|Year : 2022 | Volume
| Issue : 6 | Page : 747-764
Plant-derived compounds for the treatment of schistosomiasis: Improving efficacy via nano-drug delivery
AA Eze1, MO Ogugofor2, EC Ossai3
1 Department of Medical Biochemistry and Molecular Biology, Faculty of Basic Medical Sciences, College of Medicine, University of Nigeria, Enugu Campus, Enugu, Nigeria
2 Department of Chemical Sciences (Biochemistry Programme), Coal City University Enugu, Enugu State, Nigeria
3 Department of Biochemistry, Faculty of Biological Sciences, University of Nigeria, Nsukka, Enugu State, Nigeria
|Date of Submission||16-Mar-2021|
|Date of Acceptance||12-Apr-2022|
|Date of Web Publication||16-Jun-2022|
Dr. E C Ossai
Department of Biochemistry, Faculty of Biological Sciences, University of Nigeria, Nsukka, Enugu State
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Schistosomiasis is a neglected infectious tropical disease that is second in occurrence only to hookworm infection in sub-Saharan Africa. Presently, chemotherapy is the main method of control and treatment of this disease due to the absence of a vaccine. However, Praziquantel, which is the only chemotherapeutic option, lacks efficacy against the early developmental stages of schistosomes. A number of plant-derived compounds, including alkaloids, terpenes and phenolics, have displayed in vitro and in vivo efficacy against Schistosoma species. This review explores how the application of nanotechnology can improve the efficacy of these plant-derived schistosomicidal compounds through the use of nano-enabled drug delivery systems to improve bioavailability.
Keywords: Chemotherapy, efficacy, nano-drug delivery, plant-derived compounds, praziquantel, schistosomiasis, schistosomicidal
|How to cite this article:|
Eze A A, Ogugofor M O, Ossai E C. Plant-derived compounds for the treatment of schistosomiasis: Improving efficacy via nano-drug delivery. Niger J Clin Pract 2022;25:747-64
|How to cite this URL:|
Eze A A, Ogugofor M O, Ossai E C. Plant-derived compounds for the treatment of schistosomiasis: Improving efficacy via nano-drug delivery. Niger J Clin Pract [serial online] 2022 [cited 2022 Jun 28];25:747-64. Available from: https://www.njcponline.com/text.asp?2022/25/6/747/347598
| Introduction|| |
Schistosomiasis is a tropical helminthic infection with distinct acute and chronic phases, propagated by trematode worms of the genus Schistosoma, with at least 90% of the infected subjects living in Africa. Reports place the global number of infections at over 97 million with a total of about 291 million subjects at risk of being infected in about 78 countries. Schistosomiasis manifests as either the intestinal or the urogenital infection that are together caused by five main species of Schistosoma, namely S. mansoni, S. japonicum, S. mekongi, S. guineensis (and related S. intercalatum) for intestinal schistosomiasis, and S. haematobium for urogenital schistosomiasis. Human-to-snail transmission is initially brought about through the infection of species-specific freshwater snails by miracidia produced from schistosome eggs deposited with stool or urine into the freshwater habitat. Ultimately, the snail-to-human transmission is propagated by larval cercariae shed by infected snails; these cercariae burrow through the skin to mount an infection in the human host.
The methods for schistosomiasis detection come under three groups, namely, microscopic, serologic and molecular methods. Urine and stool microscopy are still the reference diagnostic methods for the detection of urogenital and intestinal schistosomiasis, respectively, because these methods do not require a high level of infrastructural support and are hence cheap and easy to use. On the other hand, the sensitivity of microscopic methods for schistosomiasis diagnosis is directly proportional to the disease burden. Hence, false-negative results are common for subjects with low disease intensity, as is the case in the early stages of schistosomiasis. Serologic tests are useful for the detection of schistosome infections in non-endemic regions, but may not detect fresh infections where the antibody response by the host is yet to be mounted. On the other hand, infections by closely related Cestode worms could result in significant false-positive tests. For diagnosis in endemic regions, where circulating host antibodies from past infections could cause false-positive tests, serologic testing needs to be superseded by a confirmatory test. Conversely, adult schistosome antigens can be detected and levels are estimated in serum as the circulating anodic antigen (CAA) and in urine as the circulating cathodic antigen (CCA). It, however, takes about 5–6 weeks after S. mansoni infection for either CAA or CCA to build up to detection levels. The concentration of the CCA was found to correlate with the magnitude of S. mansoni infection,, hence circulating antigens can potentially be monitored to check the efficacy of treatment during chemotherapy.,, An up-converting phosphor-lateral flow circulating anodic antigen (UCP-LF CAA) assay was found to be more sensitive than the point-of-care circulating cathodic antigen (POC CCA); however, both circulating antigen methods were more sensitive than the Kato Katz method for S. mansoni detection. Finally, molecular diagnosis of schistosomiasis depends on polymerase chain reaction (PCR) amplification of parasite genes which gives accurate parasite detection. Real-time PCR performed on DNA isolated from urine samples was more sensitive in S. haematobium detection than urine microscopy. Diagnosis of schistosomiasis can be carried out using a number of DNA-amplification techniques including the isothermal methods, namely the loop-mediated isothermal amplification and the recombinase polymerase amplification which do not require the thermal cycler nor the electrophoresis of amplicons. The strengths and limitations of the different DNA-amplification methods in schistosomiasis detection are set out in a recent review. In the absence of an antischistosomal vaccine, the control of Schistosoma depends on chemotherapy supported by sensitive detection assays. Presently, the chemotherapeutic options against schistosomes are quite limited and need to be improved. This review discusses one of the approaches to improve schistosomicidal chemotherapy, namely the application of nano-drug delivery to plant-derived drug candidates.
