Phytomedicines have been serving as a crucial source of drugs sinceancient times, their usage has been increased due to their therapeutic activity and less side effects rather than the other medicines. Both developing and developed countries are focusing on the popularity of herbal drugs mainly due to their natural origin and low side effects. Fast-growing nanotechnologies have provided strong support for developing innovative novel herbal drugs. Nutraceuticals are foods and food constituents that provide health benefits beyond basic nutrition, but many nutraceuticals show poor bioavailability. Applications of nanotechnology have granted to overcome the challenges and technical barriers related to the solubility, bioavailability, stability and delivery of bioactives from foods. The rapid growth of nutraceutical nanotechnology carries great promise to provide new and effective functional foods as a tool for preventing and possible even bringing a cure to some non-communicable diseases. Numerous studies are already reported in different types of preparative methods of nanomaterials in the field of nanotechnology for herbal drug delivery and nutraceuticals (Figure 1) [1-5]. The current review focuses on the introduction of nanotechnology in herbal drugs and nutraceuticals for nanomedicine and functional foods. It is also highlights important and rapid developments in biomedical and food technology.

Figure 1: Schematic representation of various methods of preparation of nanotechnology in herbal drugs and nutraceuticals.

Nanotechnology in herbal drugs

Nanotechnology can be used to enhance delivery of poorly water soluble herbal drugs, targeted delivery in a cell or tissue, also a cross tight epithelial and endothelial barriers, release of large herbal molecules, co-delivery to two or more drugs and observation of sites of drug delivery by incorporating herbal drugs with imaging modalities [6-8]. Applications of nanotechnology formulated herbal drugs are schematically represented in Figure 2. Table 1 summarizes the various nanostructured herbal formulations, their different applications and biological activities.

Figure 2: Schematic representation of applications of nanotechnology formulated herbal drugs and nutraceuticals.

Table 1: Nanostructured herbal formulations.

Herbal and nanomedicine researchers have discovered that therapeutic nanoparticles (NPs) can provide as more effective drug delivery system than conventional forms of drugs. Nanocarriers transdermal gel (NCTG) was formulated from optimized nanotransfersomes of diclofenac diethylamine (DDEA) and curcumin (CRM) for providing a sustained and targeted effect. Due to nanoparticulate size of NCTG achieving higher absorption of the drug plus co-administration of lecithin; providing hydration gradient to the vesicles, increase permeability, decreased degradation and clearance by surfactant than that from marketed gel and plain curcumin gel was reported [9]. Formulated and optimized nanotransfersomes of DDEA and CRM provided a large surface area with high penetration potential and achieved high bioavailability [10]. pH-sensitive nanoparticles of curcumin-celecoxib combination were formulated as a potential therapy for uncreative colitis [11]. Curcumin solid lipid nanoparticles (CRM-SLN) were prepared with a high-loading capacity and chemical stability for the treatment of oral mucosal infection [12]. Curcuminloaded hydrogel nanoparticles of hydroxyl propyl methyl cellulose (HPMC) and polyvinyl pyrrolidone (PVP) were successfully formulated and exhibited a significant improvement in anti-malarial action [13].

Biosynthesis of silver nanoparticles (AgNPs) were demonstrated by leaf extract of Mukiascabrella, it exhibited significant antimicrobial activity against MDR-GNB nosocomial pathogens [14]. AgNPs have been synthesized by Mukundanet al. [15] using an aqueous leaves extract of Bauhinia tomentosa Linnand their in vitroanticancer activity has also been studied.Fluorescent AgNPs were synthesized using Artemisia annualeaf extract and these AgNPs were biocompatible, which was confirmed by checking the cytotoxicity against human erythrocytes and they showed significant fluorescence and antibacterial activity [16].

Gold nanoparticles (AuNPs) were synthesized by using a gall extract of Pistaciaintegerrima and they have potential for various biomedical and pharmaceutical applications particularly with significant antifungal and antinociceptive activity [17]. Phytofabrication of nickel nanoparticles (NiNPs) from Aeglemarmelos Correa (AMC) aqueous leaf extract was investigated NiNPs can be used as excellent anti-inflammatory agents and drug carriers [18]. Magnetic nanoparticles (MNPs) based drug delivery approach for co-delivering of curcumin and temozolomide has been implemented and this system has been well efficient in provoking greater anti-cancerous activity [19].

In vitroefficacy against the complications of diabetes mellitus (DM) and the in vivotoxicity was evaluated by using an aqueous extract from Syzygiumcuminiseed (ASc) and of polymeric nanoparticles containing ASc (NPASc). NPASc demonstrated a high inhibitory activity against ox-LDL particles and showed high in vitro activity [20]. Solid lipid nanoparticles (SLNPs) can be used as vehicles for phenolic compounds rich extracts. Witepsol and carnauba were tested for the production of solid lipid nanoparticles (WSLNPs ad CSLNPs) loaded with medicinal herbs, sage and savory extracts. WSLNPs showed to be a more suitable vehicle for herbal extracts, with high stability during digestion and a significant release percentage of phenolic compounds in the small intestine [21].

