Karem Ghoneim. / Journal of Science / Vol 4 / Issue 5 / 2014 / 272-292.

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CANTHARIDIN AS PROMISING CHEMOTHERAPEUTIC AGENT IN THE MODERN MEDICINE: A COMPREHENSIVE REVIEW

Karem Ghoneim

Faculty of Science, Al-Azhar University, Cairo, Egypt.

ABSTRACT Blister beetles of the families Meloidae and Oedemeridae (Order Coleoptera, Insecta) release yellow oily droplets of haemolymph from their leg (and may be antennal) joints as a defensive measure when disturbed. The active ingredient in this exudation is cantharidin (CA). Historically, CA has been used as a chemotherapeutic agent in the traditional medicine among Asian, African and European peoples. CA, as a natural or chemically synthesized compound, is used in the modern medicine to treat various diseases. Norcantharidin is the most famous among the synthesized CA analogues and derivatives. CA and its analogues have been applied for some dermatological cases such as warts, verruca vulgaris, corn, molluscum contagiosum and leishmaniasis. In oncology, CA and its analogues exhibit promising therapeutic effects because they induce apop tosis of human cancer cells of hepatoma, colo-rectal carcinoma, oral carcinoma, esophageal carcinoma, leukemia, bladder carcinoma, melanoma, etc. In addition, CA and its analogues have been experimentally and clinically investigated for some other diseases such as heart failure, hepatitis, neurological disorders and innate immune system. Furthermore, CA and CA -related compounds, such as Endothall and palasonin, act as a potential source of antimalarials and antihelminthics. The multi-drug resistance is one of the major obstacles in the treatment of human cancer. CA and some of its analogues have been studied as promising agent to overcome this problem. On the other hand, several drug-delivery systems have been evaluated for improving the clinical uses of CA and its analogues.

Keywords: Dermatology, antileishmaniasis, antimalarials, antihelminthic, anticancer, chemotherapy.

INTRODUCTION In Coleoptera (Insecta: Arthropoda), only This exudation contains toxic material 'CA'. The main Meloidae (true blister beetles), Oedemeridae (false blister function of CA in the blister beetles is to preserve their beetles) and Staphylinidae (rove beetles) release vesicant eggs from predators beside some other functions [16-19]. chemicals, the first two release cantharidin (CA) and the However, CA, among the most widely known insect latter releases paederin [1]. Family Meloidae is virtually natural products, usually attracted a great attention of cosmopolitan but absent only from New Zealand, many investigators and research institutions because of its Antarctica and most Polynesian islands [2-5]. Global toxicosis for man and painful or fatal diseases for horses zoogeography and systematic approaches of this family and other livestock [20, 21]. Many reports on different had been reviewed by Ghoneim [6], different biological aspects of veterinary and medical impacts of CA are aspects of this family had been reviewed by Ghoneim [7], available in the literature [22-28]. and various agronomic and biodiversity impacts had been Natural products still play a major role as drugs, reviewed by Ghoneim [8]. Oedemeridae is a family of and as lead structures for the development of synthetic worldwide distribution. The available literature contains molecules [29]. In the future, natural compounds and their several reported works on the distribution and systematics derivatives will continue to be a rich source for drug of this family in the world [9-15]. Blister beetles are discovery [29-31]. Ratcliffeet al. [32] reviewed several commonly known as "oil beetles" because they release insect products derived from honey, venom, silk, CA, yellow oily droplets of haemolymph from their leg joints whole insect extracts, maggots, and blood-sucking (and may be from the antennal joints) when disturbed. arthropods. Traditional Chinese medicine (TCM) has

Corresponding Author:- Karem Ghoneim Email:[email protected]

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been practiced by Chinese communities worldwide for product and its isolation and chemical synthesis beside its many generations, and there is rich information in the major forms and related compounds. available literature related to the therapeutic use of TCM [33]. Unfortunately, there are increased reports on the 1. CANTHARIDIN AS A NATURAL INSECT adverse reactions of some TCM products [34]. In some PRODUCT African and Asian countries, 80% of populations depend CA is one of the oldest-known toxins from on traditional medicine for primary health cure. insects and has been known to humans for more than Traditional African medicine (or "Muti") involves the use 2000 years due to its physiological activities such as remedies made of herbal and/or animal parts and blistering [20, 43]. The function and intrinsic role of CA traditional rituals in the treatment of a variety of ailments in the courtship behaviour of family Meloidae has been [35]. never fully established. It was suggested that CA might be CA has a long history in both folk and traditional used by female when selecting a mate at close range [20]. medicine. It, as contained in the bodies of blister beetles As pointed out in the iron cross blister beetle Tegrodera or isolated from them, has been used by human since the alogaSkinner, individual males donated a large CA- time of Hippocrates, if not before, as a vesicant, containing spermatophore to their mates, and body size lubrificant, internal remedy for various diseases, was correlated with the size of the cantharidin-producing aphrodisiac, and poison [36, 37]. Although CA has a long, accessory glands [49]. When attacked or disturbed, adults infamous reputation for being an aphrodisiac [38],it is not of blister beetles release haemolymph droplets in so called a true aphrodisiac and can cause fatal poisoning [39]. In "reflex bleeding". The highly toxic CA in the addition to human and animal toxicosis caused by haemolymph, is a well defensive reaction against the cantharidin [40], human dermatosis had been reviewed by aggressive creatures. As reviewed by Ghoneim[19], CA is Ghoneim [41]. considered responsible for the repellent properties of Blister beetles are still used and misused by meloid haemolymph against a wide variety of predators. people as a type of 'Insect Viagra' (aphrodisiac agent) As pointed out by some authors [4, 50], adult female of [42]. In Europe, CA appeared in "Materia Medica", a blister beetle uses her own CA and transferred CA for medical monograph written by Pedanios Dioskorides in herself and also to cover or coat her eggs for protecting 50 to 100 AD [43]. Hippocrates prescribed CA as a them against the potential predators. treatment for dropsy [44]. Later in history, the Marquis de Sade was brought to trial for poisoning an entire orgy 1.1. Cantharidin from the chemical standpoint with Spanish fly (blister beetle) in 1772. As late as the CA was isolated from some blister beetles [51]. last half of the 19th century, CA obtained from Meloe It was isolated and crystallized from the red-headed spp., as well as other blister beetles, was used as specific blister beetle Epicauta hirticornisin Assam, India treatments of hydrophobia, particularly in Europe and [52].Einbinder et al. [53] indicated that CA (2,3-di- northern Africa. Beside its use against hydrophobia, CA methyl-7-oxabicyclo [2.2.l] heptane-2.3- dicarboxylic obtained from the blister beetle Meloe proscarabaeus was acid anhydride) is the principal active ingredient amongst used as a diuretic [45] and as a cure for rheumatism in the various compounds present in Mylabris. The chemical Sweden [46]. In South Africa, the Tswanas grind CA- structure and properties of CA had been reported in the producing beetles into a powder and use it in a medicine literature (e.g., [54-56]). It is a bicyclic terpenoid or called "seletsa" as an aphrodisiac, as an abortifacient, and anhydride of cantharidic acid with chemical formula for "purifying the blood" [38]. C10H12O4. Today, there are many kinds of Mylabris-based Although the CA biosynthesis in the blister pharmaceutical preparations on the Chinese market, such beetles had been studied by some researchers [50], it was as compound Mylabris injection (Aidi injection, State a debatable issue along several decades ago and the Permit No.Z52020236) and compound Mylabris capsules mechanism in vivo was not completely understood. In (State Permit No.Z19993294; State Permit order to clarify the biosynthesis mechanism of CA in No.Z200003270; State Permit No.Z20000427), all of Mylabris calida Palla, Jia et al. [57] studied the protein which have proved to show good anticancer effects. In expression profile during the early and advanced stages of addition, so many companies synthesize the CA as a the process. Also, Jiang et al. [58] investigated the commercial product for the medicinal purposes in the relationship between CA biosynthesis and the mevalonate world, under different trade names [47, 48]. pathway. Although CA was purified and crystallized in The present review deals primarily with the uses of CA 1810 by Robiquet from Spanish fly Lytta vesicatoria [59], and its analogues as chemotherapeutic agents in the it took 150 years of research to be fully synthesized modern medicine focusing on dermatology, cancer, drug [50].The first attempt was carried out by a German resistance, parasitic infections, heart failure and some chemist von Bruchhausen [60] but the first effective liver diseases. It discussed, also, CA as a natural insect synthesis of this compound was made in 1951 by the

