Therapeutic Applications of Nano-Phytopharmaceuticals

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This entry is adapted from the peer-reviewed paper 10.3390/nano12020238

Phytopharmaceuticals have been widely used globally since ancient times and acknowledged by healthcare professionals and patients for their superior therapeutic value and fewer side effects compared to modern medicines. Dose reduction, improved bioavailability, receptor-selective binding, and targeted delivery of phytopharmaceuticals can be likely achieved by molding them into specific nano-formulations.

nano-formulations phytopharmaceuticals herbal medications nanomaterials

1. Introduction

Nanotechnology is a vital tool for medical sciences. The introduction of nanomedicine, using nanotechnology combined with drugs or diagnostic molecules, has improved the ability to target specific cells or tissues that require treatment and repair. These nanomaterials have been proven to be produced at a nanoscale level and are safe to introduce into the body. It is possible to modify a variety of nanocarriers’ characteristics that include their constituents, size, shape, bioavailability, surface properties, and target specificity to achieve or enhance desirable pharmacological targets ^[1]^[2] Several strategies have been implemented to increase the drug-target specificity. Recently, several studies have reported improved efficacy of therapy when combined with nanomaterials ^[3]. Pure herbal medicines are often considered less effective compared to pure constituents that are mainly demonstrated to have reduced intestinal absorption when administered orally ^[4]. This is the reason behind the pharmacological activity/loss associated with pure constituents and such problems can be overcome using new drug delivery systems, such as nanotechnology.

Nanoparticulate delivery of drugs can generally improve drugs’ solubility, bioavailability, stability, pharmacological activity, increase target specificity, promote transport across membrane, prolong circulation times, and reduce systemic and organ toxicity ^[5]^[6]. Various treatments are being investigated with the use of nanoparticle drug delivery systems for diseases, such as infectious diseases, autoimmune diseases, cardiovascular diseases, neurodegenerative diseases, ocular diseases, fungal infections, iron deficiency, and pulmonary diseases ^[7]^[8]. However, the greatest advances were seen in the treatment of cancer with several nano strategies being used clinically after approval by the FDA in the United States of America ^[9]. Recently, more attention has shifted towards novel drug delivery systems using nanoparticles for herbal and plant-based drugs ^[10].

Plant-based medicine has some limitations which hinder its use and production in the mainstream disease treatment and therapy. There are several chemical constituents in a plant’s extract that lead to its medicinal properties. The active constituents of plant extracts like tannins, flavonoids, alkaloids, phenylpropanoids, and terpenoids are water-soluble but show poor absorption from their inability to cross lipid membranes and have large molecular sizes, which then results in low bioavailability and efficacy ^[5]^[11]^[12]. There are also concerns of safety due to the incompatibility of some plant extracts with other components in a drug formulation which can lead to undesirable effects ^[11]. High systemic clearance of these compounds also leads to low therapeutic levels in the blood resulting in no therapeutic effect ^[13]. Furthermore, poor reproducibility of in vitro effects in vivo prevents many plant-based medicines from clearing clinical trial phases ^[14]. Nanomedicine aims to overcome these limitations and to improve the delivery of plant-based medicines to treat various diseases. Nanoparticle drug delivery systems can potentially improve the stability, solubility, and bioavailability of encapsulated plant extracts, promote its movement across lipid membranes, and prolong its circulation, all while delivering the active constituent to a specific target site ^[5]^[6]^[11] (Figure 1). Liposomes, dendrimers, polymeric NCs, polymeric micelles, metallic NPs (magnetic, gold), SLNs, nanocapsules, nanospheres, and nanogels are some of the examples of nano-based drug delivery systems that are presently under investigation ^[10].

Figure 1. Representation of delivery of phytopharmaceuticals using nanotechnology. The figure was made with www.biorender.com (access date: 17 December 2021) and adapted from DOI: 10.3390/nano12020238.

