Current Advances in Nanotechnology-Mediated Delivery of Herbal and Plant-Derived Medicines

Phytomedicine has been used by humans since ancient times to treat a variety of diseases. However, herbal medicines face significant challenges, including poor water and lipid solubility and instability, which lead to low bioavailability and insufficient therapeutic efficacy. Recently, it has been shown that nanotechnology-based drug delivery systems are appropriate to overcome the above-mentioned limitations. The present review study first discusses herbal medicines and the challenges involved in the formulation of these drugs. The different types of nano-based drug delivery systems used in herbal delivery and their potential to improve therapeutic efficacy are summarized, and common techniques for preparing nanocarriers used in herbal drug delivery are also discussed. Finally, a list of nanophyto medicines that have entered clinical trials since 2010, as well as those that the FDA has approved, is presented.


Introduction
Phytomedicines also called herbal medicines, are mixtures of plant metabolites containing pharmacologically active compounds with some healing and therapeutic properties.due to the benefits such as fewer adverse effects and low cost, herbal medicines have been used since ancient times as therapeutic agents in various diseases.In addition, over one-third of all FDA-approved new molecular entities are natural products and their derivatives. 1,2The first plantderived drug was painkiller morphine, with a mechanism of inhibiting the discharge of neurotransmitters from presynaptic neurons and was authorized for utilization in 1827. 3Later, many other products were developed, including paclitaxel, which is used today as an anticancer agent in ovarian, breast, lung, and other cancers and extracted from the pacific yew plant (Taxus brevifolia). 4,5he significant steps to obtain herbal extracts or oils from plant materials generally include harvesting (to suppress plant metabolism at the right time), drying (to protect the active substance by inhibiting enzymes), size reduction (to increase the surface area and thus the improvement of solvent extraction) and extraction (in order to obtain therapeutic portion and omission of inert parts).Finally, the resulting extract can be traditionally formulated in various dosage forms such as solid, liquid, and semi-solid, or encapsulated in novel drug delivery systems such as liposomes, pyrosomes, polymeric NPs, etc. [6][7][8] Despite the prominent pharmacological actions of herbal drugs in various diseases, several challenges, including pharmacokinetic drawbacks such as low bioavailability and limited absorption and physicochemical challenges like poor water and lipid solubility, large molecular size, and instability, can reduce their efficacy, primarily upon oral administration. 9,10An effective drug delivery system is needed to overcome the abovementioned barriers, reduce repeated administration, and increase patient compliance. 11n recent decades, nanotechnology-based delivery systems have received much attention in phytomedicine.][14] This review outlines the challenges of phyto/ herbal medicines, including physicochemical and pharmacokinetic drawbacks.Different types of nanocarriers are also discussed as novel and efficient strategies in herbal drug delivery with the potential to overcome the above-mentioned challenges.Some of the common techniques used for the formulation of nanoparticles (NPs) have been reviewed.Therefore, an overview of FDA-approved nanophytomedicines as well as those being used in clinical trials since 2010, has been provided.

Herbal medicines: Challenges
Herbal medicines are a mixture of various ingredients with different physicochemical properties. 15In addition, poor gastrointestinal (GI) absorption and consequent low oral bioavailability of herbal drugs are due to various factors, including high molecular weight, poor solubility in GI fluids, limited permeability through cell membranes, degradation in the GI tract, hepatic presystemic metabolism, and P-glycoprotein (P-GP/ MDR1/ABCB1)]-mediated gut efflux. 16,17Therefore, the development and preparation of herbal formulations face various challenges.
Nanotechnology-based techniques have been developed to overcome the above-mentioned limitations and increase the bioavailability of herbal medicines.

Nanotechnology for herbal drug delivery
The importance of nanotechnology Nanotechnology can be used to develop products with novel and improved actions and physicochemical properties particularly in the medical field. 180][21] Different classes of nanocarriers, including lipid-based NPs, polymer-based NPs, and inorganic NPs, have been used for drug delivery in phytomedicine, which will be discussed in detail below.A schematic of common nanocarriers is shown in Figure 1.