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American chemist Stork who and co-workers reported the Afterwards, many experimental studies had been first natural product synthesis featuring a [4 + 2] conducted. Rosenberg et al. [78] suggested a self- cycloaddition in the stereo-controlled synthesis of CA application of CA (0.7% solution in acetone-flexible [61]. Then, some other efforts had been done for the CA collodion) for treatment of warts.Commercially, there are synthesis [62]. For review of different aspects of CA some formulations consisting of 0.7% - 0.9% CA can be physiology, see Ghoneim [63]. purchased. Camphor or pine oil is often added to proprietary formulations to lend a medicinal aroma [79]. 1.2. Major cantharidin forms and related compounds Also, topical preparation containing salicylic acid (30%), As pointed out by Li et al. [64], the content of podophyllin (5%) and CA (1%) was found effective to total CA is higher than the content of free CA in the treat the plantar warts in children [80]. Recently, a topical family Meloidae, as well as bound CA may exist in the combination of CA, podophyllotoxin, and salicylic acid forms of magnesium cantharidate and calcium was found to be safe and effective in the treatment of cantharidate. Using the gas chromatography, Li [65] simple and mosaic plantar warts [81]. Kartal et al. [82] determined the CA forms in 12 species of Meloidae in evaluated the efficacy and safety of topical CA in the China. Their results suggested that the existing form of treatment of recalcitrant facial flat warts. Pathological bound CA might be the magnesium cantharidate, calcium transformation of the skin into a thick and hard callus due cantharidate, potassium cantharidate. to repetitive trauma or friction is commonly known as In a related matter, there are few compounds corn. Effectiveness of tangential excision together with structurally similar to CA, known as CA-related topical CA had been evaluated on 72 patients. This compounds (CRCs), have been found in blister beetles. treatment method is a simple, minimally invasive and CA has never been detected in plants, but the first CRC, reliable treatment for calluses [83]. palasonin (demethylcantharidin)(C9H9O4) was discovered To treat Verruca vulgaris by using the blister [66]. This CRC was initially isolated from the seeds of the beetle's haemolymph, the CA content could kill efficiently Indian tree known as Flame of the forest, Butea V. vulgaris virus and had no side effect for natural skin monosperma [67], Synonym Butea frondosa [68]. [84]. In addition,Molluscum contagiosum (MC) is a However, analyses of species from the families Meloidae common viral disease of childhood caused by a poxvirus, [69], Cleridae, and Staphylinidae [70] gave the first which presents with small, firm, dome-shaped, evidence for simultaneous presence of CA and palasonin umbilicated papules. It can spread through close skin-to- in haemolymph and tissues of the individual insects. skin contact and many patients autoinoculate themselves, Moreover, variable titers of palasonin were detected in the making MC a dynamic disease [85]. In TCM and bodily extracts from some blister beetles [71], staphylinid traditional Vietnamese medicine, CA (derived from the beetles [70], and the clerid beetle (Trichodes apiaries, bodies of the Spanish fly L. vesicatoria) has been used to Cleridae) [72]. It is to be noted that the second CRC, treat MC virus infections and associated warts palasoninimide(C9H10O3N) was reported by Dettneret [86].Treatment options of MC include destructive al.[69]. Cantharimides (C10H13NO3), whose therapies (curettage, cryotherapy, CA, and keratolytics, anhydrideoxygen atoms are replaced by basic amino among others), immunomodulators (imiquimod, acids, and cantharimide dimers, which consist of two cimetidine, and candidaantigen), and antivirals cantharimide units combined with a tri-, tetra-, or (cidofovir). Because of concerns over its safety, some pentamethylene group, had been reported in the Chinese physicians has lost favor to use CA for MC. Silverberg et meloid Mylabris phalerata Pall. [73, 74]. Few years ago, al. [87] attempted to determine the safety, efficacy, and CA, palasonin and cantharidinimide were extracted from parental satisfaction of CA therapy for MC in 300 the blister beetle Mylabris impressa stillata (Baudi) [25]. children who were treated in a pediatric dermatology In addition, Endothall is a synthetic herbicide and known clinic at a large referral hospital. In these patients, CA as CA-related compound (7-oxabicyclo [2.2.1] heptane- therapy was extremely effective and well tolerated, and 2,3-dicarboxyli acid) [75]. parental satisfaction was high. Therefore, CA is a safe and 2. PHARMACEUTIC USES OF CANTHARIDIN IN effective therapy for MC in children. Recently, Mathes DERMATOLOGY and Frieden [88] discussed the use of CA as a treatment The CA uses against the skin cancer will be option for MC and described their first-line treatment discussed thereinafter but the uses of CA against skin approach for those MC needing CA treatment.Langley et diseases other than cancer can be reviewed herein. The al. [89] reported a case of toxic shock syndrome within 24 first suggestion to use CA as a chemotherapeutic agent in hours of topical application of a CA preparation for warts was provided by Epstein and Kligman [76].In cosmetic treatment of MC. This case highlighted a Epstein’s classic article, 56% of digital and 33% of potentially life-threatening complication of CA use for a periungual warts were cleared after a single application of common skin condition. Therefore, the survey achieved CA and the others required one or two additional by Coloe and Morrell [90] may be informative for the treatments with a long-term cure rate of about 70% [77].

