Introduction
Herbal sources contain a variety of bio-actives, which are also called phytochemicals. Many of the herbal bio-actives have therapeutic effects and distinguished chemical properties that allow them to be favorable candidates for phytomedicines. For example, compared to the synthetic active pharmaceutical ingredient, herbal bio-actives carry a larger number of chiral centers in their structures, which makes them sterically more complex and inflexible molecules. The inflexibility increases the receptor-binding ability of the molecules, which gives them more stereospecific biological activity and makes them favorable for medicinal use. Furthermore, herbal molecules contain a higher amount of oxygen and nitrogen atoms rather than synthetic drug molecules. This makes their ability to make hydrogen bonds with receptors better and as a result, increases the affinity and efficacy of the medicines (1,2).
The history of traditional herbal medicines, which are the precursors of phytopharmaceuticals, dates back to ancient times. The usage of herbal sources as healing remedies goes back to the ancient era in China, India, Egypt, Europe, Latin America, and Africa. Since then, many advances have been made in the field of herbal medicine. From the 15th century till the early 19th century, evolutions in phytomedicine reached their peak. Many books that were written in different languages were published, classification and naming systems were developed, and many important herbal active substances were isolated (1-3). Nowadays, many of the officially approved and widely used medicines are produced by isolating phytochemicals from herbal sources, which were used centuries ago, such as morphine, guaifenesin, and digoxin. In recent years, the importance of phytochemicals in modern drug research and development has increased with the use of molecular docking programs to determine biological target binding affinities and interactions. Moreover, it is indicated that around 50% of the current medicines are made from natural resources and over one-third of all new molecular entities are from natural sources and their byproducts (4,5).
Although traditional pharmaceutical dosage forms such as tablets, capsules, syrups, solutions, decoctions, and ointments are still used today, problems related to the absorption, biotransformation, and stability of phytochemicals reduce the efficacy, bioavailability, and in some cases safety of herbal medicines (6). Conventional pharmaceutical dosage forms are also providing an immediate release of phytoconstituents in general. However, the use of advanced drug delivery systems offers advantages to overcome mentioned problems and they also provide extended release with maximum efficacy associated with minimum side effects. Research on the development of herbal formulations by using novel drug delivery systems and the use of nanotechnology-based systems have gained special attention. One of the nano drug delivery systems is nanofibers, which have unique properties and are widely used in the treatment of different diseases such as infections, allergies, rheumatic diseases, inflammatory diseases and cancer (7). Studies to formulate novel drug delivery systems which use new technologies like nanotechnology are still taking place in many places around the world. Some of the recently developed drug delivery systems are nanogels, nanotubes, nanomicelles, microcapsules, nanoparticles, microemulsions, liposomes, niosomes, transfersomes, phytosomes, nanosuspensions, nanofibers, etc. These systems are used to deliver one or more active pharmaceutical ingredients or phytoconstituent with different new pharmaceutical dosage forms such as transdermal systems, buccal or mucoadhesive systems, oral or ocular systems, etc. (8).
In this review article, the use of the nanofiber-based drug carrier systems to deliver herbal bio-actives through various administration routes will be given with the examples of recent studies.
Nanofibers as Drug Delivery Systems
Nanofibers are structures with a diameter smaller than 1,000 nm. Because of having large surface area, high porosity, and being flexible, they are preferred in many applications including drug research and development, drug delivery, burn and wound healing, and tissue engineering. With 3D printing of electrospun nanofibers, models such as neural, mucosal, blood-brain barrier and tumor tissue models that stimulate physiological and pathological tissues can be produced , which have a huge potential to improve in vivo simulated tests in drug development studies (9). Additionally, nanofibers play an important role in the field of regenerative medicine, which can recover important tissues such as heart, blood vessels, nerves, bones, cartilages, tendons, and joints. This is possible with the combination of 3D printing and electrospinning techniques to form biomimicking nanofiber scaffolds and patches loaded with stem cells (9,10).
The unique specifications of nanofibers have made them widely used in treatment of different diseases such as infections, allergy, hypertension, rheumatic diseases, inflammatory autoimmune diseases, diabetes, intracranial aneurism, Alzheimer’s, cardiovascular diseases, gastrointestinal diseases, AIDS, and cancers (11,12).