| Chemotherapeutic Control of Schistosomiasis|| |
Praziquantel is the chemotherapy of choice and the only approved drug for use against Schistosoma. It is the prevailing agent for both preventive chemotherapy and the treatment of schistosomiasis infections in endemic regions of the world. Praziquantel is administered as a 40 mg/kg single-dose therapy, and is active against all the species of Schistosoma while its predecessors, oxamniquine and metrifonate, are active against individual Schistosoma species, S. mansoni and S. haematobium, respectively. Nilutamide, an antiandrogen agent used for cancer treatment, displayed high activity against S. mansoni when administered as a single-dose oral therapy. This high activity was, however, achieved with relatively high doses of nilutamide ranging from 100 to 200 mg/kg even when administered in combination with praziquantel, and S. mansoni was not killed at 50 mg/kg of the drug. The artemisinins, including artemether and artesunate, are efficacious against all Schistosoma species. Artemether (at 400 mg/kg) and mefloquine (at 200 mg/kg) were found to be bioactive against juvenile S. mansoni in immune-compromised mice. Hence, these antimalarials can be potentially utilized in combination therapies against schistosomes. One potential practical problem that could arise from employing the artemisinins as anti-schistosomes is the selection of artemisinin-resistant Plasmodium parasites. However, their present use as antimalarials in schistosome-endemic regions should also be beneficial to the control of schistosomiasis. Praziquantel performed better against schistosomes than the combination of artesunate, sulfalene and pyrimethamine, thus justifying its continuous use irrespective of the shortcomings including lack of efficacy against immature stages of schistosomes as well as reports of resistance. New drugs are therefore urgently needed which would among other things be efficacious against both the juvenile and the adult stages of schistosomes, with mild or no side effects.
| Plant-Derived Compounds with Activity Against Schistosomes|| |
A number of structurally diverse therapeutic agents have been sourced from natural products and their derivatives. Natural products or secondary metabolites are chemical substances or compounds obtained from living organisms. They are called secondary metabolites because they are the products of secondary metabolism, and thus are not directly implicated in the growth, development and reproduction of an organism. Natural products of plant origin are normally found in the leaves, bark, stem or root of the plant. Some of the natural products of plant origin include alkaloids, phenolic compounds, flavonoids, terpenoids, tannins, saponin and steroids. Most of them have been reported to possess several medicinal properties and are responsible for the medicinal properties of several plants.
Plants with schistosomicidal activities
Solanum nigrum L. is a plant that belongs to the Solanaceae family [Table 1]. It is widely found in Europe, Asia, North America and Africa. S. nigrum L. is one of the largest and most variable species of the genus known as “Black Nightshade. Just like other Solanum species, S. nigrum is widely used as a medicinal plant in various countries. Some of its medicinal uses include hepatoprotective, antioxidant anti-inflammatory, cytotoxic, anticancer and anticonvulsant effects.,,, It was also found to have a significant and potentially useful molluscicidal activity.
A suppression of worm load by 98.2% was observed in mice pre-infected with S. mansoni cercaria after exposure to 25 ppm methanol S. nigrum green fruit extract for 30 min. The remaining worms could not lay eggs in the liver and intestine of the infected mice. However, a 100% reduction of worm load was observed at 50 ppm of the extract.
The ability of S. mansoni cercariae to infect mice was suppressed (expressed as a significant reduction in worm burden) following exposure to LC50 (25 mg/L) concentration of S. nigrum methanol extract. In addition, a significant decrease in hepatic and intestinal egg loads was observed. The observed schistosomicidal activity of S. nigrum corroborated previous in vivo studies that indicated a significant reduction in the number of worms per infected mouse after the administration of aqueous crude extract of S. nigrum leaves.
Rauwolfia vomitoria belongs to the family of Apocynaceae [Table 1]. The root bark and stem bark of R. vomitoria have aphrodisiac, astringent, antipsoric, abortive, cardiotonic, hypotensive, hemostatic, dysenteric, emetic, insecticidal, anthelmintic, diaphoretic, expectorant, vulnerary and febrifugic properties. In addition, the stem bark extract displayed an in vitro cercariacidal activity against S. mansoni which was attributed to the flavonoid constituents. R. vomitoria bark and stem extracts were also found to induce the depletion of motor activity and the death of fully matured S. mansoni worms after 120 h of in vitro incubation and also cause the uncoupling of all paired worms and wrecking of their tegument.
Millettia thonningii is a deciduous plant that belongs to the family of Papilionaceae [Table 1]. It is indigenous to tropical West Africa., M. thonningii is widely applied in traditional medicine for treating a number of ailments such as dysentery, diarrhoea, dysmenorrhoea, amenorrhoea, and as anthelminthic and analgesics for intestinal pains. Pretreatment with 10 mg/L M. thonningii chloroform extract effectively inhibited worm load after 30 min of exposure in post-infected mice. This schistosomicidal effect was attributed to the possible interference in the life cycle and development of S. mansoni in a mouse. Also, the efficacy of the dichloromethane extract of M. thonningii seeds against both the miracidia and cercariae of S. mansoni was found to be dependent on the concentration, resulting in 100% mortality of adult S. mansoni worms following exposure to 100 mg/L for 72 h. Moreover, 50 mg/L of the extract was able to paralyze three-quarters of the adult while uncoupling all paired worms. Two compounds, alpinumisoflavones and robustic acid, were identified as the schistosomicidal bioactive compounds in the dichloromethane extract. Alpinumisoflavones were found to exert stronger schistosomicidal activity against miracidia and cercariae of S. mansoni than the robustic acid. The inhibition of NADH dehydrogenase of the electron transport chain has been suggested as the possible mechanism of schistosomicidal activity of the dichloromethane extract, and bioactive compounds of M. thonningii.,
Tetrapleura tetraptera is a perennial tree that grows in the rainforest belt of West, Central and East Africa. T. tetraptera [Table 1] was shown to exert lower toxicity towards earlier developmental stages of S. mansoni than the adult worms. Aridan and aridanin are glycosides purified from T. tetraptera and found to break up the Schistosoma life cycle by its anti-cercariae, anti-miracidia and anti-mollusca effects. The incubation of S. haematobium with aridan at a concentration of 400 ppm showed a significant effect on both the miracidia and cercariae within 30 min of the incubation. In addition, oleanolic acid, an aglycone of aridan and aridanin, was suggested to be an important schistosomicidal bioactive compound in the plant extract. Aridanin at 0.25 mg/mL inhibited the formation of the cercariae of S. bovis and S. mansoni in snails that were hitherto shedding cercariae. In addition, pretreatment of the cercariae of S. mansoni or S. bovis with aridanin or aridan significantly reduced the number of worms subsequently recovered from the infected mice.