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breadth of CA usage, the most frequently used protocols, aberrant mitotic spindles and metaphase growth arrest. and common side effects. Although the activity of CA is usually attributed to its Leishmaniasis has been identified as a major high affinity towards Type 1 and 2A serine/threonine public health problem in many countries. Chemical drugs protein phosphatases, several studies suggest that CA has are the best way for treatment of leishmaniasis. Using additional cellular targets. Specifically, CA has been drugs for treatment of leishmaniasis are moderately toxic reported to stimulate xanthine oxidase activity and to and have the risks of recurrence and unsatisfactory side inhibit N-acyltransferase and cAMP phosphodiesterase in effects [91]. CA was assessed as anti-leishmaniasis agent liver cells, suggesting a complex mode of action [97, 114, since different doses were evaluated on Leishmania major 115]. Using the HIP and HOP genome-wide assays, (MRHO/IR/75/ER) both in vitro (promastigote and Hillenmeyer et al. [116] discovered that a large number of amastigote viability) and in experimentally-infected methyltransferase deletion mutants are sensitive to CA, BALB/c mice (skin lesions). Two weeks of topical suggesting that, as a class, these enzymes may interact treatment with 0.1% CA ointment was an effective directly or indirectly with CA and participate in the method for treating cutaneous leishmaniasis in infected response to CA stress. BALB/c mice [92]. For some details, CA induces There have been several reports to show that CA apoptosis in the L. major promastigotes and infected and its derivatives are relatively ineffective as an anti- macrophages with amastigotes in a time and dose cancer agent [117]. The contradiction may be related to dependent manner [93]. As concluded by Maroufi et al. CA being less effective at alkaline pH but more active at [94], CA has a cytotoxic effect on the promastigote and acidic pH. Fukamachi et al. [118] investigated the macrophages infected with L. major. However, further cytotoxicity of lovastatin and CA under controlled pH studies are recommended to investigate the efficacy of environments in mesothelioma or pancreatic carcinoma this compound in vivo. cells. They concluded that the acidic conditions would be useful for developing new chemotherapeutic reagents. 3. CANTHARIDIN USES IN ONCOLOGY In modern pharmacology, CA plays an important 3.1. Less toxic cantharidin analogues and derivatives role in control of cell cycle regulation [95] and on the Although CA is a natural toxin that possesses cellular growth of tumor cells transformed by SV40 potent anti-tumor properties, its clinical application is antigen [96]. The therapeutic efficacy of CA in the limited due to severe side-effects and highly toxic nature treatment of cancer and some refractory diseases had been mainly in the gastrointestinal tract, the ureter and the demonstrated [97]. For some details, CA has a cytotoxic kidney [111]. Its severe side effects include, also, activity against a number of primary tumor cells [97-100], dysphagia, hematemesis, dysuria [43] andmucous and clinical testing revealed little myelosuppression [43, membrane toxicity[119]. Ghoneim [40] provided a 101]. CA induces apoptosis of human hepatoma[102], comprehensive review on the CA toxicosis to human and human colon cancer, buccaland oesophageal animal. Therefore, thousands of modified analogues and carcinoma[103, 104], uterine cervical cancer, derivatives of CA had been chemically synthesized and nasopharyngeal carcinoma, cutaneous cancer, as well as their bioactivities had been studied [120] in order to human leukemia cells [102, 104, 105]. Human bladder achieve a comparable antitumor property to the mother carcinoma [100] and breast cancer [106] can be, also, compound but simultaneously produce a less toxic effect treated with CA. on non-cancer cells [105]. To understand the mode of action of CA in Kok et al. [121] reviewed their experience in the tumor and cancer treatments, earlier studies reported a chemical synthesis and biological screening of five strong affinity and specificity of it for a "CA-binding" chemically modified CA analogues on a series of human protein, which has been isolated and identified as protein carcinoma cell lines. Very recently, Deng et al. [122] phosphatase 2A (PP2A) [107]. As pointed out by provided up-to-date review on the therapeutic use, numerous authors [108-110], CA acts as a weak inhibitor mechanism and interesting properties of CA analogues. of calcineurin (PP2B) but as a potent inhibitor of three For some details, a series of glycerophospholipid families (PP1, PP2A, and PP5) of structurally related conjugates of CA and its analogues were synthesized in a PPases. It is known that the liver cytosol is one site that is one-pot reaction, using hexaehtyl phosphorus triamide, rich in PP2A [111] and from in vitro experiments, the activated by a catalytic amount of iodine, as the level of PP2A inhibition parallels cytotoxicity [112]. phosphorylating reagent [123]. Because thefluorinated Bonnesset al.[113]characterized the biological activity of CA analogues represent a rewarding synthetic target, also CA in culture cells (A549 and HeLa) and developed small with respect to an altered metabolism which was observed interfering RNA (siRNA) and antisense oligonucleotides for ∞-monofluoroalkanoic acids,Essers et al. [124] capable of markedly suppressing the expression of several reported the synthesis of four fluorinated CA analogues. CA-sensitive phosphatases. Their studies indicated that Williams et al. [106] screenedseven CA derivatives CA-induced apoptosis is preceded by the formation of against the human neuroblastoma and breast cancer cells