2. Therapeutic Applications of Nano-Phytopharmaceuticals

2.1. Nano-Phytopharmaceuticals in Neurological (CNS) Disorders

Despite enduring efforts to deliver medicinal drugs to the brain tissue, these treatment regimens are compromised by low bioavailability due to the blood-brain barrier (BBB), a natural protective layer consisting of capillary endothelial cells, pericytes, and tight junctions ^[15]. This near-impermeable barrier impedes the entry of most macromolecules and allows only the minutest particles (<400 Da) to cross into the nerve tissue. Indeed, less than 5% of conventional therapeutic molecules in various stages of pharmaceutical development may penetrate this physiological barrier ^[16]. Therefore, CNS-targeted natural product formulations in nanocarriers hold infinite promise. Evidence suggests that nutraceuticals and phytochemicals exert therapeutic effects in neurological diseases, owing to their antioxidant, anti-inflammatory, and neuroprotective mechanisms ^[17]^[18]. Coupled with nanoscale delivery systems which improve solubility, enhance retention rates ^[19], and with the ability to permeate through the BBB, there is hope yet for effective treatment of neurological disorders. The following topic discusses two herbal compounds, curcumin and ginseng, and their significant potential for use in neurotherapeutics through nano-encapsulation.

A derivative of the South Asian turmeric plant rhizome, Curcuma longa (turmeric), the polyphenol curcumin has amassed quite a reputation in nutraceutical development for various diseases, including cancer and inflammatory conditions ^[20]. The healing properties of this yellow spice date back to ancient civilizations, featuring strongly in Ayurvedic therapy. Nevertheless, the relatively poor bioavailability due to dismal water solubility and rapid intestinal clearance impedes the therapeutic effects of conventional drug delivery, paving the way for the advent of nano-formulations.

The role of nanoparticulate systems to treat glioblastoma was recently highlighted using different strategies, such as improving their diffusion through the BBB ^[21]. In a glioblastoma study, Schmitt et al. demonstrated that curcumin encased in liposomal carriers (LipoCur) proved to be superior in reducing the proliferation and reactivity of human microglia and astrocytes (human fetal astrocyte cell line, SVGA) compared to the free compound. Immunostaining of murine organotypic brain segments challenged with lipopolysaccharide (LPS) for eight days, revealed that LipoCur was equally effective in reducing glial scarring ^[20].

Aside from CNS cancers, chronic degenerative conditions such as Alzheimer’s disease (AD) fall under intense scrutiny from researchers. Characterized by neurofibrillary tangles of tau proteins and “senile”amyloid-β (Aβ) plaques in the brain, the condition is notoriously challenging to diagnose and treat due to the late onset of symptoms, usually decades after the onset of pathological changes ^[22]. Neuro-inflammation is recognized as one of the primary mechanisms underlying neuronal degeneration, and thus is a target for natural product (NP) research. Malvajerd and colleagues encapsulated curcumin in solid lipid nanoparticles (SLNs) (entrapment efficiency 82 ± 0.49%) and nanostructured lipid carriers (NLCs) (94 ± 0.74%), and found that NLCs resulted in the highest bioaccumulation of curcumin in rat brains compared to free compound and SLNs ^[23].

Poly (d,l-lactic acid-co-glycolic acid, PLGA) and polymer NPs are known to be biocompatible and thus show great potential in disarming neuroinflammation in another 5xFAD mice Alzheimer’s disease model ^[24].

Kim et al. established a formulation of red ginseng water extract with gold nanoparticles (WERGGN) and established its antioxidant activity through DPPH, ORAC, and ABTS assays. WERGGN treatment on neuron-like PC-12 cells revealed cytoprotective effects, mainly due to the decreased intracellular oxidative stress. In addition, levels of neurotransmitter degradation enzymes such as acetylcholinesterase and butyrylcholinesterase were also inhibited, suggesting that WERGGN promoted synaptic impulse transmission ^[25]. Nonetheless, the dosage of ginseng extract, when co-administered with a synthetic drug (e.g. selegiline), determines the pharmacokinetics in the body: lower doses result in poorer bioavailability due to CYP1A2 induction, while higher concentrations cause inhibition of CYP3A4 and thus enhanced systemic exposure ^[26].