The persimmon leaf extract was successfully formulated as a stable self-nanoemulsifying drug delivery system (SNEDDS) formulation that had significant improvement in solubility, in vitro release and bioavailability compared with Naoxinqing tablets [22]. SNEDDS formulation of the optimized quercetin (QT) formulae offered superior protective effect against liver damage, compared with QT against paracetamol-induced hepatotoxicity. Sefsol and linoleic-acid-optimized SNEDDS formulation showed no symptoms associated with toxicity and offered a protective effect against paracetamol-induced hepatotoxicity [23]. Potential utility of SNEDDS for formulating Zedoary turmeric oil (ZTO) extracted from rhizome of Curcuma zedoaria was demonstrated by improved aqueous dispersion activities, stability and oral bioavailability. The formulated ZTO-SNEDDS could serve as a partial lipid phase with double advantages of increasing drug loading as well as minimizing the amount of requirement of the inert oils [24]. Shi et al. were prepared a multi-unit drug delivery system (MUDDS) for a Chinese medicine NiuhuangXingxiao Wan (NXW) to enhance the bioavailability and efficacy. NXW was formulated into four units, such as realgar, frankincense and myrrh oil (FMO), musk, and bezoar. The assay of in vivo antitumor activity shown that the efficacy of NXW-MUDDS was significantly higher than the NXW [5].

Incorporation of four prenylatedflavanones isolated from Eysenhardtiaplatycarpa leaves into nanoemulsion and poly lactic-co-glycolic acid (PLGA) NPs as anti-inflammatory agents for topical administration was investigated. Among four prenylatedflavanones, 5-hydroxy-7-methoxy-6-prenyl flavanone loaded nanoemulsion and polymeric nanoparticles could be proposed as potential topical anti-inflammatory formulations with the best properties for the treatment of inflammatory disorders [25]. Oleanolic acid (OA) was efficiently encapsulated in methoxypoly(ethylenglycol) (mPEG) with poly (lactic acid) [mPEG-PLA] and mPEG-poly(lactic-co-glycolic acid) (PLGA) NPs as nanoformulations for cancer therapy. All OA-loaded NPs system produced significant cytotoxic effects through apoptosis on cancer cell lines [26]. Polycaprolactone (PCL)/polyvinylpyrrolidone (PVP) nanofiber mat containing crude bark extract of Tecomella undulate were prepared and evaluated for their antibacterial properties. Extract loaded PCL/PVP nanofiber mat had inhibited the growth of bacterial strains which indicated that it could act in the treatment of wound healing or dermal bacterial infections [27]. Centellaasiatica (CA) extract was successfully incorporated into electrospun membranes to improve wound healing in a rat model. The wound areas that were covered with electrospun gelatin membranes containing CA (EGC) membranes exhibited more collagen deposition and a higher number of capillaries than the wound areas to which the other treatments were applied. Hence EGC membranes can be used as a potential material for wound dressings [28].

Nanotechnology in nutraceuticals

Nanotechnology platforms are widely being used to create delivery systems for nutraceuticals and bioactive natural products with poor water solubility. Some of the extensively studied nutraceuticalnanomaterials are discussed here. Figure 2 depicts the potential applications of nanotechnology in nutraceuticals. Table 2 summarizes the potential applications of nutraceuticals formulated as nanomaterials.

Table 2: List of nutraceuticals formulated as nanomaterials and their characteristics.

Hydrophobins (Hyd) used for nanoencapsulation of nutraceuticals for food enrichment is very much interesting they bid to hydrophobic materials like vitamin D₃ (VD₃). Hyd provided excellent protection to VD₃ against degradation. Moreover, Hyd were found to be promising nanovehicles of hydrophobic nutraceuticals for food and beverages enrichment [29]. Folic acid was encapsulated with two different matrices (whey protein concentrate (WPC) and a commercial resistant starch) and two different encapsulation techniques (spray drying and electro-spraying). Greater encapsulation efficiency was observed using WPC as encapsulating matrix. Electrospraying is a promising method in the food industry for encapsulation applications [30]. Emulsification-diffusion method (EDM) is an excellent alternative to prepare nanocapsules from food constituents. Formation of nanocapsules with DL-α-tocopheryl acetate and β-carotene has confirmed the versatility and reproducibility of the EDM when batches with different materials are prepared under optimal conditions [31].

