drug delivery and diagnostic imaging.AuNSs are of paramount importance because of their biocompatibility, nontoxicity, surface plasmon resonance, insignificant immunogenicity and surface functionalization.AuNSs may be used for accurate and targeted drug delivery in the specific cells along with radiotherapy.Singhana et al. (2014) explored NIR activated AuNSs based drug delivery systems and cancer theranostics.

Quantum Dots (QDs)
Quantum dots are tiny microscopic metal or semiconductor particles that hold a certain number of electrons and, upon light excitation can emit light in all the colors of a rainbow depending on their size.QDs whentagged with specific molecules are capable of identifying the specific tissues.Various surface modifications can prevent aggregate formation, reduction in nonspecific attachment and facilitate tissue specific targeting in case of in vivo imaging approaches.Functionalization of QDs can be done by modifying protecting ligands (Mulder et al., 2009) and addition of targeting groups viz.lipoproteins and peptides.Near-IR QDs tagged with a monoclonal antibody against tumour cells are common QDs used for targeted delivery.Development in this area is being appraised by many researchers (Papagiannaros et al., 2010).For various bioapplications,surface functionalization of QDs can be carried out (Juzenas et al., 2008)  Covalent or non-covalent binding of specific molecules like antibodies, peptides, and aptamers onto QDs, could be used for targeted delivery of hydrophilic therapeutic molecules like small interfering RNA (siRNA) and antisense oligodeoxynucleotide (ODN).These nanocomposites are like 'magic bullets', which can bind to specific cells/ tissues and cure it by releasing therapeutics on the site.QD based nano vehicles can be tracked in real-time due toemission of signals which make them suitable for in vivo imaging, localization of metastasis and cancer diagnostics (Belletti et al., 2017;Ambwani et al., 2015).Belletti et al. (2017) reported that the single-emulsion process for curcumin loading into NPs with encapsulation efficiency about 35%.Nanonization of phytopharmaceuticals displayed increased surface area to volume ratio, improved stability, solubility and bioavailability, reticuloendothelial system (RES) uptake, better penetrability and retention, site-specific targeting, controlled release, etc (Goyal et al., 2011;Naghsh, 2015).

Biosafety of Nanosized herbal formulations
Even though nano-delivery based herbal preparations have shown their potential applicability by overcoming the inadequacies of conventional herbal formulations, however, their safety concerns should not be ignored (Ambwani et al., 2015).For exploitation of nanotechnology in the area of biomedicine it is essential to ensure their biocompatibility and safety as well as to rule outany probability of undesired toxic effects of nanoformulations to human/ environment.In case of herbal remedies, nano-delivery approaches can be fruitful in enhancing the therapeutic ratio or index by increasing the gap between minimal dose required to exhibit the curative effects and minimum toxic level dose that display unwanted side effects.In spite of the potential benefits, there is a need for intensive toxicological examination of different nano-herbal formulations.The alteration in the physico-chemical, optical, structural attributes of engineered nanomaterials may lead to numerous unpredicted interactions with different biological components which can lead to toxic side effects (Chan et al., 2010) Presently there are no guidelines, regulations or standard procedures in place for methodical toxicological analysis of NPs.The imprecise and ambiguous conclusions associated to NPs toxicity shed disbelief on the potential of nanomedicine and cause pointless apprehensions in the public mindset (Yildirimeret al., 2011).However, suitable nano-herbal formulations can be prepared after thorough analysis of various interactions between engineered NPs and target cells, resultant toxicity itsscientific rationale.