It is essential to note that nanomaterials have potential limitations and the adverse effects on CNS were described previously ^[27]^[28]. For example, one study showed that female mice that were intranasally treated with titanium dioxide nanoparticles (TiO₂ NPs) (0.5 mg daily for 1 month) produced apoptosis, affected brain development, and oxidative stress (caused increased lipid peroxidation, protein oxidation, catalase expressions, and release of glutamic acid and nitric oxide) ^[28]. These authors also concluded that an intranasal spray of TiO₂ NPs could be translocated into the CNS and cause potential lesions of the brain ^[28]. Similarly, Fe₂O₃ magnetic NPs (0.15–15 mM) also showed toxicity and c viability in a neuronal cell line in vitro ^[29]. Whereas another study showed that toxicity of zinc and silicon NPs is relatively low, but the neuronal toxicity of NPs depends on the materials used ^[27]^[30]^[31]. Therefore, the toxicity of NPs is present, and depends on the formulation, particle size and concentration or treatment protocols of specific NPs.

2.2. Nano-Phytopharmaceuticals in Cardiovascular Disorders

Since CVD require most often long-term medication, treatment regimens become complex and create a burden for the patient especially when multiple medicines are prescribed and must be taken for life ^[32]^[33] Although these therapeutic drugs have been successful in halting the progression of the disease, thereby improving the quality of life of patients, most of these cures only the symptoms and may not repair or regenerate the damaged tissues. In addition, CVD medication has different side effects, such as antiplatelet drugs may cause diarrhea, rash, or itching ^[32]. Others can cause abdominal pain, headache, chest pain, muscle aches, and dizziness. In the case of anticoagulants, their side effects can lead to bleeding and necrotic or gangrenous skin. Given the excessive side effects of current therapies, alternative therapeutic approaches like medicinal plants and natural products are preferred. Against this premise, a better treatment for CVD that would not burden the patients is necessary. Hence, it is important to explore new technologies and drugs to lessen the use of conventional treatments. The lower toxicity, chemical diversity, cost-effectiveness, and therapeutic potentials of natural products make them the popular choice of medicine compared to other products ^[34]. With the combination of nanoformulation methods to deliver phytomedicines, it becomes more effective with improved solubility, bioavailability, circulation time, surface area-to-volume ratio, nil systemic adverse side effects, and drug delivery efficiency of these medications. The introduction of nanomedicine using a combined nanotechnology with drugs or diagnostic molecules has improved the ability to target specific cells or tissues that require treatment and repair. These nanomaterials are produced on a nanoscale level and are safe to introduce into the body. Hence, applications for nanotechnology in medicine include imaging, diagnosis, or the delivery of drugs that will help medical professionals treat various diseases including cardiovascular diseases ^[35]^[36]. The functionality of the most recent nano-formulated medicinal plants and/or natural products against various cardiovascular conditions such as hypertension, atherosclerosis, thrombosis, and myocardial infarction is expected to be maximized.

Some plant extracts/compounds used for treatment of CVD that are nano-formulated for efficient delivery to their target are listed in Table 1. Among the extracts used for CVD, curcumin, quercetin, and resveratrol were the most applied natural products, respectively. However, curcumin, despite its curative potential, has poor aqueous solubility and consequently, minimal systemic bioavailability along with rapid degradation ^[37]. These characteristics restrict the utilization of curcumin a medical perspective. Liposomes have found uses in drug delivery of poorly water-soluble drugs. Such drug-loaded liposomes can be fabricated by a wide variety of nanotechnology methods such as ethanol injection, thin-film hydration, sonication, high-pressure extrusion, reverse-phase evaporation, calcium-induced fusion, and supercritical fluid methods, among others ^[37].