Mechanical properties of nanofibers such as high surface area-to-volume ratio, high porosity, amorphous structure, and flexibility make them useful materials for designing different drug delivery systems (9).
Nanofibers may enhance drug dissolvability. The bioavailability of drugs is directly related to their solubility and dissolution rate (13). Unfortunately, most of the novel drugs are in a lipophilic character which means that they have low water solubility and as a result low bioavailability. To solve this problem, drugs can be loaded into nanofibers produced from water soluble polymers. Due to their high surface area and porosity, the dissolution rate of the drugs may increase significantly (13,14).
Among all advantages, the adjustable properties of nanofibers may be their most important feature. Nanofibers can be designed by modifying their production parameters for controlling polarity, fibers diameter, porosity and nanofiber mat thickness to fit any drug delivery requirement (12,13).
One more advantage is the high loading capacity of nanofibers and their modifiable release ability (14). Drug release is adjusted depending on drug loading methods. Some of these methods are co-electrospinning of drugs and polymers, surface immobilization of the drug on nanofibers, sheath, co-axial and layer-by-layer nanofibers. The most suitable method must be chosen according to the purpose of the medication because this affects the drug release process (15). For example, while the co-axial electrospinning method is used to release drugs immediately, matrix-type nanofiber, Core-shell nanofiber, and sandwich technologies may be used to produce prolonged-release nanofibers (13).
There are various methods to prepare nanofibers and between them, the electrospinning method is the most favorable nanofiber production technique. The other widely used methods can be given as drawing method, template synthesis, phase separation, self-assembly, etc. (16). Electrospinning is a method of producing nanofibers by exposing polymer solution to electrostatic energy, which stretches the polymer and reaches the nanoscale (17). The electrospinning system consists of 4 main parts: syringe pump, power source, needle, and collector (18). While the solution is slowly pumped from the syringe through the needle, the solution surface is electrically charged because of the high electric field in the needle. Due to this charge, the surface tension force of the solution is overcome and as a result, a filament occurs. This filament continuously spins and stretches till it reaches the collector surface where nanofibers are collected (19). The properties of the formed nanofibers may be affected by many parameters such as voltage, needle tip-to-collector distance, molecular weight of the polymer(s) and the flow rate, viscosity, surface tension, and the conductivity of the solution (20). By adjusting these parameters, the properties of the nanofibers can be easily designed to have any intended purpose (21). Morphology of the fibers can also be controlled by the selection of polymer(s) to make many types of nanofibers. Besides being a cost-effective method, the versatility and flexibility of this process make electrospinning the most favored method to produce nanofibers (19).
Nanofiber-based Herbal Drug Carrier Systems for Different Delivery Routes
Nanofiber drug carrier systems can be used to deliver active pharmaceutical ingredients through various routes such as topical, transdermal, oral, and transmucosal routes. Taking advantage of natural substances for mostly their antimicrobial, antioxidant, anti-inflammatory, and wound healing activities and nanofibers with unique properties, a variety of research took place to investigate nanofibers incorporated with natural substances for drug delivery applications. The schematic representation of nanofiber-based herbal drug carrier systems via various drug delivery routes is given in Figure 1. Herbal drugs incorporated nanofiber-based carrier systems according to different delivery routes are summarized in this part.
Topical/Transdermal Drug Delivery Route
Topical drug delivery is a local route applied topically to treat skin diseases like bacterial, fungal, and viral infections such as eczema and psoriasis. Transdermal drug delivery differs from topical delivery by being suitable for both local and systemic delivery types. After applying the drug onto the skin, it diffuses through skin layers until reaching blood vessels and joins systemic circulation (22). In the transdermal drug delivery route, the drug does not undergo the first pass metabolism effect of the liver. However, the main challenge of this route is the stratum corneum barrier of the skin. Therefore, nanofiber based drug carrier systems can be used to enhance transdermal drug delivery (23).