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in vitro. Deng et al. [125] synthesizedtwelve novel In a study to clarify the mode of action of CA compounds by the [3+2] 1,3-dipolar cycloaddition analogues, Shan et al. [144] concluded that the reaction of 5,6-dehydronorcantharidin derivatives of cytotoxicity of synthetic CA analogues is likely to be substituted aromatic amines with nitrile oxides. Then, associated with their protein phosphatase 2A inhibitory they investigated their anti-tumor activities. Kok et al. activity. However, the exact anticancer mechanism of [126] synthesized two CA analogues and assessed their NCTD on human cancer cells remains poorly understood. cytotoxic activity on a series of human cancer cell lines. Jiang et al. [145] tried to understand this puzzle when Goksu et al. [127] had been interested in the synthesis of discovered that NCTD can induce the apoptosis of HL-60 bioactive CA analogues that represent aryl-modified cells and inhibit the fissiparism, and the domino effect bicyclic imide systems. They synthesized endo-N- was obviously correlated with the time and dosage. To phenylbicyclo [2.2.1] hept-5-ene-2,3 dicarboximide from explore the effects of NCTD on proliferation and killing cyclopentadiene and N-phenylmaleimide and exo-N- activity of cytokine-induced killer cells (CIK), Liu et al. phenyl-7-oxa-bicyclo [2.2.1] hept-5-ene-2,3- [146] carried out a study suggesting that NCTD promoted dicarboximide,from furan. the proliferation of CIK cells and enhanced their anti- One of the most famous synthetic demethylated tumor activity, which will provide a new approach for analogues of CA is norcantharidin (NCTD)(7- adoptive immunotherapy of CIK. oxabicycloheptane-2,3-dicarboxylic acid anhydride). It Thousands of platinum complexes have been synthesized was synthesized with furan and maleic anhydride through and evaluated for their anticancer activity. Several review Diels-Alder reaction [128].Many experiments have articles have appeared during recent years dealing with demonstrated that NCTD can inhibit the growth of tumor the synthesis, preclinical screening, and mechanism of cells in vitro and in vivo [24, 114, 129]. In comparison action of platinum-based anticancer drugs [147, 148]. The with CA, NCTD has the advantage of easy synthesis platinum complexes were found to exhibit potent in vitro and reduced intrinsic toxicity, while retaining its antitumor activity against L1210 mouseleukemia and a anticancer activity [104]. Its anticancer effectshad been range of human cancer cell lines [149]. Synergism or recorded against a diversity of malignancies by inducing combination of NCTD with a platinum moiety has cell anoikis and apoptosis, inhibiting invasion and produced a series of TCM-based platinum compounds angiogenesis [130] as well as suppressing metastasis which demonstrate selective cytotoxicity toward SK-Hep- [131]. Unlike the conventional chemotherapeutics, NCTD 1 (human liver) cell line and circumvention of cross- is preferentially toxic to cancer cells rather than normal resistance [33]. A series of platinum complexes derived cells [132], making this small molecule promising in from integrating NCTD with different isomers of 1, 2- cancer treatment [133-135]. diaminocyclohexane had been synthesized by Yu et al. Furthermore, a remarkable research effort had [150]. These integrated drugs had been found to exhibit been devoted to synthesize NCTD analogues with low superior in vitro anticancer activity against colorectal and biological toxicity [98, 136, 137]. A number of amide- human hepatocellular cancer cell lines. In general, some acid NCTD analogues were prepared containing two of the CA-based platinum complexes may possess a novel carboxylic acid residues. Although further studies are dual mechanism of antitumor action: inhibition of PP2A required to explore the anticancer properties of these and platination of DNA[33]. compounds in vivo, it is clear that the development of analogues more potent than the lead compound, NCTD, 3.2. Cantharidin and its analogues for cancer has been successful in the field of development of chemotherapy selective phosphatase inhibitor drugs [138]. CA and its analogues had been assessed for the Cantharimides, (or cantharidinimides) and chemotherapy of human breast cancer. The effects of norcantharimides are CA analogues. A number of NCTD on the growth of highly-metastatic human breast norcantharimides had been synthesized from NCTD and cancer cells were investigated by in vitro and ex vivo had been shown to possess interesting anticancer activity assays [121]. According to Huang et al. [151], NCTD [139, 140]. The cantharidinimide derivatives containing inhibited the in vitro growth of human breast cancer aliphartic, aryl, and pyridyl groups showed some effect in MDA-MB-231 cell line in dose- and time-dependent vitro against HepG2 and HL-60 cells [141]. Tseng et al. manners. The anti-cancer effect of NCTD on two human [142] obtained a novel type of cantharidimides for testing breast cancer cell lines, estrogen receptor (ER)- HS-578T their cytotoxicity in human carcinoma cell lines. Although and ER+ MCF-7 cells, had been investigated by Yang et the structural modification of CA to cantharidinimides al. [152]. Depending on their results, NCTD may be an might lead to the discovery of a novel class of antitumor effective anti-cancer drug against breast cancer. Effects of compounds [141],cantharimides with non-polar or acidic the same CA analogue on the cellular viability, reactive amino acid residues are only poor inhibitors of PP1 and oxygen species, mitochondrial membrane potential, and PP2A[143]. DNA damage in the human breast cancer cell line Bcap- 37 were evaluated with confocal and fluorescence