Table 1. Nano-phytopharmaceuticals for therapeutic applications in CVDs.

Nanoformulation	Phyto-Pharmaceutical	Effects	References
Liposomes	Curcumin	Anti-hypercholesterolemic, anti-atherosclerotic and protective against cardiac ischemia and reperfusion.	^[38]
PLGA nanoparticle	Quercetin	Anti-hypercholesterolemia, better cell rescue by lowering oxidized thiols and sustaining superior ATP production, improved therapeutics for ROS-based cardiac diseases.	^[39]
Solid lipid Nanoparticle	Resveratrol	Protective action of vascular walls towards oxidation, inflammation, platelet oxidation and thrombus formation	^[40]^[41]
1,2-diacyl-Sn-glycero-3-phosphocholine [EPC] and 1,2-dipalmitoyl-Sn-glycero-3-phosphocholine (DPPC) liposomes	Magnolol	Enhanced inhibitory effect on migration and hyperplasia of vascular smooth-muscle cells; Anti-platelet, anti-thrombotic, and anti-hypertensive via inhibiting MAPK family activation, Akt/ERK1/2/GSK3 β-catenin pathway, and angiotensin-converting enzyme (ACE)/angiotensin II (Ang II)/Ang II type 1 receptor (AT-1R) cascade and upregulating PPAR-β/γ and NO/guanosine 3′,5′-cyclic phosphate/PKG.	^[34]^[42]^[43]
Nano-micelles	Tilianin	Protective effects of cardiomyocytes by inhibiting inflammation and oxidative stress during myocardial ischemia-reperfusion injury	^[44]
PEGylated nanostructured lipid carriers	Baicalin	Improved myocardial ischemia; beneficial roles against the initiation and progression of CVDs such as atherosclerosis, hypertension, myocardial infarction, reperfusion and heart failure	^[45]^[46]
Liposomes	Berberine	Effect of protecting heart failure, hypertension, hyperlipidemia, insulin resistance, arrhythmias, and platelet aggregation.	^[47]^[48]

Quercetin acts as an antioxidant on cells but is hindered by its high metabolism rate. In order to control this, quercetin is encapsulated in poly [lactic-co-glycolic] acid (PLGA) nanoparticles ^[39]. This guarantees secure and controlled release of the quercetin, and permits cell enlistment, attachment, expansion, and articulation of heart proteins in local myocardium.

Resveratrol’s capacity for protective action makes it one of the commonly used compounds against CVD. However, its poor pharmacokinetic properties, such as low aqueous solubility, low photostability and extensive first-pass metabolism, result in poor bioavailability and hinder its clinical potential ^[49]^[50]. To resolve this issue, the use of lipid nanoparticles offer the possibility to develop new therapeutics. Further, solid lipid nanoparticles hold great promise for reaching the goal of controlled and site-specific drug delivery ^[34].

Other compounds used for CVDs are Magnolols, Berberine, Tilianin and Baicalin. These compounds require nanoformulation to maximize their use. Magnolols as a phenolic polyhydroxy compound have poor aqueous solubility and low oral bioavailability which limit their clinical use. Therefore, various formulations such as liposomes ^[51], solid dispersions ^[52], emulsions ^[53], and nanoparticles ^[54] have been developed to ameliorate the water solubility and bioavailability of it.

2.3. Nano-Phytopharmaceuticals in Pulmonary Disorders

To curb the increasing threat of respiratory diseases, there is an immediate need to explore some alternatives to the use of antibiotics, and an ecofriendly, cost effective, efficacious and durable strategy to combat these global respiratory problems. Thus, the field of nanotechnology provides a promising technology against respiratory diseases. In the past, various studies have shown very effective and interesting results. In addition to their antiviral properties, the application of nanoparticles (NPs) provides a potential strategy to manage infections caused by multidrug-resistant organisms (MDROs) ^[55]^[56]^[57]. NPs exhibiting antibacterial activities can target multiple biomolecules and have the potential to reduce or eliminate the evolution of MDROs ^[58]. Plant extracts are complex mixtures that provide a rich arsenal of molecules, such as flavanones, flavones, flavonols and chalcones, fatty acids, amino acids, terpenoids, aldehydes, and alcohols ^[59], with high redox potential ^[60]. Furthermore, biogenic synthesis produces potential, stable, and better-defined materials ^[61]^[62].