Curcumin is a polyphenolic flavonoid that is obtained from the rhizomes of Curcuma longa (turmeric) and has various therapeutic benefits such as anti-inflammatory, antimicrobial, antioxidant, anticancer, antiaging, antidiabetic, and wound healing effects. For this reason, it has been the topic of many recent studies including topical and transdermal delivery (23). Sampath et al. (24) investigated curcumin incorporated poly(lactic-co-glycolic acid) nanofibers to treat squamous carcinoma, which is one of the most deadly skin cancers. In vitro release and cell viability studies showed that curcumin incorporated nanofibers had prolonged drug release without initial burst and good anticancer activity against squamous carcinoma cell lines. In another study, curcumin was incorporated into cellulose acetate phthalate electrospun nanofiber transdermal mats by Ravikumar et al. (25). It was shown that the prepared formulations controlled in vitro transdermal delivery of curcumin for up to 24 h. Also, Ariamoghaddam et al. (26) evaluated curcumin incorporated gelatin/albumin and PVA nanofibers as transdermal anti-obesity patches. More than 50% of the loaded curcumin was released from the nanofibers after 20 hours and curcumin patches were effective in obesity treatment according to the in vivo studies on rats. Tetrahydro curcumin is the major metabolite of curcumin which has similar pharmacological properties with curcumin but is more polar. Ravikumar et al. (27) prepared tetrahydro curcumin into poly(e-caprolactone)/poly(ethylene glycol) composite electrospun nanofibers and evaluated its in vitro drug release properties. It was demonstrated that the prepared nanofibers released the herbal drug according to the Higuchi kinetics model of diffusion mechanism with case II relaxation behavior and anomalous transport for 24 h and it was considered as ideal transdermal patches with the application once daily.
Acne vulgaris is a chronic skin inflammation caused by Propionibacterium acnes infection associated with oily skin caused by over release of sebum. Side effects like skin irritation related to drugs used in the treatment of acne vulgaris require advanced pharmaceuticals. In this regard, Tang et al. (28) developed a combination of extracts that incorporated poly(vinyl alcohol)/chitosan nanofibers. Houttuynia cordata, Portulaca oleracea and Centella asiatica extracts were used to inhibit Propionibacterium acnes, reduce inflammation, and hydrate the skin, respectively. This combination exhibited good antibacterial activity against Propionibacterium acnes and the produced nanofibers showed a rapid efficiency in mild-to-moderate facial acne in a short-term clinical study.
Herbal bio-actives are frequently used for wound or burn healing applications. Propolis is a resinous product collected by honeybees (Apis mellifera) from various plant sources, which has antibacterial, antifungal, and antioxidant activities. It was incorporated into poly(lactic acid) nanofibers to enhance its pharmacological activities and bring moisturizing and breathability properties to the wound dressings by Sutjarittangtham et al. (29). While the prepared formulation was able to inhibit Proteus mirabilis and Escherichia coli at the concentration of 4% (w/v), it was able to suppress Staphylococcus aureus and Staphylococcus epidermidis at 2% (w/v) concentration. Jin et al. (30) compared efficiencies between polycaprolactone nanofibers loaded with Indigofera aspalathoides, Azadirachta indica, Memecylon edule or Myristica andamanica extracts as wound dressings. The results showed that Memecylon edule loaded nanofibers exhibited the best metabolic activation in human dermal fibroblasts proliferation assay with the least cytotoxicity. In another study, Sadri et al. (31) found that chitosan/poly(ethylene oxide) nanofibers incorporated with green tea leaf (Camellia sinensis) had high potential as a wound dressing. Besides their good antibacterial effect against Escherichia coli and Staphylococcus aureus strains, these nanofibers have moisturizing, breathable, and highly stable properties, which are suitable for wound healing. Henna (Lawsonia inermis) is also one of the herbal drugs which is useful for wound healing due to its antibacterial, antifungal, antioxidant, anti-inflammatory and analgesic activities. In this regard, Yousefi et al. (32) incorporated henna into chitosan/ poly(ethylene oxide) nanofibers to obtain better wound healing results from Lawsonia inermis extract. It was demonstrated that henna nanofibers were biocompatible and had good in vitro antibacterial activity and accelerated wound healing in in vivo studies. Also, Hajilou et al. (33) prepared a wound dressing from Gamma oryzanol extract incorporated into poly(e-caprolactone)/chitosan nanofibers. Gamma oryzanol is a crude rice bran oil extraction with antioxidative, antiinflammatory, and antibacterial activities. In vitro studies suggested that the prepared dressings had the ability to suppress bacteria, enhance collagen deposition and accelerate wound healing which made it suitable as a wound dressing.