Echinops kebericho is an erect massive rootstock-bearing perennial herb that grows up to a height of 1.2 m belonging to the genus Echinops. It is known to contain some secondary metabolites like alkaloids, polyphenols, saponins, phytosterols, carotenoids, lignans, sesquiterpene alcohols, acetylenic and thiophene compounds, and essential oil. Significant reductions in egg count and worm burden were observed in the mice that received the graded doses of the 70% ethanol extract of Echinops kebericho compared against the tween 80 treated positive control. Also, significant reductions in faecal egg count of 64.44%, 42.96% and 26.82% were observed in mice that received 1200, 600 and 300 mg/kg/day, in that order. Furthermore, a reduction in worm burden of 65.71, 47.86 and 31.43% at the different doses was observed. The high egg reduction was attributed to lower worm recovery due to the death of the adult worms or reduced fecundity of female worms already present.
Miconia willdenowii is a plant of the family Melastomataceae that has been identified as a promising bioactive source of schistosomicidal compounds. The ethanol extract of this plant at 200 μg/mL was found to kill about 65% of S. mansoni worms in a concentration-dependent manner, with 25–75 μg/mL concentrations giving rise to 50% mortality of the worms. Moreover, the hexane fraction of M. willdenowii at 75 μg/mL caused the death of 80% of the worms, while 50 μg/mL of the same extract killed a quarter of the worms, indicating that the schistosomicidal bioactivity of the plant extract could result from non-polar bioactive compounds in the plant extract. Further purification of the hexane fraction of the plant extract revealed that the specific bioactive compound responsible for the observed schistosomicidal activity was primin. Incubation of S. mansoni with primin at various concentrations ranging from 5.0 to 28.0 μg/mL indicated that primin exerted a strong schistosomicidal activity in a dose-dependent manner, showing a comparable antischistosomal activity as 2 μg/mL praziquantel.
Malus domestica, Citrus limon and Allium cepa
The administration of the methanolic extract of M. domestica at 7 weeks post-infection (p.i) at 300 and 200 mg/kg caused a percentage worm reduction of 85.93 and 72.22%, respectively, in S. mansoni infected mice. Administration of 2 g/100 g b.w A. cepa mixed with a standard pelleted diet caused a significant reduction of liver and intestinal worm load, and percentage of immature ova in infected mice. On the other hand, administration of A. cepa extract at 500 and 300 mg/kg body weight gave a worm reduction of 72.59 and 58.52%, respectively, while C. limon at 200 and 100 mg/kg caused a reduced worm infection of 42.96 and 29.63%, respectively. In addition, the methanolic extracts were able to improve the host antioxidant system as reflected by increased glutathione reductase in the treatment groups, unlike the control group where the S. mansoni infection caused an imbalance between the host antioxidant system and free radicals' generation.
Curcuma longa and Nerium oleander
S. mansoni adult worms were killed following 24 h of in vitro incubation in not more than 100 μg/mL of Curcuma longa L. and Nerium oleander L. extracts. In addition, different organic extracts of C. longa indicated varied efficacies, with the highest schistosomicidal activity being exerted by the chloroform extract. Also, Curcuma longa significantly reduced both male and female S. mansoni worm burden when administered either 1- or 4-week post-infection.
Clerodendrum umbellatum poir leaves
Clerodendrum umbellatum is of the Lamiaceae family and is commonly found in Tropical Africa, Central America and Tropical Asia.
The average count of faecal S. mansoni eggs produced by infected mice treated with 80 and 160 mg/kg concentrations of the aqueous extract of C. umbellatum leaves was remarkably reduced by 75.49 and 85.14%, respectively, compared to the infected untreated mice. In addition, significant reductions of worm load by 52.05, 78.57 and 96.94% at doses of 100, 200 and 400 mg/kg in that order were observed after the treatment of infected mice with the different doses of the methanol fraction of Clerodendrum umbellatum leaves. Also, the egg count in the faeces, liver and intestine reduced significantly in the infected mice that received the graded doses of the extract.
Bioactive compounds with schistosomicidal activity
Alkaloids occur naturally in certain flowering plants and contain carbon, hydrogen and nitrogen. Some plant families like Solanaceae, Papaveraceae, Ranunculaceae and Amaryllidaceae [Table 1] are known to have varieties of alkaloids, many of which exert schistosomicidal effect against S. mansoni.
Epiisopilosine is one of the several alkaloids that have been reported to possess schistosomicidal activity. Epiisopilosine's mechanism of action has been attributed to high concentrations of serum antibodies against antigenic tegument proteins. Serum antibodies of mice interact with the surface membrane of Epiisopilosine-exposed adult worms, as was demonstrated for arachidonic acid. The schistosomicidal effect of Epiisopilosine on S. mansoni in mice was expressed as an exceptional drop in the egg count, which includes a rise in the number of both the immature eggs as well as the mature non-viable (dead) eggs. Moreover, Epiisopilosine was found to compromise the fertility of the worms by reducing the ability of female worms to lay eggs; this ability to affect the fecundity of worms is an essential feature of an effective schistosomicidal lead compound. Also, the result revealed that treatment with 100 mg/kg of Epiisopilosine resulted in a decreased total worm count. Also, Epiisopilosine could have direct ovicidal action due to its ability to cause the mortality of several eggs.
The in vitro exposure to 3.125 μg/mL of Epiisopilosine caused the death of all exposed S. mansoni adult worms following 96 h of exposure. Mating and egg-laying were disrupted when adult worms were exposed to Epiisopilosine at concentrations higher than 1.5625 μg/mL, and a moderately reduced motor activity and alterations to the tegument were observed.
Piplartine is an alkaloid/amide from many species of the genus Piper (Piperaceae family) that shows strong promise as an anticancer agent. Piplartine was found to exert in vitro schistosomicidal efficacy against mature and immature stages of S. mansoni at submicromolar as well as a concentration-dependent morphological alteration in the tegument of parasites. Accordingly, a lone dose of 400 mg/kg piplartine was found to decrease the worm count by 60.4% in mice infected with S. mansoni while 200 mg/kg piplartine exerted a medium decrease on worm count of 50.3%.