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microscopy. The results indicated that NCTD induced a However, the available treatment and surgical options dose-dependent DNA damage and reduced the G1 peak in have proven to be inadequate in controlling the Bcap-37 cells. The G2/M peak of Bcap-37 was also mortality and morbidity associated with this disease. decreased by the higher concentration of NCTD [153]. Therefore, it is necessary to intensify the research efforts In connection with thehuman melanoma(the to develop new therapeutic agents for its prevention and most serious type of skin cancer), treatment of A375-S2 treatment [163]. Modern clinical studies have shown cells with NCTD led to several typical characteristics of thatCA has a certain inhibitory effect on ascites hepatoma apoptosis. The inhibitory effect of NCTD on human and primary liver cancer [164]. Treatments with NCTD, melanoma, A375-S2 cells, was partially reversed by the Adriamycin and hepatic artery ligation were studied. The inhibitors of pan-caspase, caspase-3 and caspase-9. results simply showed that NCTD may has a role in the Results of An et al. [154] suggested that NCTD induced chemotherapy of primary liver cancer [165]. Wang et al. A375-S2 cell apoptosis and the activation of caspase and [97] isolated CA from Mylabris phalerata Pallas and mitochondrial pathway were involved in the process. On examined its cytotoxicity on human hepatocellular the other hand, An et al. [155] investigated the roles of carcinoma cells (Hep 3B cells). It was found as a potent mitogen-activated protein kinase (MAPK) and protein inhibitor since it could prohibit the progression of all kinase C (PKC) in A375-S2 cell apoptosis induced by phases of the Hep 3B cell cycle. Recently, Chang et al. NCTD. Their results suggested that the activation of p38 [163] recorded an inhibitory effect of NCTD on the MAPK promotes the process of NCTD-induced A375-S2 proliferation and induced apoptosis of HepG2 cells in cell apoptosis and that PKC plays an important regulation a concentration-dependent manner. Gall bladder role in the activation of MAPKs. Recently, Liu et al. carcinoma is a highly lethal and aggressive disease with [156] suggested that NCTD is a potential therapeutic early metastasis, strong invasion and poor prognosis. agent for melanoma because NCTD inhibited melanoma Most patients with this disease are at the advanced and cell viability and induced apoptosis in vitro. unresectable stage and should be considered for palliative One of the most interesting aspects of the treatment such as chemotherapy and radiotherapy. NCTD chemotherapeutic uses of CA and its analogues is inhibits the proliferation of human gall bladder carcinoma thedigestive system cancer. Koket al. [104, 157] indicated GBC-SD cells in vitro and the expression of their that KB cells (in oral carcinoma) were more sensitive to proliferation-related gene proteins PCNA and Ki-67 NCTD-induced cytotoxicity compared to normal buccal [166]. keratinocytes. They concluded that NCTD may be of To et al. [167] investigated the potential value in treating oral cancers. NCTD was reported as an synergistic effect of combining NCTD with a platinum- anti-cancer agent against gastric cancer [119]. It inhibited based antitumor agent (such as cisplatin, carboplatin, or the activity of PP2A and was able to promote the cell oxaliplatin) in vitro against SK-Hep-1 human cycle from G1 to S phase with subsequent G2/M arrest hepatocellular carcinoma. Their results supported a new [150]. Effect of sodium cantharidinate on the approach for augmenting cytotoxic effect of established angiogenesis of nude mice with human gastric cancer was platinum-based drugs with NCTD in treating this studied. This CA analogue could inhibit the tumor growth carcinoma and other solid tumors. A novel palladium (II) by down-regulating VEGF expression of the tumor cell complex with demethylcantharate and 2,2΄-bipyridine was and the tumor angiogenesis [158]. Qinin® (semi-synthetic synthesized and the antiproliferative activity of the derivative of CA) injection had been developed and complex against human hepatoma cells (SMMC7721) in manufactured by Guizhou magic Pharmaceutical Co., Ltd vitro was evaluated by Wang et al. [168]. The synergistic in China. Zhan et al. [159] found Qinin® injection effect of CA analog'LB1' (a novel inhibitor of protein combined with chemotherapy enhancing clinical benefit phosphatase 2A) with doxorubicin on human Hep G2 response, improving quality of life of gastric cancer hepatocellular carcinoma cells was investigated. LB1 patients and reducing side effects of chemotherapy. CA could enhance the effect of doxorubicin in the uses against pancreatic cancer cells had been documented chemotherapy against hepatocellular carcinoma cells by some works. It efficiently inhibited the growth [169]. Recently, a relative successfulness of paclitaxel ofcancer cells, but presented a much lighter toxicity effect against tumors was observed. It was found that NCTD against normal pancreatic duct cells [160].Li et al. [161] enhanced paclitaxel-induced apoptosis in liver cancer cell investigated the apoptosis inducting effect of CA on HepG2 [170]. pancreatic cancer cell line PANC1 and CFPAC-1. They CA was reported to provoke apoptosis in colo-rectal concluded that CA can induce apoptosis in pancreatic cancer [171, 172]. Two series of demethylated CA cancer cell lines by activating caspase, up-regulating the analogues had been synthesized which showed selective expression of pro-apoptotic genes and down-regulating cytotoxicity in colon cancer cells while remaining the expression of anti-apoptotic genes. inactive in normal colon cells [173].The relationship As reported in the literature,hepatoma is one of between NCTD anticancer mechanism and integrin αvβ6 the most common and worldwide malignancies [162]. was investigated by Peng et al. [174]. They presumed that

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NCTD induced HT-29 colon cancer cell apoptosis extracellular matrix (ECM) must be degraded. CA was through the αvβ6–ERK signaling pathway. Recently, reported to inhibit the migration and invasion of A549 Huang et al. [172] studied colo 205 cells after treatment human lung cancer cell. Very recently, Kim et al. [183] with CA and demonstrated its molecular mechanisms in investigated the pharmacokinetics of CA in the A549 apoptosis. Their results indicated that CA induced growth human lung cancer cells. Shortly, CA inhibits the inhibition, G2/M phase arrest and apoptosis in colo 205 activation of phosphatidylinositol 3-kinase/Akt signaling cells. pathway. This leads to the selective attenuation of one of Taking into account thathematologic cancers the gelatinases, matrix metalloproteinase 2, which can include those cancers of the blood and blood-forming degrade components of ECM, and inhibits migration and tissues. They include acute and chronic leukemias, invasion of A549 human lung cancer cells. Hodgkin's and non-Hodgkin's lymphomas, and multiple With regard tohuman bladder carcinoma, Kuoet myeloma (a cancer of the bone marrow) [135]. CA and its al. [171] selected TSGH 8301 cells for examining the analogues had been used against the haematologic effects of CA on cell cycle arrest and apoptosis. Their cancers. In contrast to most other anticancer drugs, CA results showed that CA induced G2/M arrest and and NCTD stimulate the production of white blood cells apoptosis which is mitochondrial-dependent and via JNK by bone marrow, while other anticancer drugs have the signal pathways offering new information to show CA- unwanted side effect of inducing myelosuppression [135]. induced apoptosis in these bladder carcinoma cells. The available literature contains results of several Pharmacokinetically, Huang et al. [184] investigated the published works about this area. CA had been reported as effects of CA on migration and invasion of human a cause of leukocytosis (increase of number of white bladder cancer cells. Depending on their results, CA blood cells in the blood) [103, 175]. Sagawa et al. [176] potently inhibited the migration and invasion of TSGH- investigated the in vitro effects of CA for its antimyeloma 8301 cancer cells through inhibiting the p38 and JNK1/2- activity. They concluded that CA inhibited the cellular modulated MMP-2/-9 signaling in vitro. growth of human myeloma celllines.Koket al. [177] The inhibitory effect of CA on metastasis-related synthesized the CA analogues, CAN 029 and CAN 030. ability of human highly metastatic ovarian carcinoma cell Although both exhibited an apoptotic induction ability on line HO-8910PM was studied [185]. On the other hand, cancer cells, they were still relatively toxic towards non- the inhibitory effect of Nd3, a derivative of NCTD, on the malignant haematological disordered bone marrow. proliferation of human ovarian cancercell line SKOV3 Another CA analogue, CAN 037, was synthesized and was explored. Nd3 inhibited SKOV3 cell proliferation assessed on the acute myelogenous leukaemia cell lines. more than NCTD did, blocked cell cycle at G2/M phase, CAN 037 exerted a role on the acute myelogenous and induces apoptosis [186]. For chemotherapeutics of leukaemia (AML) cell line, KG1a. Apoptosis was ovarian carcinoma and prostate carcinoma, Hill et al. involved in the action of CAN 037 including the [139, 140] provided a valuable contribution to synthesize activation of the caspase family. Caspase-dependent cell a novel series of norcantharimides. death pathway may be necessary but not essential in CAN Medulloblastoma is a fast-growing and high- 037-induced apoptosis of KG1a cells [178]. As reported grade tumor. It is the most common of the embryonal by Dorn et al. [179], CA has been described to modulate tumors. It is one of the leading causes of morbidity and the hepatic leukemia factor competitor NFIL3. NCTD mortality in pediatric cancer. Cimmino et al. [187] may be suitable in the treatment of drug-resistant assessed the anticancer activity of CA and NCTD against leukemia [103]. With regard to the mechanism of CA medulloblastoma, as cell lines in vitro and in athymic action in leukemia cells, Efferth et al. [180] suggested that nude mice in vivo. Intra-peritoneal administration of it causes oxidative stress that provokes DNA damage and NCTD inhibited the growth of intra-cerebellum tumors in p53-dependent apoptosis. orthotopic xenograft nude mice. They suggested that It is important to point out that CA and some of NCTD has potential therapeutic applications in the its analogues have apoptosis-inducing effects in the treatment of medulloblastoma as a result of its ability to human lung cancer.As reported by Zhang et al. [181], CA cross the blood-brain barrier and its impairment of Wnt- can induce A549 cells apoptosis mainly via regulation of β-catenin signaling. Bax, bcl-2 and survivin expression. In addition, Kok et al. [126] synthesized two CA analogues and assessed them 4. CHEMOTHERAPEUTIC USES OF on the A549 non-small cell lung carcinoma cell lines by CANTHARIDIN FOR SOME OTHER DISEASES monitoring the intracellular adenosine triphosphate level. 4.1 Cantharidin for heart failure NCTD, in general, may has a wide therapeutic and/or CA has been demonstrated to act as a adjuvant therapeutic application in the treatment of vasoconstrictor and positive inotrope in guinea pig [188] human lung cancer [182]. Cancer cells invade into the and human cardiac tissue in vitro [189]. These effects are blood or lymphatic vessels leading to the spread of cancer mediated in part by CA’s action as a protein phosphatase into the organs in distant sites. For cancer cells to migrate, inhibitor [107, 108]. Effects of CA on the force of