Conclusion and future perspectives
Treatment of any disease is based either on development of better drugs or by enhancing efficacy of existing drugs.For better safety and efficacy of existing formulations, different nanobased drug delivery approaches have attracted the attention of the researchers.Approaches for drug delivery have undergone many changes involving engineered materials with novel physical or chemical effects.The conventional drug delivery methods have several constraints in development of efficacious herbal drugs because oral or parenteral herbal formulations are reported to be inefficient due to several drawbacks involved.Thus it could be concluded that usage of NDS could be of paramount importance in designing herbal formulations.MNPs based herbal drug delivery systems have displayedtremendous potential for various diseases and disorders especially for cancer theranostics.MNPs based herbal formulations have shownenhanced uptake, bioavailability and accurate delivery.
Globally, herbal and natural products are gaining pace.Thus amalgamation of "herboceuticals" with nanotechnology would improve their therapeutic potential for treatment of various chronic diseases.Nanosized herbal drugs are studied in different biomedical research institutions.The significantattributeneeded in herbal drugs are their site-directed sustained delivery with enhanced curative potential, patient compliance and without unwanted toxic side effects and hypersensitive reactions, etc.Hence, NDS based herbal formulations will boost their ability to treat different chronic health conditions and impart tremendous fitness benefits.This type of multidisciplinary research including traditional herbal therapeutics together with novel modern drug delivery systems has given way to the development of attractive nanosized herbal drugs as future phytopharmaceuticals that would prove to be of paramount value for enhancing the health of people.

Gomes et al., 2014).
(Galib et al., 2011;Pal et al., 2014)yurveda" is anancient Indian health care system that is based on plants and herbomineral preparations.Biologically prepared metal nanoparticles known as "Bhasma" are used for the treatment of various diseases/ disorders in Ayurveda(Galib et al., 2011;Pal et al., 2014).Nano-forms of certain metals are commonly used in Ayurveda: gold (Au), silver (Ag), copper (Cu), iron (Fe), lead (Pb), tin (Sn) and zinc (Zn) (Sarkaret al., 2010).For development of such formulations, biocompatibility and therapeutic efficacy of phytochemicals found in the plants play central role in choosing various herbs.Herbo-mineral formulations may exhibit enhanced therapeutic properties because of their physiological compatibility, insignificant toxicity and natural origin.Tremendous applications of such nanomaterials based herbal preparations in the field of biomedicine have led to an innovative concept of 'Herbo-nanoceuticals' ( (Iravani, 2011;Shah et al., 2015)d out through many natural compounds viz.vitamins, carbohydrates (sugars), phytochemicals present in plant extracts, microbes, biodegradable polymers etc. Plant extracts are used for the commercial preparation of MNPs because of the presence of phytocompoundshaving strong reducing potential(Iravani, 2011;Shah et al., 2015).Polyphenols with their hydroxyl side chains are the main phytocompounds present in the plant extracts that possess the ability to act as reducing agent.
. At present, still there is a lack of methodical toxicological profiling of nanomaterials and nanomedicines, with insufficient and sometimes contradictorysafety and toxicity data available.Voigt et al. (2014) reported Polybutylcyanoacrylate NPs (PNPs) to be non-toxic and thus could be useful in the field of nanomedicine.However, Sadat et al. (2016) gave a concise summary of the alterations in various attributes of PNPs due to a different size and surface charge and what problems could arise during in vivo experimentations.Some studies have been conducted to exhibit either in vitro or in vivo toxic effects of various NPs (Wang et al., 2013; Ambwani et al., 2016, Datta et al., 2018; Ambwani et al., 2018).Several contradictoryin vivo/ in vitro reports are available regarding nanomaterials toxicity.Metal oxides are reported to exhibit enhanced oxidative stress (Bonner, 2007).Foremost reason of formation of reactive oxygen species (ROS) due to NPs exposure is presence of pro-oxidant functional groups on the surface of NPs, active redox reactions happening on the surface of NPs especially in case of MNPs and different interactions between cells and MNPs.Entry of NPs inside the cells can activate various immune cells like macrophages and neutrophils that are potent phagocytes and generate ROS/reactive nitrogen species (RNS) once activated (Ambwani et al., 2015, Datta et al., 2018; Ambwani et al., 2018).NPs toxicity could be due totheir dose and route of exposure as well as differentphysic-chemical attributes of NPs.Another important feature in toxicity profiling of NPs is gettingconflicting results duringin vitro and in vivo toxicity analysis of same NP.