Lipid-based nanocarriers for herbal drug delivery
In addition to the benefits mentioned in the previous section, lipid-based NPs such as solid lipid nanoparticles (SLNs), liposomes, and phytosomes also have the advantages of biocompatibility and the ability to improve the aqueous solubility of poorly soluble herbal drugs. 22Lipid-based nanocarriers are prepared using various materials and methods depending on their target.Challenges like scale-up and physical instability such as aggregation must be considered in the choice of preparation method. 23Following the preparation of NPs, parameters such as size, morphology, and surface properties should be determined because they play an essential role in the cellular uptake and pharmacological effects of NPs. 24iposomes are vesicular NPs which consist of concentric lipid bilayers made of amphipathic phospholipid molecules that assemble to create spherical structures in aqueous media and surround part of the solvent. 25In addition to increasing the solubility of the loaded drug, the liposome has been considered as a suitable carrier in herbal delivery in terms of its ability to load both hydrophilic and lipophilic drugs besides improving bioavailability and therapeutic efficacy. 26,27n 1989, an Italian pharmaceutical and nutraceutical company, Indena, successfully generated complexes of phospholipids (phosphatidylcholine) and plant actives called Phytosome ® and then patented the innovation.28 Phytosomes (refer to Figure 1), also called phytolipid delivery systems, are more stable than liposomes.Because, unlike liposomes, they have a chemical bond in their structure.Phytosomes increase the bioavailability of poorly soluble herbal medicines by increasing their absorption in GI.Some of the phytosomes comprising various phytoconstituents such as grape seed, hawthorn, Ginkgo biloba, milk thistle, ginseng, and green tea are commercialized in the USA.29,30 In 1990, SLNs as colloidal NPs which containing lipids that are in solid state at room and body temperature were developed.SLNs have advantages such as excellent physicochemical stability and higher protection compared to other NPs such as liposomes and polymeric NPs.2 Table 1 summarizes the studies performed on the most common herbal medicines loaded in lipid-based NPs in the last 5 years.

Polymeric nanocarriers for herbal drug delivery
Recently, polymeric NPs have attracted more attention as a drug delivery system in phytomedicine.These NPs have a particle size of 10 to 1000 nm and are divided into two categories of nanospheres and nanocapsules based on structure.Nanospheres are polymeric matrices in which the active substance is uniformly dispersed, while nanocapsules have a core-shell structure with a polymeric shell, and the active ingredient is encapsulated in the core or is adsorbed on the polymeric membrane.Biodegradable and biocompatible synthetic or natural polymers are used to prepare polymeric NPs.][67] Dendrimers have been extensively studied in herbal delivery among polymers due to their unique polyvalency, monodispersity, and controllable structure. 68Dendrimers consist of three parts: the central core, the generations, and the terminal groups.The drug can be attached to the terminal group either covalently or non-covalently and it can be encapsulated in the hydrophobic core.Polyamidoamine (PAMAM) is the first commercialized dendrimer, which is also used to increase the absorption of poorly water-soluble drugs. 69,70olymeric micelles with a core-shell structure (10-100 nm) are another polymeric NPs that are formed by self-assembly of block copolymers consisting of both a hydrophilic block and a hydrophobic block in an aqueous medium.The hydrophobic core provides benefits such as increased solubility and protection against degradation and intracellular accumulation of the drug.The outer hydrophilic layer can achieve improved biocompatibility and active targeting.2][73] The studies conducted on the delivery of most common herbal medicines using different polymeric NPs during the last 5 years are summarized in Table 2.

Inorganic nanoparticles
Recently, various types of inorganic NPs, such as metal NPs, mesoporous silica nanoparticles (MSNs), carbon nanotubes (CNTs), and magnetic NPs, have been used for applications in drug delivery.
Metal NPs, the most important of which are quantum dots (QDs), gold, silver, platinum, iron (II, III) oxide, titanium dioxide, and zinc oxide, were discovered by Faraday in 1908.][92] MSNs are capable of carrying large amounts of cargo due to their large surface area and porosity.In addition, they are widely used in both oral and parenteral drug delivery due to because of unique properties such as excellent chemical stability and biocompatibility. 93,94NTs are relatively more compatible than other inorganic NPs.These NPs, which have a tubular structure, are obtained by curling up graphite sheets and are divided into two categories: single-walled carbon nanotubes (SWCNTs) and multi-walled carbon nanotubes (MWCNTs).SWCNTs can increase the solubility and bioavailability of herbal medicines.In addition, due to their hollow structure and the possibility of surface functionalization, they play an essential role in improving the physical and chemical properties of herbal drugs. 95,96agnetic NPs are another group of inorganic NPs, among which Fe 2 O 3 in the form of superparamagnetic NPs is not sensitive to oxidation compared to other magnetic NPs such as nickel and cobalt, so it has the potential application in biomedicine, mainly targeted drug delivery.In fact, the possibility of accumulation of magnetic NPs in the target tissue by applying an external magnetic field leads to target therapy. 97he studies performed during the last 5 years on the delivery of most common herbal medicines using different types of an inorganic nanocarriers are summarized Higher cellular uptake Enhanced cytotoxic effect against HCT116 cells 80 10-Hydroxycamptothecin Improved liver targeting and absorption 88

Curcumin
Antibacterial activity Enhanced penetration into the biofilms and antibacterial activity in Table 3.