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contraction and phosphatase activity in nonfailing and compounds showing a slight stimulating effect on failing human hearts were evaluated. The positive xanthine oxidase [114]. inotropic effect of CA was similar in nonfailing and failing human hearts, accompanied by a similar inhibitory 4.3. Cantharidin for neurological disorders effect of CA on the phosphatase activity [189]. CA was The synaptic transmission at the mouse observed, also, to increases force of contraction in neuromuscular junction has been affected by CA since it isolated myocardial and vascular preparations by inhibits the mobilizations of synaptic vesicles and enhancing the phosphorylation state of myocardial and depresses Ca (2+) release from sarcoplasmic reticulum vascular regulatory proteins [164]. To shed some light on and that protein phosphatases participates in the this process, Narayan et al. [190] examined whether the modulation of motor function [196]. With regard to the protein phosphatase inhibitor CA blocks the anti- neurodegenerative diseases, both protein phosphatase adrenergic effect of adenosine A(1) receptor stimulation. inhibitors PP1 and PP2A are necessary for the splicing Their results suggested that activation of protein reaction [197]. As found by Novoyatleva et al. [198], phosphatases mediate, in part, the anti-adrenergic effect reducing PP1 activity promotes usage of numerous of adenosine A(1) receptor activation in ventricular alternative exons, demonstrating a role of PP1 activity in myocardium. Also, some experiments were carried out by splice site selection. Recently, CA was used as a starting Chu et al. [191] to examine whether the protein point to synthesize a series of phosphatase activity that phosphatase inhibitor CA inhibits the negative inotropic were subsequently tested for their effect on alternative effect induced by endothelin‐1 and carbachol in isolated neuronal splicing (for details, see Zhang et al. [199]). canine ventricular trabeculae. Their results indicated that Tauopathies are a class of neurodegenerative the activation of phosphatase that is susceptible to CA is diseases associated with the pathological aggregation of involved in both the endothelin‐1‐ induced and the tau protein in the human brain. Tau protein has a carbachol‐induced negative inotropic effect. However, causative role in Alzheimer’s disease and multiple other CA derivatives can be developed in the future, offering neurodegenerative disorders. The primary function of tau new therapeutic options for the treatment of human protein is to facilitate assembly and maintenance of cardiac failure [42]. In the guinea pig, cardiac effect of microtubules in neuronal axons. As found experimentally, CA was compared to that effect of the CA-related inhibition of PP2A by CA caused an increase in soluble compound endothall. In contrast to CA, endothall failed levels of total tau and phosphorylated tau. Inhibition of to increase force of contraction, though it inhibited PP2A also caused mislocalization of phosphorylated tau protein phosphatase activity. Thus, endothall is not an to cell bodies and initial neuritic segments [200]. On the appropriate tool to study the function of protein other hand, the drug abuse-induced neurodegeneration phosphatases in the mammalian heart [75]. can be triggered by elevated production of reactive oxygen species (ROS). The amphetamine (AMPH)- 4.2. Cantharidin for hepatitis mediated dopamine (DA) release increased nearly two- Since approximately 170 million people are fold in striatal rat brain slices pretreated for 30 min with infected with Hepatitis C virus (HCV) worldwide, HCV 1000 μM CA. These findings proved the lack of ROS infection is a serious global health problem [192]. HCV inhibitory action on protein phosphatase activity in acute causes acute and chronic hepatitis, often associated with AMPH-mediated DA efflux [201]. It is worth pointing out an increased risk of developing chronic liver disease and that antioxidants interfere with the oxidation process by hepatocellular carcinoma [193]. In TCM, three reacting with free radicals, chelating catalytic metals and compounds purified from natural products, CA, also by acting as oxygen scavengers. Therefore, the cephalotaxine andhomoharingtonine, are commonly used preparation of more effective new antioxidants is a very against the viral hepatitis B and C. Romero et al. [194] important area of research. Peksel et al. [202] investigated assessed the activity of these compounds against the reducing power, free radical scavenging, superoxide flavivirus using the bovine viral diarrhoea virus (BVDV) anion radical scavenging and metal chelating activities of as a surrogate for hepatitis C virus (HCV). It was some NCTD and bridged perhydroisoindole derivatives. suggested that these compounds are useless for the Among the synthesized derivatives, some had been found treatment of infection by flaviviruses, but potentially as potent antioxidants and thus they represent a new class useful in combined therapy against hepatitis B. CA uses of antioxidant and antiradical agents. in the treatment of hepatitis B was also reported [195]. NCTD has been used for the treatment of hepatitis. Since 4.4. Cantharidin for innate immune system the enzyme xanthine oxidase is involved in this disease, Innate immune system serves as the first defense fourteen CA analogues and cantharidimide derivatives to protect the host from the invading pathogens in a non- were tested for their effects on this enzyme. The disodium specific but instant way [203]. Different pathways have cantharidate, norcantharidin, dehydronorcantharidin, been involved to eliminate the invading pathogens in disodium dehydronorcantharidate were among the tested innate immune system which are different from acquired