Glycoalkaloid isolated from Solanum seaforthianum and Solanum macrocarpon
Glycoalkaloids from Solanum macrocarpon (LC50:7.6 ppm) exerted a higher schistosomicidal activity than those from Solanum seaforthianum (LC50:8.3 ppm). The mechanism of action of Solanum glycoalkaloids against schistosomes has been attributed to two basic features. These encompass the ability of the glycoalkaloids to bind the cell membrane components which results in loss of integrity and function disturbance of the cell membrane in the worm; it could also be due to the inhibitory action of glycoalkaloids on acetylcholinesterase enzyme in the worms., However, glycoalkaloids possessing chitotriose trisaccharide-like solamargine are normally more active than alkaloids containing the solatriose trisaccharide such as solasonine with respect to the disruption of cell membrane integrity and acetylcholinesterase inhibition.
Nerolidol (3, 7, 11-trimethyl-1, 6, 10-dodecatrien-3-ol)
Nerolidol is an aliphatic sesquiterpene alcohol contained in the essential oils of some plants. It has some industrial uses such as in the production of cosmetics and non-cosmetics products such as detergents., Some pharmacological effects of Nerolidol include antiulcer, antioxidant, antinociceptive, antimicrobial, antiparasitic and schistosomicidal activities. The incubation of S. mansoni with nerolidol at concentrations between 15.6 and 250 μM resulted in the separation of all the mature worm couples into single male and female worms as well as structural changes in the tegument of mature schistosomes, and the complete killing of all male mature worms at a dose of 62.5 μM following 48 or 72 h of exposure in vitro. The possible mechanism of the schistosomicidal activity of nerolidol could be related to its lipophilicity. The lipophilicity of nerolidol enables it to permeate the plasmatic membranes of the schistosome and hence may interact with intracellular molecules of parasites.,
Incubation of S. mansoni with dihydrocitronellol at a 10 mM dosage decreased the motility of the worms, and at 80 mM, dihydrocitronellol triggered complete parasite mortality in 24 h while 20 mM killed the worms in 120 h. During the interval of exposure to dihydrocitronellol, the schistosomes stayed paired with both male and female worms displaying high sensitivity to dihydrocitronellol schistosomicidal activity.
Parthenolide is a sesquiterpene lactone obtained from Artemisia absinthium and Tanacetum parthenium. Parthenolide at different concentrations of 50, 25 and 12.5 μM caused the 100% mortality of adult worms by inducing a morphological alteration of the tegument on the S. mansoni surface. The observed destruction of tubercles in the adult male worms by parthenolide was reported to be similar to those caused by other natural products including piplartine, (+)-limonene epoxide, cardamonin and licoflavone B. Incubation with parthenolide caused the separation of the male and female worms, thereby inhibiting the mating process and oviposition.
The possible in vitro schistosomicidal activity of parthenolide has been attributed to its chemical structure. Parthenolide, like other sesquiterpene lactones, is known to contain α, β-unsaturated carbonyl group such as an α-methylene-γ-lactone which could react with nucleophiles like sulfhydryl groups of cysteine., Schistosomal tegument and tubercles are known to possess several cysteine residues which could react with parthenolide, thereby resulting in morphological alterations and enzyme inhibition in the schistosome tegument., Moreover, parthenolide has been reported to cause alterations in the morphology of schistosomes as well as loss of plasma membrane integrity and mitochondria dysfunction.
Sclareol is a diterpenoid that displays schistosomicidal activity. A dose-dependent schistosomicidal activity was observed when different concentrations of sclareol were incubated with juvenile and adult S. mansoni, resulting in an inhibited production of the pathogenic eggs at the lowest concentration tested. An IC50 of 14.2 and 12.3 μM were recorded for the phenotype and motility loss, respectively.
Artemisinins are sesquiterpene lactones that contain endoperoxide bridges (C-O-O-C). They are isolated from three species of the genus, Artemisia; the commonest of which is Artemisinin annua L. A little quantity of artemisinins is present in Artemisinin apiacea Hance and Artemisinin lancea Vaniot., Artemisinins are readily soluble in most aprotic solvents and sparingly soluble in water. They break down in protic solvents, which could be attributed to the opening of the lactone ring. Even though the precise mechanism of schistosomicidal activity of artemisinins is not well described, heme-mediated cleavage of the endoperoxide moiety which initiates the formation of reactive oxygen species has been reported to play a significant role.
The most common artemisinin derivatives include artesunate, artemether and arteether. Artemisinin derivatives such as artesunate and artemether exert greater schistosomicidal activity on female worms compared to the males, thereby reducing the worm eggs count. The schistosomicidal activities of artemether and arteether were found to compare favourably to praziquantel. A Schistosoma susceptibility test of artemether using different developmental stages of S. japonicum in rabbits indicated a significant worm reduction of approximately 90% following treatment with a lone dose of 15 mg/kg b.w artemether.
Flavonoids are an important natural product commonly found in fruits, vegetables and certain beverages. They consist of a vast assembly of polyphenols possessing a benzo-γ-pyrone structure and are produced in the phenylpropanoid pathway. Flavonoids possess some important medicinal properties such as antioxidant, anti-inflammatory, antimutagenic and anticarcinogenic, and thus play an integral role in nutraceutical and pharmaceutical processes.
Eucalyptus camaldulensis flavonoid compounds
Flavonoids, including gallic acid, taxifolin, methyl gallate, quercetin, luteolin and hesperidin, have been identified as the possible bioactive compounds present in ethylacetate extract of E. camaldulensis. E. camaldulensis is a plant commonly used for the treatment of Schistosoma infections in folklore medicine. A 200 mg/L dose of 5 n-hexane/EtOAc (20:80 v/v) fraction of E. camaldulensis ethylacetate extract produced a 100% mortality in miracidia and cercariae following a 20 and 30 min of non-stop S. mansoni exposure, respectively. The schistosomicidal activity of the plant fraction was attributed to the inhibition of essential antioxidant enzymes in the worms. It could also be that the bioactive compounds induced a pro-oxidative effect or modulated important oxidants essential for sustaining cellular functions as well as physiological processes.