Pineapple (Ananas comosus) contains a substance namely bromelain, which has a burn healing effect. Bayat et al. (34) loaded bromelain into chitosan nanofibers and investigated the physicochemical properties and release profile of this delivery system. Chitosan-2% (w/v) bromelain nanofibers were found to be effective in burn injuries with good physicochemical properties and release profile as well as low cytotoxicity. In another study, Motealleh et al. (35) prepared poly(e-caprolactone)/polystyrene nanofibers loaded with Chamomilla recutita (L.) Rauschert extract. Due to the major active substance of chamomile, apigenin, the formulation showed good antibacterial activity against Staphylococcus aureus and antifungal activity against Candida albicans. Moreover, 15% of chamomile-loaded nanofibers reached about 90% of cell proliferation efficiency and gave 10 times better results than unloaded nanofibers. Moreover, in vivo studies showed that the nanofibers could treat up to 99±0.5% of wounds in 14-day duration.
Capsaicin is a chemical found in peppers and used as a temporary analgesic for muscle and joint pain. Capsicum extract was loaded into poly(vinyl alcohol) or cellulose acetate nanofibers and in vitro drug release, skin permeation, and cytotoxicity characteristics were investigated. Compared to cellulose acetate, poly(vinyl alcohol)-based nanofibers showed better release and skin permeation properties. MTT assay results showed a small decrease in the cell viability via drug loading when compared to blank nanofibers (36).
Blumea balsamifera, or in its other name sambong, was used for centuries in some South-eastern countries as a remedy for different skin diseases such as eczema, beriberi, dermatitis, etc. In a study, Badshah et al. (37) produced electrospun cellulose acetate nanofibers loaded with sambong oil to investigate its wound healing properties. The results confirmed that sambong oil loaded nanofibers had good cell viability and antibacterial activity but inadequate antioxidant properties. Lavender oil majorly contains the compounds linalool and linalyl acetate, which has antibacterial, anti-inflammatory, and antifungal pharmacological effects. Sofi et al. (6) incorporated polyurethane nanofibers with lavender oil and silver nanoparticles. The prepared nanofibers with concentrations of 15% lavender oil and 5% silver nanoparticles exhibited good in vitro antibacterial activity against Escherichia coli strains. Plai (Zingiber Cassumunar Roxb.) has been used extensively as a traditional herbal medicine due to containing antimicrobial, anti-inflammatory, antioxidative and analgesic substances. To improve its efficacy in topical medicines, cosmetics, and skincare products, Tonglairoum et al. (38) prepared Plai oil incorporated poly(vinyl pyrrolidone) nanofibers. In vitro release study showed that Plai oil was released from the nanofiber formulations rapidly at first, but then prolonged release was achieved up to 24 hours. In another study, Wongkanya et al. (39) loaded Plai (Zingiber cassumunar Roxb.) oil into electrospun poly(lactic acid) nanofibers and examined its properties using (E)-1-(3,4- dimethoxyphenyl) butadiene (DMPBD) as a marker. DMPBD is a compound found in Zingiber cassumunar Roxb., which is exhibiting anti-inflammatory activity. In vitro release characteristics and skin penetration and irritation properties were tested. Of DMPBD 80% was released from the nanofibers after 12 hours and 50% of DMPBD permeated through the skin due to the highly lipophilic nature of the substance. Also, Plai oil nanofiber patches did not show any skin irritation.