High-pressure homogenization method
In the high-pressure homogenization method, lipid particles are converted into nanoscale particles using high pressure and high shear stress.This method, divided into hot and cold homogenization, is widely used to produce lipid-based NPs, including emulsions, liposomes, and SLNs at large scales.In both cases, the first step involves dissolving of the drug in the molten lipid.In hot homogenization, homogenization is applied to the pre-emulsion at a higher temperature than the melting point of lipid.In contrast, in cold homogenization, homogenization of suspension is performed at room temperature. 118,119

Solvent emulsification-diffusion method
In this method, the polymer or lipid is dissolved in an organic solvent and then emulsified into an aqueous phase containing an emulsifier.Finally, the solvent is evaporated under a vacuum to form polymeric or lipid-based NPs.
The advantage of this method over the homogenization method is the lack of high temperature, so it is a suitable method for formulating temperature-sensitive drugs.However, organic solvents may cause toxicological problems. 120,121-precipitation method Co-precipitation is the most used method for the preparation of metal oxide and core-shell NPs.It is a costeffective, fast, straightforward, and easily transposable on a larger scale method for industrial applications.This method gives nanomaterials via high purity and doesn't require high pressure or temperature and hazardous organic solvents.122

Phase coacervation
Coacervation is one of the common methods of microencapsulation and is divided into two categories: simple and complex.In simple coacervation, a colloidal solute such as ethyl cellulose or chitosan is used, while in the case of complex coacervation, a polymer solution is prepared by the interaction between two oppositely charged agents such as gelatin and chitosan.Generally, this method involves the phase-separation of two separate liquid phases to form a polymer-rich phase (coacervate) and a polymer-depleted phase (equilibrium solution). 123,124lting out method Both the drug and polymer are first dissolved in a solvent in this method.Then, the solubility of the polymer is reduced by adding an electrolyte, and as a result, it precipitates and encapsulates the drug.This technique is primarily used for the preparation of nanospheres. 125,126

Supercritical fluid-based methods
The supercritical fluid technique with the potential to produce NPs with a narrow size distribution without solvent residues in the final product is considered an essential tool for preparing a wide range of biomedical nanomaterials.Carbon dioxide and water are most commonly used supercritical solvents in this method. 127he basis of this method is the dissolution of the drug and carrier materials (e.g., polymer) in the supercritical solvent at critical temperature and pressure and then its expansion by spraying in the expansion chamber at lower pressures, which leads to the deposition of materials and the formation of NPs. 128

Nanoprecipitation technique
Nanoprecipitation techniques, also called solvent displacement methods, were developed by Fessi et al. 129 Usually, in this method, the polymer and drug are dissolved in a water-miscible solvent and then added to a non-solvent.The solubility of the polymer decreases as soon as it enters the nonsolvent and the polymer precipitates encapsulate the drug.The presence of an emulsifier or stabilizer, such as poloxamers is vital to avoid the aggregation of NPs during the nanoprecipitation process. 130

Self-assembly methods
Self-assembly is the spontaneous arrangement of individual units to create well-defined structures, which is more suitable for preparing two-dimensional nanostructures such as nanosheets.Self-assembly can occur under the influence or in the absence of external intervention, which is called dynamic and static processes, respectively. 131,132inical trials and FDA-approved herbal drug delivery nanoformulations Cosmetochem Company specialized in the production of a range of botanical extracts in a liposomal powder named Liposome Herbasec ® .Similarly, a line of Phytosome ® technology-based products has been developed and commercialized by the Indena Company.Both liposomal and phytosomal NPs are very efficient penetration enhancers, so they are used as drug carriers for skin with the ability to increase the bioavailability of plant extracts. 15,133n addition, different companies have offered various nanoformulations of anticancer phytomedicines.A summary of anticancer nanophytomedicines, which have entered clinical trials and have also been approved by the FDA, is given in Table 4.

Conclusion
Despite the potential use of plant-derived drugs in the treatment of various diseases, they have considerable limitations due to their high molecular weight, high required dose, poor solubility, and high toxicity.Novel nanotechnology-based drug delivery systems, including polymeric, lipid, and inorganic nanocarriers are beneficial in overcoming these limitations.Nanocarriers containing herbal medicines provide benefits such as increased therapeutic efficacy and bioavailability.Today, many herbal and plant-derived nanoformulations have been approved by the FDA, and many clinical studies are underway in this field.

Figure 1 .
Figure 1.Schematic representation of common nanocarriers for herbal drug delivery

Table 1 .
A summary of lipid-based herbal nanoformulations

Table 3 .
Inorganic NPs used in herbal nanoformulations

Table 4 .
Clinical trials and FDA-approved anticancer nanophytomedicines