M. thonningii extract contains isoflavonoids that have been reported to exert schistosomicidal activity,, by inhibiting NADH dehydrogenase of the electron transport chain, hence suggesting that the mechanism of action might involve the obstruction of energy metabolism. However, the evaluation of schistosomicidal activities of the different fractions of the dichloromethane extract of M. thonningii showed that the alpinumisoflavones fraction was more efficacious than the robustic acid fraction on both miracidia and cercariae of S. mansoni. Alpinumisoflavones at a dose of 50 mg/L caused 100% mortality of the worms while 25 mg/L killed 90% of worms after 72 h exposure.
Essential oils are aromatic fluids obtained from distinct parts of plants, including the leaves, flowers, peels, buds, seeds and barks by techniques such as steam distillation and are useful as food flavors. Presently, essential oils are promising alternatives for praziquantel against S. mansoni.,
Lavandula angustifolia mill essential oil
Lavandula angustifolia mill is an aromatic, medicinal plant of the Lamiaceae family which is globally distributed., The essential oil extracted from L. angustifolia is useful in folk medicine for treating diverse diseases, with activities ranging from carminative, antiflatulence, anticolic and relaxant. In addition, this essential oil has been found to be a central nervous system depressant that acts as an anticonvulsant, spasmolytic agent, sedative, local anaesthetic, antioxidant, bactericidal and mast cell degranulation inhibitor., However, the gas chromatography–mass spectroscopy analysis of L. angustifolia essential oil revealed that monoterpenes (45.0%) such as borneol, epi-α-muurolol, d-bisabolol, precocene I and eucalyptol are the main constituents.
Incubation of adult S. mansoni with the essential oil from L. angustifolia at 200 μg/mL caused a 100% mortality of S. mansoni mature worms post 24 h. The in vitro LC50 values of this essential oil against adult S. mansoni worms at 24 and 120 h of exposure were 117.7 and 103.9 μg/mL, respectively. Minimal motor activities were observed in 75% of the mature S. mansoni worms exposed to 100 μg/mL of this essential oil for 24 h in comparison to the negative control (RPMI medium and 0.1% dimethyl sulfoxide added to RPMI medium).
Tanacetum vulgare L. essential oil
Tanacetum vulgare is a plant of the Asteraceae family and is generally useful in traditional medicine as a vermifuge and anti-inflammatory. The aerial parts of T. vulgare are useful in the treatment of migraine, neuralgia and rheumatism, and as an anthelmintic and insect repellent.
The incubation of adult S. mansoni with T. vulgare leaf extracted essential oil at 200 μg/mL and caused the death of all the adult worms after 24 h. Also, T. vulgare extracted oil at 50, 100 and 200 μg/mL and caused profound tegumental changes in adult worms after 72 h of incubation, with a 50% reduction in the worms' viability compared to the negative control.
A. cepa L. (RED ONION) essential oil
A. cepa belongs to the family Amarillydaceae and is widely known for its strong aromas and flavours. The medicinal properties of A. cepa bulbs and its essential oil include antioxidant, antibacterial, antimutagenic and antitumor., Profiling of schistosomicidal activities of A. cepa bulbs extracted essential oil indicated high schistosomicidal efficacy (25–75%) and shrinking rate (50–70%) at 500 μg/mL over a period of between 1 and 24 h of incubation. In addition, the butanol fraction of A. cepa methanol extract exerted strong schistosomicidal efficacy (25–50%) and the highest shrinking rate (25–75%) at 500 μg/mL over a period of between 1 h and 24 h.
Tetradenia riparia (Lamiaceae) essential oil
Tetradenia riparia (Hochst.) Codd. is a plant that belongs to the Lamiaceae family. It is commonly called false myrrh and is known to have aromatic properties as well as a number of medicinal uses. The plant extract and essential oil are useful in treating toothache and dental abscesses, malaria, pains and diseases caused by worms, bacteria and fungi., The incubation of S. mansoni with T. riparia essential oil profoundly decreased the motor activity of mature S. mansoni worms following 120 h of exposure. Incubation of S. mansoni with 100 μg/mL T. riparia essential oil caused 100% mortality of the worms.
| Available Nano-Drug Delivery Systems for Antischistosomal Drugs|| |
The advent of nanotechnology has generated a lot of interest in the scientific community towards the development of novel carrier systems composed of nanomaterials for the control, targeted release and improved bioavailability of bioactive compounds of pharmaceutical interests. Nano-drug delivery of schistosomicidal drugs has been employed to address the challenges inherent in the use of the free drugs, such as low bioavailability due to poor aqueous solubility, fast hepatic clearance, the incidence of drug resistance and adverse reactions. The two major drugs in use for the treatment of schistosomiasis are praziquantel and oxamniquine, the former being the most used due to its low cost and high therapeutic window of effectiveness against the adult forms of the three Schistosoma species. The younger worms of the parasites reside in systemic circulation and as a result, the efficacy of praziquantel on them is low due to their less exposure to the drug,, owing to its high metabolic rate to inactive or less efficacious compound after oral administration. With 2–3 weeks residence of the schistosomula in the liver between infection and maturation, high oral dose of praziquantel is usually recommended to mitigate the effect of first-pass metabolic clearance and to achieve efficacious levels in the larval tissues. Here, we discuss several different nano-drug delivery systems developed for the treatment of schistosomiasis.
Liposomes are spherical carrier systems made up of one or more layers of lipids capable of forming bilayer structure [Figure 1]. They are formed in an aqueous solution via the self-assembly of amphiphilic molecules., In 1988, praziquantel was encapsulated into liposomes for elucidation of the molecular mechanism of interaction between the drug and lipid membranes, spurring one of the first studies on the use of nanotechnology for schistosomiasis treatment. One year after, tartar emetic encapsulated into liposome under in vivo study was shown to prevent schistosomiasis infection compared to the free drug. The chemoprophylactic property of liposomal encapsulated praziquantel was also reported in mice, revealing hepatic targeting and sustained release of the drug. This resulted in a high survival rate and considerably lower amount of worms in the liver of mice treated with praziquantel encapsulated into liposomes compared to non-encapsulated drugs. About two decades ago, oxamniquine, the anthelmintic drug only active against S. mansoni, was encapsulated into liposomes with over 85% efficiency and when injected subcutaneously to a murine model a day before parasite infection, the number of parasites was reduced by 97%.
|Figure 1: Various nanodrug delivery systems for treatment of schistosomiasis. Note: Graphics are original|
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Tartar emetic encapsulated into stealth liposomes showed reduced toxicity of antimony and targeted delivery to S. mansoni parasites in mice. At an intraperitoneal dose of 11 mg Sb/kg, the liposomal-encapsulated tartar emetic showed a 55% reduction in parasite count compared to the control group. However, at an increased dose of 27 mg Sb/kg, the total parasitic reductions were 67 and 87% when the liposome-encapsulated tartar emetic was injected subcutaneously and intraperitoneally, respectively.