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immune system [204]. The recognition to pathogen- for P. falciparum during release of mature merozoits from associated molecular patterns by germ line-encoded erythrocytes [216]. pattern-recognition receptors is one of the most essential More than 16,000 species of nematodes pathways for host to distinguish the pathogens from self- (roundworms) are parasitic. Nematodes commonly tissues [205]. A family of innateimmune receptors, known parasitic on humans include ascarids (Ascaris), filarias, as Toll-like receptors (TLRs), is widely expressed on the hookworms, pinworms (Enterobius) and whipworms cell surface of most immune cells [206]. The activation of (Trichuris trichiura). Baylisascaris usually infests wild TLRs can stimulate immune cells and cause the secretion animals, but can be deadly to humans, as well. Dirofilaria of cytokines and chemokine to modulate innate and immitis heartworms are known for causing heartworm acquired immune response [207]. For investigating the disease by inhabiting the hearts, arteries, and lungs of function and mechanism of NCTD in regulation of TLR4- dogs and some cats.Haemonchus contortus is one of the associated immune response in macrophages, Zhao et al. most abundant infectious agents in sheep around the [208] investigated the influence of this CAanalogue on world, causing great economic damage to sheep (For host defense against invading pathogens by acute details, see [217-219]). peritonitis mouse model, ELISA, Q-PCR, nitrite With the major problems with resistance in quantification, phagocytosis assay and gelatin parasitic nematodes of livestock to anthelmintic drugs, zymography assay. Their results demonstrated that NCTD there is an urgent need to develop new nematocides. could facilitate lipopolysaccharide-mediated signaling Protein phosphatase inhibitors, such as CA and a number immune response through promoting the phosphorylation of analogues with the same pharmacophoric units but no of AKT/p65 and transcriptional activity of NF-kB adverse toxic effects on well-defined, cultured human (nuclear factor-kB). Thus NCTD can be considered a cells [139, 140, 220], show unique potential for the novel immune regulator in promoting host defense against development of nematocides [221]. Campbell et al. bacterial infection. [222]investigated the activity of more than fifty analogues against the barbers pole worm Haemonchus contortus, an 4.5. Cantharidin and cantharidin-related compounds intestinal parasite that affects livestock. They concluded against parasitic infections that a major advantage of NCTD analogues over some Plasmodium falciparum is a protozoan parasite other currently available anthelmintics is that they can be and the causative agent of the most virulent form of produced in one to two steps in large amounts at low cost malaria in humans [209]. As declared by Bajsa et al. and high purity, and do not require any additional steps [210], malaria is still a dangerous disease, despite the for the isolation of the active isomer. NCTD analogues availability of antimalarial drug. This situation is partly have been, also, shown to display anti-parasitic activity caused by the high ability of P. falciparum to evolve against the same nematode H. contortus [135]. Some resistance to the most commonly used drugs during the CA/NCTD analogues [140, 223, 224] are known to constant selection pressure. Therefore there is an urgent display relatively specific inhibitory activity against PP1 need of new drug development against new enzyme and PP2A phosphatases, which indicates that some of targets of this protozoan parasite. Bajsa et al. [211] them could be designed to selectively inhibit essential determined IC50 of 81 different CA analogues against serine⁄threonine phosphatase of nematodes [221]. chloroquine-susceptible (D6) and -resistant (W2) strains The anthelmintic activity of different species of of P. falciparum. At least two features of NCTD the tree Butea has been reported against Ascaridia galli, analogues make them a potential source of antimalarials. Ascaris lumbricoides, earthworms, Toxocara canis, Sixty NCTD analogues were tested and most chemical oxyurids, Dipylidium caninum and Taenia [225]. Extract modifications caused reduction in the antiplasmodial of Butea monosperma seeds showed significant activity below that of CA. Three of them had similar or anthelmintic activity in vitro [226].The crude extracts greater activity than CA [210]. were investigated for their anthelmintic activity of B. One of the CA-related compounds isEndothall. It monosperma against earthworms (Pheretima posthuma), has been widely used for effective control of several sub- roundworms (Ascardia galli) and tapeworms (Raillietina mersed aquatic plant species [212]. It wasreported to spiralis). The anthelmintic activity of alcohol and ethyl possess herbicidal activity in 1948 by Niagara Chemical acetate extracts of leaves of B. monosperma has been Company and was registered for use as a plant growth demonstrated [227]. Recently, some other regulator by the Sharples Chemicals Company in 1951 pharmacological properties had been reported for the [213]. Endothall has shown the best in vitro same tree [68, 228, 229]. The tree Butea frondosa (= B. antiplasmodial activity among the commercial herbicides monosperma) contains an antihelmintic principle [214]. This compound inhibits protein phosphatases (PP1 palasonin [230]. and PP2A) from mammals and plants [215]. Some studies Palasonin is a CA-related compound which was had shown that the function of enzyme PP1 is essential found to be effective against ascarids, stomach worms of sheep, oxyurids of mice, and hook worms of dogs [231].