A food waste, watermelon (Citrullus lanatus) peel extract, was formulated as poly(vinyl alcohol) nanofibers to investigate antioxidant and antibacterial effects. The results revealed that watermelon peel extract incorporated nanofibers had better antimicrobial activity against both Escherichia coli and Staphylococcus aureus strains compared to watermelon peel extract itself. Furthermore, the prepared nanofibers were found to have a 22% enhanced antioxidant activity with a sustained release rate which could reach even 72 hours (40). Also, Lin et al. (41) used green electrospinning to produce poly(ethylene oxide) nanofibers loaded with grape seed extract, which had good antioxidant activity. It was shown that the prepared nanofibers significantly enhanced the proliferation of the skin fibroblasts and protected them against oxidative stress, indicating that they were potential delivery systems to be used in tissue regeneration, wound healing, and cosmetics applications.
Colchicine is a natural substance found in Colchicum autumnale and Gloriosa superba L. It has cytotoxic effects and can be used efficiently in melanoma, which is the most fatal skin cancer. Morad et al. (42) loaded colchicine into electrospun poly(vinyl alcohol)/chitosan nanofibers to reveal its transdermal performance against melanoma. Both skin permeation and cell viability tests proved the effectiveness of colchicine transdermal nanofiber patches in melanoma management. In another study on the treatment of melanoma, acemannan polysaccharides of aloe vera mediated green synthesized titanium dioxide nanorods loaded resveratrol incorporated poly(vinyl alcohol) nanofibers were produced. By activating apoptosis-promoting caspase enzymes, this formulation exhibited enhanced selective cytotoxicity with fewer side effects (43). Agnes Mary and Giri Dev (44) evaluated the effects of aloe vera loaded nanofibers on the proliferation of human dermal fibroblasts. It was shown that aloe vera nanofibers resulted in a high proliferation rate without any cytotoxic effects. Depending on the results, it was suggested that aloe vera nanofiber scaffolds could be used in skin tissue engineering. In the other study, resveratrol, which was found in grapes and many other plants, was loaded into electrospun poly(vinyl pyrrolidone) and hydroxypropyl-b-cyclodextrin nanofibers to increase its solubility. The results revealed that the nanofiber formulations enhanced water solubility and skin penetration of the drug and exhibited good antioxidant and anti-inflammatory activities (45).
Vitamins are found in many natural nutrients and are used widely as supplementary products. Many studies were carried out to investigate vitamin delivery through the transdermal route to overcome the limitations such as solubility and absorption problems (45-48). Vitamin B12 in poly(e-caprolactone) based nanofibers, all-trans retinoic acid or vitamin A acid and a-tocopherol or vitamin E in cellulose acetate based nanofibers, ascorbic acid in poly(vinyl alcohol) based nanofibers and folic acid in poly(vinyl alcohol) based nanofibers were investigated for transdermal delivery and all of them showed promising results (49-52).
Oral Drug Delivery Route
Oral route for controlled drug release is usually used to release the drug slowly into the gastrointestinal tract and enable effective drug concentrations for a prolonged period of time (50). Nanofibers are advantageous as oral drug delivery systems due to the properties of improving drug solubility and reducing applied drug dose. Malik et al. (51) evaluated poly(lactic acid) nanofibers loaded with diacerein as a gastroretentive drug delivery system. The results demonstrated that the developed nanofibers exhibited zero lag time and approximately 61.3% of the herbal drug was released in 30 h, thus facilitating slow drug release with improved drug solubility.
Transmucosal Drug Delivery Route
Transmucosal drug delivery is another systemic and/or local drug application route. All tissues with mucosal membrane are parts of this route, including buccal, ocular, nasal, vaginal, and rectal administrations. The buccal route includes both oromucosal and sublingual applications. Because of the rapid absorption and high bioavailability of drugs in this route, it is commonly used for local and systemic drug delivery and is considered as an alternative to many oral drugs (52). Nanofibers are flexible, mucoadhesive, and stable in oral mucosa depending on the polymer type used in nanofiber production. Due to this, nanofiber-based drug carrier systems are applicable to the buccal cavity either as patches or scaffolds.
Fast dissolving nanofiber formulations composed of poly(vinyl alcohol) and D-a-tocopheryl poly(ethylene glycol) succinate were produced by Nam et al. (53) for oral phloretin delivery against oral cancers. The anticancer activities of phloretin were assessed in oral squamous cell carcinoma cells from the buccal cheek. The antiproliferation efficacy and apoptotic activity of the nanofiber formulations were significantly higher than that of the phloretin solution. Nam et al. (54) also developed poly(vinyl alcohol) and Soluplus based nanofiber mats for the delivery of Angelica gigas Nakai extract against oral cancers. The nanofiber formulations showed instant wetting (within 2 seconds) and rapid disintegration (within 3 minutes) properties compared to plain nanofibers, which could be used as a fast-dissolving mat for the treatment of oral cancers.