Praziquantel encapsulated into liposome formed from phosphatidylcholine was found to decrease egg count and parasite load of schistosome in mice compared to normal control. Similarly, it was demonstrated that oral treatment of mice with liposome-encapsulated praziquantel at 300 mg/kg 45 days after infection resulted in the reduction of parasite number by 68%, the egg number by 79% and the hepatic granulomatous number by 98.4% compared to controls. This was attributed to improved bioavailability of the drug encapsulated into a liposome, and targeted delivery of same to the liver leading to greater absorption of the drug by the parasite tegument owing to its high affinity to the liposomal phospholipids. The positive effect of liposomal praziquantel in mice was further improved in the presence of hyperbaric oxygen, which helped to stimulate the host's immune system against the parasite.
A two-phase system of non-miscible liquids of either oil-in-water (O/W) or water-in-oil (W/O) emulsion stabilized by amphiphilic molecules and with droplets size of about 200 nm constitutes nanoemulsion. It is a particulate system used mainly to improve the solubility and bio-accessibility of non-aqueous soluble drugs and bioactive molecules in which the compounds are encapsulated in small oil droplets dispersed in a large continuous aqueous phase.
Most schistosomicidal drugs are water-insoluble compounds, which limit their optimal utilization as pharmaceutical products. 2-(Butylamino)-1-phenyl-1-ethanethiosulfuric acid (BphEA) as a schistosomicidal agent was encapsulated into nanoemulsion droplets to improve its bioavailability and efficacy. The nanodispersion formed with droplet diameters ranging between 200 and 250 nm was able to kill female worms and decrease the mobility of male ones after incubation, unlike the free drug. The death of the worms was reported to have resulted from the binding of the negatively charged membrane of S. mansoni to the positively charged surfaces of the nanoemulsion droplets, leading to the unloading of the BphEA molecules into the worms. Similarly, aqueous dispersion of PZQ was improved 75-fold through the encapsulation into nanoemulsion formulated using soybean oil dispersed in the water phase. The nanoemulsion formed with a droplet size of about 400 nm was stabilized by sorbitan monooleate and polysorbate 80 (7:4 w/w) for 30 days.
Solid lipid nanoparticles (SLNs)
SLNs are lipid carriers with a solid lipid matrix whose melting temperatures are higher than room and body temperatures, and with size in the nanometric range [Figure 1]. They possess an advantage over liposomes and emulsions in their ability to protect the incorporated bioactive molecules from chemical degradation and more flexible sustained release properties of the incorporated materials.
SLN entrapping praziquantel was suggested as a promising carrier for the drug. The formulation of praziquantel-loaded SLN was reported to improve the oral bioavailability of the praziquantel significantly in rats compared to the free drug. The average residence time of the drug increased significantly after intramuscular, subcutaneous and oral routes of administration of the formulation, with the subcutaneous route having the highest residence time. In the same vein, the nanostructured lipid carrier of praziquantel was shown to enhance the efficacy and sustained release of the drug against S. mansoni compared to the free drug in an in vitro experiment. In addition, SLN entrapping praziquantel was reported to exhibit enhancement in intestinal worm death in less time and decreased cytotoxicity of the drug in HepG2 cells compared to the free drug. However, intestinal permeation of the drug in the formulation was lower than that of the free drug due possibly to the size of the formulated nanoparticle (505.6 nm), which hinders adhesion of the nanoparticle to the gastrointestinal tract wall thereby limiting passage into the intervillar spaces. More recently, SLN loaded with praziquantel was found to elicit greater death of S. mansoni, and decreased toxicity of the drug on human fibroblast cell lines (L929) compared to the free drug.
Polymeric nanoparticles (PNP)
PNP are colloidal nanocarrier systems composed of synthetic or semisynthetic polymers [Figure 1]. They are used for the improvement in the delivery of pharmaceuticals and possess inherent advantages over liposomes such as modulation of drug release profile and higher stability in biological fluids.
PNP formed from poly-(l-lactic acid) co-glycolic acid (PLGA) have been used in the entrapment and delivery of the schistosomicidal agent, praziquantel. The process conditions for the formulation of PLGA nanoparticles entrapping PZQ such as duration of sonication, PZQ and PLGA concentrations, polyvinyl alcohol amount, the proportion of organic and water phases, and method of removal of organic solvent were found to impact considerably on the particle size distribution of the nanocarrier formed. Also, the PZQ entrapped in PLGA nanoparticles was found to prolong the residence time of the drug at the intestinal membrane through sustained release or protection from harsh environs of the gastrointestinal lumen, thereby facilitating the uptake of the drug by the parasites for a longer time. Optimization of process condition was shown to result in nearly 100% encapsulation efficiency for praziquantel in homogenously dispersed poly (methyl methacrylate) nanoparticles formed via in situ miniemulsion polymerization.
Metallic nanoparticles represent the most suitable and convenient nanomaterials used in biomedical research, owing to their remarkable electrical, optical and physical properties, and have been used significantly in drug delivery and gene targeting, among others. They have been reported to possess therapeutic benefits, and efforts have been made by researchers to synthesize metallic nanoparticles from microorganisms as environmentally friendly sources. Examples of such metallic nanoparticles include silver, gold and cadmium sulfide nanoparticles. Among the common metallic nanoparticles, gold and silver nanoparticles [Figure 1] have been used in the schistosomiasis treatment.