VD₃ was entrapped in whey protein isolate (WPI) nanoparticles prepared with different calcium concentration. Composition of nanoparticles with calcium can perform a compact structure providing reduction of VD₃ degradation during storage time. WPI nanoparticles containing VD₃ can be used for enriching of clear or non clear drinks such as herbal beverages, fruit drinks or low fat food [32]. Dual nutraceuticalnanohybrids consisting of folic acid (FA) and calcium were prepared based on layered double hydroxide (LDH) structure through exfoliation-reassembly hybridization method FA/LDH nanohybrids showed higher contents of essential nutrients in human health and they could be considered as dual nutraceuticalnanomaterials [33]. Hosseiniet al. [34] were explored the potential application of the protein-polysaccharide soluble nanocomplexes as delivery systems for nutraceuticals in liquid foods. The complexation between β-lactoglobulin (BLG) and four nutraceutical models including β-carotene, folic acid, curcumin and ergocalciferol was investigated under different conditions and the low water soluble nutraceuticals were successfully entrapped within electrostatically stable nanocomplexes [34]. Nanocarriers made with hempseed oil or a blend of amaranth and hempseed oils were investigated for a concomitant encapsulation and release of the carotenoids enriched plant extract. The nanocarriers have a great potential for clinical applications as a new delivery system for other lipophilic plant extracts enriched in bioactive compounds [35]. A novel lipid-free nano-CoQ10 system formulated and stabilized by various surfactants and the bioavailability of CoQ10 was evaluated by oral administration of CoQ10 formulation in Sprague-Dawley rats. The formulation can be an effective vehicle for improving oral bioavailability of CoQ10, it was confirmed by the observation of significant increase in the maximum plasma concentration and the area under the plasma concentration time curve [36]. The bioavailability of heptadecanoic acid and CoQ10 was investigated for the influence of droplet size and oil digestibility by a rat feeding study. The developed nanoemulsion based delivery system has increased oral bioavailability of lipophilic nutraceuticals [37]. Food grade biopolymers, proteins and polysaccharides can be used to create a diverse range of delivery systems suitable for encapsulating, protecting and delivering lipophilic functional components such as omega 3-fatty acids, conjugated linoleic acid, oil-soluble vitamins, flavors, colorants and nutraceuticals [38]. Novel organogel-based nanoemulsions were developed for oral delivery of curcumin and improvement of its bioavailability. In vitro lipolysis profiles revealed that the digestion of nanoemulsion was significantly faster and more complete than the organol. Organogel based nanoemulsion can be used for oral delivery of poorly soluble nutraceuticals with high loading capacity, which has significant impact in functional foods, dietary supplements and pharmaceutical industries [39].

Supercritical assisted injection in the liquid antisolvent process has been used for the production of α-tocopherol nanoparticles suspensions and produced NPs can be used as supplementation and as an antioxidant in food, cosmetics and pharmaceutical industries [40]. The potential of native and thermally modified lactoferrin (LF) to form co-assembled vehicles for the delivey of (-)-Epigallocatechin-3-gallate (EGCG) was investigated by Yang et al. LF-EGCG nano and submicrometer particles could act as protective vehicles for EGCG and a beneficial aid for the development of controlled release of other bioactive materials [41]. The effect of clove essential oil (CO) and its major constituents, eugenol, formulated in water-based microemulsion was studied on fatty liver and dyslipidemia in high-fractose-fed rats. CO and eugenolmicroemulsion (EM) produced significant improvement in fatty liver and dyslipidemia with consequent protection from cardiovascular disease and other complications of fatty liver [42]. Two nutraceutical induction methods, DMSO dilution in water and acidification were used for enzymatically synthesis of dextran NPs to entrap hydrophobic nutraceutical, the isoflavonegenistein. The DMSO method was found to be more suitable for inclusion of genistein in dextran, resulted in a high genistein load and high percentage of nanosized particles [43].

Future perspective

Nanotechnology in drug delivery has been manifested into nanoformulations that can have unique properties both in vivo and in vitro, especially in targeted delivery. A few clinical studies have done to great effect in small animal models, but the translation of the small animal results to clinical successes has been limited [44]. Successful translation requires revisiting the meaning of nanotechnology in drug delivery, understanding the limitations of nanoparticles, identifying the myth persistent in the field, and facing inconvenient facts. For this approach to be successful, it may require fine-tuning of the procedure to maximize the usefulness of the nanoparticle to the drug delivery system. Nanoparticle researchers need to realize is that clinical application of any formulation requires approval by the Food and Drug Administration (FDA) or its overseas equivalent. The safety and efficacy of new formulations must be proven through controlled clinical studies. Doxil^® is the first FDA approved nanodrug in 1995 based on the three unrelated principles (i) prolonged drug circulation time and avoidance of the reticuloendothelial system due to the use of polyethylene glycolatednanoliposomes, (ii) high and stable remote loading of doxorubicin driven by a transmembrane ammonium sulfate gradient, which also allows for drug release at the tumor and (iii) having liposome lipid bilayer in a “liquid ordered” phase composed of the high temperature (53 ᵒC) phosphatidylcholine and cholesterol [45]. Even though, large reward, nearly two years after Doxil-related patents expired, there is still no FDA-approved generic “Doxil” available. The complexity of FDA approval of generic Doxil, the current situation is even more complex. Accordingly turning the potential of nanoformulations into clinically useful requires clear setting and reasonable goals. The challenges in drug delivery using nanoformulations can be overcome through understanding the limitations of nanoformulation approaches by FDA regulations and maximizing the existing capabilities of nanoformulations.

Overall, this review indicates that nanotechnology has great potential for delivering herbal drugs and nutraceuticals, and in light of the comprehensive health problems, its utilization for effective disease prevention and health promotion is necessary and to be anticipated. Even though nanotechnology offers promising approaches in herbal drug delivery and nutraceutical applications, additional innovative research is needed to address the cost effective and long-term safety of the nanomaterials.