Silver nanoparticles (AgNPs) have shown broad applications in the medical system, such as anti-inflammatory, anti-angiogenesis, antiplatelet, antifungal, anticancer, and antibacterial activities ^[63]^[64]^[65]^[66]. Nowadays, AgNPs have been reported as biomedical therapeutic agents, such as wound dressings, and long-term burn care products and antibacterial lotions ^[67]; They also exhibit antiviral activities against influenza A virus, hepatitis B virus, human parainfluenza virus, herpes simplex virus, and human immunodeficiency virus ^[68]^[69]. They prevent the anchoring and binding of the virus to the host and cell receptor, respectively, and hence they deactivate the virus by denaturing the surface.

AgNPs inhibit the binding of the virus by interacting with the glycoprotein (gp120) of the sulfur-bearing groups distributed in the lipid membrane of the virus ^[70]. In another study, the virus inactivation was observed when the nano-silver was combined with the nucleic acid of the virus and modified the structure of the capsid and affected the replication ^[71]. Along with such surface modification, AgNPs also show synergistic antiviral activity. In one study, it was reported that curcumin, when used as both a reducing and stabilizing agent prevented viral replication, and blocked the budding of viruses ^[72]. Similarly, the AgNP surface, when modified through chemical methods with drugs like zanamivir, amantadine and oseltamivir, was able to interact with virus particles directly, which destroyed the virus and blocked its entry ^[73].

Gold nanoparticles (AuNPs) provide superior properties ^[74], and various methods for the preparation of gold nanoparticles have been well reported ^[63]. Compared to silver nanoparticles, AuNPs display better results in in vivo studies. AuNPs can interact with the haemagglutinin (HA) glycoprotein and can oxidize the disulfide bond, resulting in the inactivation of the virus ^[75]. Surface properties are useful in targeting the virus. The sulphonates are organic sulphates that were used to interact with the capsid proteins of the virus cell and prevent the HA activity ^[76].

In nanoscience, the carbon dots (CDs) also play an important role due to their unique properties. CDs prevent the viral infection as they have hydroxyl and carboxyl groups on their surfaces that interact with viral membranes ^[77]. To improve the activities of CDs, antiviral agents like plant extracts are grafted on the surface that involves a two-step reaction. The functionalized antiviral agent shows the inhibition of the virus into the cell that has a broad-spectrum action for the enveloped and the non-enveloped viruses ^[78].

Another important nanotechnology-based materials are based on graphene, (GO), which also have biomedical applications ^[79]. To prevent viral infection in the host cell, GO has been used with organic and metallic nanoparticles that show antiviral activities ^[80].