The prophylactic role of gold nanoparticles was reported in schistosomiasis infection in the brain of mice. Gold nanoparticles were administered to the infected mice resulting in improvements in tissue structural impairment, norepinephrine and dopamine levels, oxidative stress status and regulation of gene expression of the animals. In another study on the effect of gold nanoparticles against renal impairment caused by S. mansoni, the nanoparticles were found to delay the histological damages and oxidative stress status of the kidney, and also restored the dysfunctional gene expression regulation. A study with silver nanoparticles against schistosomiasis showed a significant reduction in the S. japonicum cercariae infection, through rapid induction of cercariae tail-shedding, nervousness, and the release of cercariae, in accordance with the dosage. Most recent studies with silver and gold nanoparticles revealed their lethality to snails and cercariae in vitro, and their potential to inhibit in vivo larval infection of S. mansoni.
In the area of vaccine development against schistosomiasis, gold nanorods functionalized with rSm29 protein through an amine linkage were revealed to be a potential strategy for immunization against the disease. The evaluation of worm burden in mice following treatment with the functionalized gold nanorods showed about 34% protection. The Th1 immunological response stimulated CD4+ and CD8+ T cells to produce a greater amount of interferon-γ and enhanced major histocompatibility complex I (MHCI) and MHCII expressions via in vitro activation of dendritic cells.
Lipid nanocapsules (LNCs)
LNCs are nanoparticulate carrier systems made up of an oily core composed of medium-chain triacylglycerols enclosed by a layer consisting of a mixture of a phospholipid and pegylated surface-active agent [Figure 1]. With sizes ranging between 20 and 100 nm, they are formulated via an inverted phase of the water-in-oil emulsion through cycles of temperature increase and decrease.
LNC was used in encapsulation of miltefosine, an alkylated phosphocholine used in the management of cutaneous metastases of breast cancer and visceral leishmaniasis, and with considerable schistosomicidal activity against young worms of S. mansoni. The encapsulation of the drug into LNCs improved its bioavailability, reduced its erythrocyte hemolytic activity and significantly enhanced its schistosomicidal activity. With the incorporation of the positively charged surfactant – cetyltrimethylammonium bromide (CTAB), or negatively charged oleic acid into the nanocapsule, optimal schistosomicidal action of the drug was reported.
In a similar study, two different formulations of miltefosine encapsulated in LNCs – one with positively charged CTAB and another with negatively charged oleic acid, were developed against both adult and young worms of S. mansoni in an infected animal model. The formulations resulted in a 91.6 and 76.8% decrease in total adult worm load, and an 82.7 and 96.7% reduction in young worm load for the positively charged and negatively charged formulations, respectively, for a single oral dose.
In a more recent study, the pharmacodynamics and pharmacokinetic properties of praziquantel-loaded LNCs formulation were evaluated in an animal model infected with S. mansoni, one week after a single 250 mg/kg oral dose. The formulation, with tolerable cytotoxicity, considerably enhanced the efficacy of the drug evidenced by a decrease in total worm load, improved hepatic pathology and large-scale deterioration of worm tegument and suckers.
| The Place of Nanotechnology in the Control of Schistosomiasis Using Plant-Derived Compounds|| |
As described in Section 3, a number of crude plant extracts and plant-derived secondary metabolites have been shown to exhibit in vitro and in vivo schistosomicidal effects, with greater studies done on in vitro activity than in vivo. In addition, the pharmacological and clinical investigations of whole herbal preparations, extracts and isolated phytochemicals elicit in vitro schistosomicidal benefits that do not express the corresponding in vivo clinical advantage (Khogta et al., 2020). The observed poor in vivo schistosomicidal effects of these plant-derived materials compared to their in vitro effects are commonly attributed to their low bioavailability, poor bioaccessibility and pharmacokinetic profiles following the enteral route. To overcome the above challenges, the application of nanotechnology – the fabrication and utilization of functional structures at nanometer scale, through nano-drug delivery systems, comes to the limelight. The control of functional structures at the nanometer-length scale for the encapsulation, entrapment and complexation with plant-derived compounds having schistosomicidal activities would bring about their enhanced in vivo clinical benefits via improved bioavailability, controlled/targeted delivery for safety enhancement, improved retention time, biocompatibility, lower toxicity and enhanced pharmacokinetics.
Few plant-derived schistosomicidal agents have been developed in nano-drug delivery systems, while a greater number of them are potential candidates for fabrication into nano-delivery vehicles.
Nano-drug delivery of plant extracts with schistosomicidal properties
To date, few in vivo evaluations have been done on plant extracts with schistosomicidal activities and worse still, weak in vivo activities were recorded for most of the crude extracts examined. For example, it was reported that the in vivo investigations of Ambrosia maritime and Commiphora molmol methanol extracts on S. mansoni gave an insignificant reduction in parasite load. This would not be unconnected with the low bioavailability of the bioactive phytoconstituents in the extracts that are mostly water-soluble and prone to degradation on exposure to high temperature, oxygen or light. Hence, to protect the integrity of schistosomicidal bioactive molecules in plant extracts against degradation and improve their aqueous solubility, it is imperative to employ various nano-drug delivery techniques.
A number of approaches could be employed to improve the overall in vivo clinical benefits of plant extracts with schistosomicidal activities. The use of the supercritical fluid extraction of emulsions technique to encapsulate the plant extracts is a promising strategy to improve their in vivo schistosomicidal effects (Cruz et al., 2020). Bioavailability enhancement of schistosomicidal herbal extracts can also be achieved through encapsulation in polysaccharides, or protein nanoparticles. A very important and novel promising technique for the nano-delivery of schistosomicidal herbal extracts is complexation of the phytoconstituents with phospholipids into phytosomes. Similar to liposomes that can encapsulate bioactive molecules in either the internal aqueous phase (water-soluble encapsulates) or within the phospholipid bilayer (water-insoluble encapsulates), phytosomes are fabricated into complexes of bioactive molecules (in the extracts) and polar heads of phospholipids held by hydrogen bonds. The dispersion of phytosomal complexes in the aqueous medium results in their aggregation into nano-sized micellar conjugates (ca. 100 nm) with greater stability and loading capacity than liposomes. Phytosomal technique has been reported to enhance the permeability and bioavailability of polyphenols-rich fraction of extracts and phytoconstituents of aqueous leaf extract of Moringer oleifera ethyl acetate extract of Ginkgo biloba. Therefore, nano-drug delivery systems especially the phytosomal complexation of schistosomicidal herbal extracts would go a long way in improving the bioavailability of the bioactive phytochemicals and their overall in vivo clinical potential.