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Palasonin was found an effective anthelmintic against 6. CANTHARIDIN AND ITS ANALOGUES IN THE Ascaris lumbricoides [232] and several other helminthes DRUG DELIVERY SYSTEMS [233]. The biochemical mechanism of the antihelminthic The clinical use of CA is limited because of its action of palasonin is based upon inhibition of glucose short half-life and toxicity (for review see Ghoneim, uptake affecting the energy generating mechanisms and [19]). CA was also shown to be a poorly water-soluble motor activity of the parasite [234]. Like CA, palasonin drug with low oral bioavailability (26.7%) in beagle also inhibits PPA2, albeit with much lower efficiency dogs[47]. To reduce the toxicity and other disadvantages [235]. of CA and its analogues in the clinical usage, some researchers evaluated other preparation methods of CA 5. CANTHARIDIN FOR OVERCOMING THE delivery, such as solid dispersions [241] and inclusion DRUG RESISTANCE complexes [242]. Chang et al. [243] prepared an Drug resistance, known as multi-drug resistance encapsulated CA into pegylated liposomes and studied its (MDR), to chemotherapeutic agents is one of the major activity against human breast cancer MCF-7 cells in vitro obstacles in the treatment of human cancers[236]. as well as its systemic toxicity in mice. Depending on Currently, many clinical anticancer drugs such as their results, the systemic toxicity of CA could be alkaloids, anthracycline antibiotics, and podophyllotoxins mitigated by liposome encapsulation;however, that did may easily induce MDR [237]. The mechanisms not decrease its antitumor activity. Because CA is underlying the MDR of cancer cells are complex, partially water-soluble, Dang et al. [241] investigated the including increase of drug efflux, reduction of drug solid dispersion of CA (CA-SD) in polyethylene glycol absorption, changes in the targets of anticancer drugs, 4000 (PEG 4000) to increase its dissolution rate and oral decrease of drug activity, enhancement of DNA repair bioavailability. As recorded in this study, the solubility following damage, changes in anti-apoptosis pathways, and dissolution rate of CA were improved by the solid etc. [238]. Development or discovery of safe and effective dispersion technique. In the field of developing targeting MDR reversal agents is urgently required [237]. Three drug delivery system, Li et al. [244] prepared CA- generations of the MDR inhibitors had been described by entrapped non-ionic surfactant vesicle (noisome) and Tan et al. [239]. Mamot et al. [240] discussed some evaluated its entrapment efficiency. The preparation of general approaches for overcoming MDR using liposomes CA noisome by TweenA and SpanB was found or other carriers and increasing bioavailability of drugs at practicable and successful. Very recently, Han et al. [245] sites of action. obtained similar results which revealed that the CA- The available literature contains several reports entrapped non-ionic surfactant vesicles could be a suggesting CA and its analogues as a novel and potent promising delivery system for enhancing the antitumor MDR reversal agent tumor chemotherapy. Exposure of activity and simultaneously reducing the toxicity of CA. HL-60 (Human promyelocytic leukemia) cells to CA Because NCTD injection causes urinary organ resulted in the decreased expression of multidrug damnification, Zhang et al. [246] prepared a NCTD w/o resistance-associated protein genes. Therefore, CA may microemulsion as an alternative to improve the solubility be used as an oncotherapy sensitizer, and the increased and enhance the liver uptake of this CA analogue. Their expression of genes in modulating cytokine production pharmacokinetic results showed that NCTD and inflammatory response, which may partly explain the microemulsion had relatively longer circulating time in stimulating effects on leukocytosis [175]. mice than NCTD (alone) injection after a single Also, Zheng et al. [26] reported that CA can intravenous injection at a dose of 5 mg/kg. On the other effectively reverse MDR via down-regulation of MDR1 hand, Poly(L-lactide-co-glycolide)-alginate microspheres gene expression. With regard to CA analogues, Yi et al. containing NCTD were effective in destroying the cancer [103] suggested the use of NCTD in the treatment of cells. These microspheres also exhibited excellent drug-resistantleukemia. Since oral cancer cells with embolization and therapeutic effects on rats with mutant p53 or elevated Bcl-XL levels showed resistance transplanted tumors [247]. Lipid microspheres (LM) have to multiple chemotherapeutic agents, NCTD may recently been used as intravenous carriers for drugs, overcome the chemoresistance of these cells and provide which are sufficiently soluble in oil. Because NCTD is potential new avenues for treatment [104]. To clarify the poorly soluble in both the water and oil phases, Lixin et effect of NCTD on drug resistance in breast cancer, Chen al. [248] prepared NCTD-loaded LM by transferring the et al. [134] developed doxorubicin (DOX)-sensitive and drug to the interfacial surface of the oil and aqueous DOX-resistant MCF-7 cells. Their study demonstrated phases to produce a less irritating intravenous formulation that NCTD may overcome multidrug resistance through of NCTD. In addition, Zhang et al. [249] modified the inhibiting Sonic hedgehog signaling and expression of its NCTD-encapsulated liposomes with a novel murine anti- downstream MDR-1/P-gp expression in human breast human CD19 monoclonal antibody 2E8 (2E8-NCTD- cancer cells. liposomes) and evaluated the targeting efficiency and

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specific cytotoxicity of 2E8-NCTD-liposomes to [254]. Two novel liver-targeting nanoparticles, NCTD- CD19(+) leukemia cells. loaded chitosan nanoparticles and NCTD-associated Nanotechnology provides some benefits in the galactosylated chitosan nanoparticles, were prepared field of drug delivery systems. The production and using ionic cross-linkage. The results indicated that the physicochemical characterization of particles and chitosan nanoparticles can improve intestinal absorption associated drug incorporation had been reported in a of NCTD [255]. N-Trimethyl chitosan was synthesized number of studies [250]. We have compiled here some of for preparing lactosyl-NCTD TMC nanoparticles. N- the recently reported works in the literature. Solid lipid trimethyl chitosan-encapsulated lactosyl-NCTD nanoparticles (SLNs) are one example of a feasible nanoparticles displayed efficient targeting and sustained nanosized drug delivery system. The particle matrix of a release in a hepatocarcinoma SC murine model [256]. A SLN is composed of solid lipid, which is very attractive novel hepatocyte-targeting NCTD derivative lactosyl- for the controlled release of drugs because drug mobility NCTD (Lac-NCTD) was synthesized using in a solid lipid should be considerably lower than in liquid ethanediamine as a truss arm, and lactosyl-NCTD oil, so that retarded drug release after oral administration nanoparticles (Lac-NCTD-NPs) were obtained by an ionic can be achieved [47]. Dang and Zhu [48] carried out a cross-linkage process with an entrapment efficiency of study aiming to improve the oral bioavailability of CA (80.29 ± 0.56)%. The results suggested that tumour and control its release profile in vivo using SLNs growth was effectively inhibited by all treatments, formulation. They concluded that the CA-SLNs could including NCTD, Lac-NCTD and Lac-NCTD-NPs, with improve the solubility and oral bioavailability of CA. As Lac-NCTD-NPs being the most effective, followed by reported by Zhang [251], CA drug-loaded solid lipid Lac-NCTD [257]. nanoparticles will enable the effective targeting of drug To develop charge-reversal nanocarriers for delivery in the liver lesions, reducing its toxic side effects antitumor drug delivery, Lu et al. [258] utilized the and slow-release effect. characteristic anhydride structure of NCTD and the pH- In addition to CA, solid lipid nanoparticles dependent hydrolysis of its β-carboxylic amides and containing its analogue, NCTD, had been prepared and developed novel acid-labile conjugates for the targeted characterized by Tian and Zhai [252]. These solid lipid delivery of NCTD. These targeted acid-labile conjugates nanoparticles of NCTD have high entrapment efficiency may help to reduce the side effects of NCTD and improve and good stability. A new chitosan derivative, its clinical applications. Very recently, Ding et al. [259] galactosylated chitosan (GC), was synthesized and used to investigated the drug-loaded mechanism of ion-cross- prepare NCTD-associated GC nanoparticles [253]. A linked nanoparticles (NPs) in the presence of novel formulation containing polyvinylpyrrolidone (PVP) polyvinylpyrrolidone K30 (PVP K30) and set up the K30-coated NCTD chitosan nanoparticles(PVP–NCTD– optimal PVP-coated NCTD chitosan NPs method. They NPs) was prepared and its activity was assessed in the recorded that the PVP-NCTD-NP with dual physical kidney and liver tissues of rats and mice. It was concluded drug-loaded mechanisms (physical encapsulation and that PVP–NCTD–NPs are an adequate formulation for coating of PVP) possessed higher drug content and enhancing the absorption of NCTD, and significantly showed longer sustained release. improving therapeutic effects targeting the hepatic system

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