2.4. Nano-Phytopharmaceuticals in Gastro-Intestinal Disorders

Berberis vulgaris and Curcuma longa extracts encapsulated in cationic polymer EPO (Figure 5), demonstrated significant anti-parasitic activity against Entamoeba histolytica. Furthermore, B. vulgaris encapsulated within EPO showed IC₅₀ of 26 ppm in comparison with the free extract having IC₅₀ of 34 µg/mL. The IC₅₀ of Curcuma longa loaded within EPO was found to be 19 ppm in comparison with the free extract having IC₅₀ of 38 µg/mL ^[81]. Another group of researchers used cerium oxide nanoparticles encapsulated with Nelumbo nucifera flower extract against the human colon cancer cell line (HCT 116), exhibited IC₅₀ of 4.16 mg/mL ^[81]. Garcinia mangostana has been widely used for medical applications. G. mangostana extract loaded within ethylcellulose and methylcellulose nanoparticles proved a highly protective agent for stomach ulcers with a MIC value of 6.25 ug/mL against Helicobacter pylori, which is almost the same as metronidazole. A study done by Saravanakumar and team found that silver nanoparticles encapsulated with Toxicodendron vernicifluum extract were effective against enteropathogenic bacteria, E. coli and H. Pylori, with MIC 8.12 µg/mL and 18.14 µg/mL. Acorus calamus Lim extract loaded within silver nanoparticles has shown significant inhibition in the formation of H. pylori at a concentration of 350 µg/mL. Metallic nanoparticles demonstrated promising results in inhibition of enteropathogenic bacteria in various studies. Gold nanoparticles loaded with extracts of Tribulus terrestris showed effective activity against H. pylori in a size-dependent manner, with MIC of 16.75 µg/mL at 55 nm and MIC of 18 µg/mL at 7 nm size of gold nanoparticles, respectively ^[81] (Figure 2; Table 2).

Figure 2. Encapsulation of bioactive compounds from various herbal extracts with silver, gold, cellulose, and polymeric nanoparticles to improve delivery in the gastrointestinal tract, and to prevent or cure various diseases. The figure was made with www.biorender.com (access date: 12 January 2022) and adapted from DOI: 10.3390/nano12020238.

Table 2. Nano-phytopharmaceuticals for therapeutic applications in GI disorders.

Nanoformulation	Phyto-Pharmaceutical	Enteropathogen/GI Cell Lines; IC₅₀/MIC	Reference
Polymeric (EPO)	Berberis vulgaris	Entamoeba histolytica; 26 ppm	^[81]
Polymeric (EPO)	Curcuma longa	Entamoeba histolytica; 19 ppm	^[81]
Polymeric (Cerium oxide)	Nelumbo nucifera	Human colon cancer (HCT 116); 4.16 µg/mL	^[81]
Cellulose (Ethyl)	Garcinia mangostana	Helicobacter pylori; 62.5 µg/mL	^[81]
Metallic (Silver)	Toxicodendron vernicifluum	Helicobacter pylori; 18.14 µg/mL	^[81]
Metallic (Silver)	Toxicodendron vernicifluum	E.coli; 8.12 µg/mL	^[81]
Metallic (Gold)	Tribulus terrestris	Helicobacter pylori; 16.75 µg/mL	^[81]

Apart from benefits, NPs showed adverse events, such as selenium and selenite nanoparticles in mice (2 or 4 mg/kg body weight daily) treated over a period of 15 days which showed more toxicity (growth suppression, increased liver toxicity, and reduced superoxide dismutase activity) in selenite NPs ^[82].

Nanotechnology is a vital tool for its applications in medical science, given that it is possible to obtain a variety of nanocarrier characteristics that include their constituents, size, shape, bioavailability, surface properties, and target specificity to achieve or enhance desirable pharmacological targets ^[81]. A number of strategies have been implemented to increase the drug-target specificity. Recently, several studies have reported the improved efficacy of herbal extracts for gastrointestinal disorders when associated with nanomaterials mainly due to oral absorption, greater stability, and simulated intestinal fluid ^[3]^[4]. Pure herbal medicines are often considered less effective in comparison due to their size and reduced intestinal absorption when administered orally. However, plant extracts loaded on nanoparticles are more stable in high protein environments and help to increase target specificity ^[4]. Solubility is always considered a major concern associated with plant extracts, which can be successfully upgraded using nanosystems ^[82]. These are the reasons behind a pharmacological loss associated with plant extracts and such problems can be overcome using novel drug delivery systems such as nanotechnology. The advantages of using these novel delivery systems include better absorption by smoothing diffusion through the epithelium, modification of pharmacokinetics, enhancement of intracellular penetration, and distribution with reduced toxicity, overcoming resistance and lowering cost. Nanoparticles are stable in harsh conditions like sterilization temperatures ^[82].

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