Nano-drug delivery of plant-derived bioactive molecules with schistosomicidal properties
Different plant-derived bioactive molecules with activities against schistosomiasis have been formulated into nano-drug delivery systems; however, their in vitro or in vivo bioactive evaluations were not necessarily against schistosomiasis, except for very few. Notable among them was the in vitro schistosomicidal effect of the flavonoid, curcumin encapsulated into PLGA nanoparticles. The formulated curcumin nanocarriers were found to reduce completely the parasite load and, brought about 50–100% S. mansoni couples' separation at 30 μM concentration. Other potential nano-delivery carriers for improvement in the schistosomicidal effect of curcumin include encapsulation in carbohydrate and protein nanoparticles. Another flavonoid, alpinumisoflavone (isolated from M. thonningii) with activity against schistosomiasis was formulated into polymeric micelles and the in vivo bioavailability and clinical benefits significantly improved. In addition, the in vivo pharmacological importance of flavonoids with schistosomicidal activities can be significantly enhanced via encapsulation in PNP, lipid vesicles, nanosuspensions, nanocrystals, SLNs, and nanogels, among others.
Epiisopiloturine (EPI) and piplartine are two major alkaloids with schistosomicidal properties that have been subjected to nano-drug delivery systems. The in vitro schistosomicidal effect of EPI encapsulated into liposomes was found to accomplish a 100% reduction in the schistosome load compared to the free drug. Similarly, the oral absorption of EPI was improved by incorporation into nanoemulsion, with the self-nano-emulsifying drug delivery carrier able to reduce the total female worm burden by 74% unlike that of the free drug (51%). Recently, EPI was entrapped into nanoparticles formulated with acetylated cashew gum and the nanocarriers formed showed in vitro sustained release with potential for improved in vivo bioavailability and clinical benefits. On the other hand, a 1.5-fold improved in vivo bioavailability of piplartine was achieved by encapsulation into nanoemulsions, with the formulated nanocarriers showing a considerable antineoplastic effect. Furthermore, bio-friendly nanoemulsions of piplartine for targeted delivery into mammary tissue were formulated with chitosan or hyaluronic acid as the bioadhesive. The formulation exhibited sustained release properties with less adverse effects with about 60 days of stability.
A number of terpenoids possessing schistosomicidal activities have been formulated into nano-delivery vehicles for improved bioavailability and reduced cytotoxicity. The schistosomicidal sesquiterpene found in plant essential oils, nerolidol, has been encapsulated into various nanoparticulate systems. The in vivo evaluation of nerolidol encapsulated in nanospheres on mice infected with Trypanosoma evansi led to significantly improved survival of the animals (66.66%) compared to its free form (0%) and the standard antitrypanosomal drug, diminazene aceturate (33.33%). Also, nerolidol entrapped in cyclodextrin encapsulated into liposomes was found to be stable against light than one encapsulated directly into liposomes, and could cause the death of bacteria within a few days. Most recently, nerolidol encapsulated into biocompatible nano-capsules showed potentiated anti-inflammatory activity in an animal model.
The encapsulation of the schistosomicidal sesquiterpene lactone, parthenolide, into stealthy liposomes, in combination with stealthy liposome-loaded vinorelbine, could synergistically inhibit completely the proliferation of the mammalian cancer cell line, MCF-7. Combination therapy of parthenolide and the anticancer agent, paclitaxel, was demonstrated by their encapsulation into mixed micelle conjugate and their effects on epidermal growth factor receptor-targeted cancer therapy were examined. It was shown that the targeted delivery of nano-micelle-loaded drugs was more efficacious in wiping out the cancerous cells than non-targeted micelles. In addition, parthenolide formulated into nanocrystals, in synergy with sorafenib, considerably inhibited the growth of hepatocellular carcinoma cells (81.86%) compared to the individual free drugs (48.84% parthenolide; 58.83% sorafenib).
The derivatives of the sesquiterpene lactone, artemisinin, as artesunate and artemether, possess schistosomicidal properties and have been formulated into nanoparticulate carriers to improve their aqueous solubility, bioavailability, sustained release and overall clinical relevance. The entrapment of artesunate into nano-sized lipid vesicles through dimerization with phospholipid resulted in its significantly improved in vivo pharmacological effects compared to the free drug. Also, the co-entrapment of paclitaxel and artesunate dimerized with phospholipid into nanoscaled lipid vesicles resulted in targeted delivery of the chemotherapeutics to tumour cells and improved their antineoplastic activities compared to the free drugs. Similarly, improvement in inhibition of tumour cell growth in an animal model was reported for pegylated artesunate-entrapped PLGA nanoparticles compared to the free drug.
Encapsulation of artemether in nanostructured lipid carrier and its in vivo evaluation in Plasmodium berghei-infected mice resulted in a significant enhanced decrease in parasitaemia compared to the conventional injectable formulation This was attributed to improved aqueous dispersibility, permeation, bioavailability and sustained/controlled release of the encapsulated drug compared to the free drug in solution. The enhanced solubility of the drug was also achieved when formulated into PNP by binding to human serum albumin, and when the nanoparticles were conjugated with folic acid molecules, it resulted in considerable inhibition of folate-receptor alpha-overexpressing breast cancer cells with less drug amount than non-folic acid-conjugated formulation due to targeted and sustained delivery to the diseased cells.
| Conclusion|| |
Generally, the application of nanotechnology via nano-delivery of schistosomicidal agents of plant origin would generally improve their pharmacological and clinical benefits through improved bioavailability, targeted delivery to the diseased tissues, and facilitated and sustained uptake by the parasites. As the schistosomula are present 2–3 weeks in the liver between infection and maturation, nano-drug delivery of plant-derived schistosomicidal agents would play a major role in the disease prophylaxis as a result of the sustained release properties of the nanoformulations.
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Conflicts of interest
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