Tonglairoum et al. (55) developed herbal oil (betel oil or clove oil)-incorporated nanofiber mats with antifungal activity for the prevention and treatment of Candida-associated denture stomatitis. The herbal oils released from the nanofibers rapidly inhibited the growth of Candida species within only a few minutes after contact. Also, George and Varghese (56) formulated Ocimum sanctum (Tulsi), which had anti-inflammatory, antimicrobial, antioxidant, and anticancer properties in resorbable poly(vinyl acetate) nanofibers for local periodontal therapy. Then, George et al. (57) evaluated the therapeutic effectiveness of locally delivered electrospun Ocimum sanctum nanofibers in patients with periodontitis. Ocimum sanctum nanofibers were found to be beneficial in the reduction of interleukin-1b levels, which could be used as an adjuvant in the treatment of periodontitis. In another study, tara extract (Caesalpinia spinosa) was loaded into electrospun nanofibers made of poly(e-caprolactone) and the produced nanofiber membranes indicated a potential of therapeutic application for lesions such as prosthetic stomatitis (58). Moreover, for local drug delivery in bone tissue engineering applications, graphene oxide and zinc-curcumin complex were loaded into coaxial electrospun nanofibers. The shell of the coaxial nanofibers included a blend of carboxymethyl chitosan, poly(vinyl alcohol), and graphene oxide. The prepared nanofibers enhanced the osteogenic performance and had an important antibacterial activity and thus reduced postoperative infections (59). In another study, Zadegan et al. (60) developed silk fibroin nanofibers containing Urtica dioica L. (nettle) extract at different concentrations. The prepared nanofibers released nettle in a controlled manner via Fickian diffusion and exhibited osteoblast differentiation in a dose-dependent manner.
Conclusions and Future Perspectives
In conclusion, as a part of nanotechnology, nanofibers have various application alternatives in the medical field, especially promising in drug delivery and regenerative medicine. Due to the high surface area and porosity and also the high drug loading capacity, nanofibers have gained great attention in drug release studies. Although herbal bio-actives have been widely used in various forms of products, most of them have the problems of low stability or water solubility, which can be overcomed by formulating them in nanofiber-based drug carrier systems. For example, resveratrol has increased water solubility in nanofiber formulations, and this enables skin penetration and its activity. Also, extended release can be obtained to enable effective drug concentrations for a prolonged period of time by using nanofibers. This is advantageous especially for oral drug delivery systems in terms of improved drug solubility and reduced applied drug dose in phytopharmaceuticals such as diacerein loaded nanofibers. Although herbal bio-actives including nanofibers have been used mostly in topical/transdermal systems, their use via transmucosal routes such as buccal, ocular, nasal, vaginal, and rectal administrations have increased considerably in recent years. Herbal oils such as clove oil and herbal extracts such as tara extract are widely used via these routes based on the fast-dissolving properties of nanofibers and thus increasing activity. In the light of the previous overviewed studies, nanofibers are promising nanocarriers for the development of phytopharmaceuticals in various drug delivery routes.
Peer-review: Externally peer reviewed.
Authorship Contributions
Concept: İ.E-G., L.A., E.A.Y., E.E., D.B., R.K.S., Design: İ.E-G., L.A., E.A.Y., E.E., D.B., R.K.S., Data Collection or Processing: İ.E-G., L.A., E.A.Y., E.E., D.B., R.K.S., Analysis or Interpretation: İ.E-G., L.A., E.A.Y., E.E., D.B., R.K.S., Literature Search: İ.E-G., L.A., E.A.Y., E.E., D.B., R.K.S., Writing: İİ.E-G., L.A., E.A.Y., E.E., D.B., R.K.S.
Conflict of Interest: No conflict of interest was declared by the authors.
Financial Disclosure: The authors declared that this study received no financial support.