**5. Alkaloids**

7

8

Triterpenoids are one of the most abundant natural products in plants. They exhibit huge structural diversity as more than 90 different triterpenoidal carbon skeletons are known. Further oxidative modifications and glycosidation of the skeleton generate even more diversity [22]. Oleanolic (Figure 5a) and ursolic acids (Figure 5b) are among the well-known natural occurring pentacyclic triterpenoids that widely exist in many food products and in more than 120 plant species [23]. Oleanolic acid (OA) is known to possess anti-inflammatory, antitumor, antiviral, hepatoprotective and antihyperlipidemic effects. Moreover, it has been used in Chinese traditional medicine to treat liver disorders for over twenty years. Ursolic acid (UA) is also known to exhibit a wide and interesting biological activities including anti-inflamma‐ tory, anti-ulcer, antihyperlipidameic, antihyperglycaemic, hepatoprotective, neuroprotective and anticacinogenic activities [23]. The oral bioavailability of these two natural triterpenoidal acids is greatly limited by their very poor solubility in water. In fact, this drawback limits their

**Figure 4:** Flower and seeds of *N. sativa* and the structure of thymoquinone, the main component of *N. sativa* and many other plants

Triterpenoids are one of the most abundant natural products in plants. They exhibit huge structural diversity as more than 90 different triterpenoidal carbon skeletons are known. Further oxidative modifications and glycosidation of the skeleton generate even more diversity **[**22**]**. Oleanolic (Figure 5a) and ursolic acids (Figure 5b) are among the well-known natural occurring pentacyclic triterpenoids that widely exist in many food products and in more than 120 plant species **[23]**. Oleanolic acid (OA) is known to possess antiinflammatory, antitumor, antiviral, hepatoprotective and antihyperlipidemic effects. Moreover, it has been used in Chinese traditional medicine to treat liver disorders for over twenty years. Ursolic acid (UA) is also known to exhibit a wide and interesting biological activities including anti-inflammatory, anti-ulcer, antihyperlipidameic, antihyperglycaemic, hepatoprotective, neuroprotective and anticacinogenic activities [23]. The oral bioavailability of both natural triterpenoidal acids is greatly limited by their very poor solubility in water. In fact, this drawback limits their development as a medicine as well as their use in food, health and cosmetic products.

**Figure 5.** Structures of a) oleanolic acid and b) ursolic acid

hence hinders its usage as a drug.

**Figure 6**. Structure of Asiatic acid

**Figure 6.** Structure of Asiatic acid

inflammatory, antimicrobial, and antitumor activities **[**26**]**.

**HO**

**H**

**OH**

**H**

**H**

**H**

**HO**

**Figure 7.** Basic structure of a cucurbitacin

its usage as a drug.

**HO**

348 Application of Nanotechnology in Drug Delivery

**H**

**Figure 5.** Structures of a) oleanolic acid and b) ursolic acid

**H**

development as a medicine as well as their use in food, health and cosmetic products.

**H CO2H**

**a b**

**H**

**HO**

Asiatic acid (Figure 6) is another natural derivative of oleanolic acid. This compound is known to be clinically effective on systemic scleroderma, abnormal scar formation and keloids [24]. Again, the poor solubility of this compound in water limits its bioavailability and hence hinders

Asiatic acid (Figure 6) is another natural derivative of oleanolic acid. This compound is known to be clinically effective on systemic scleroderma, abnormal scar formation and keloids **[**24**]**. Again, the poor solubility of this compound in water limits its bioavailability and

**H**

**CO2H**

Cucurbitacins (Figure 7) resemble another class of triterpenes with interesting pharmaceutical properties. Cucurbitacins are a group of highly oxidized tetracyclic triterpenoids that are widely distributed in the plant kingdom and well recognized for their bitterness and toxicity. Such compounds were initially isolated from plants belonging to the plant family *Cucurbitaceae,* but were later found to be present, either as non-glycosylated or glycosylated in many plant families including *Brassicaceae*, *Scrophulariaceae*, *Begoniaceae*, *Elaeocarpaceae*, *Datiscaceae*, *Desfontainiaceae*, *Polemoniaceae*, *Primulaceae*, *Rubiaceae*, *Sterculiaceae*, *Rosaceae* and *Thymelaeaceae*. In plants, cucurbitacins are known to act as heterologous chemical pheromones that protect plants from external biological insults **[**25**]**. Moreover, these compounds are known to possess a broad range of potent biological activity due to their cytotoxic properties. In traditional medicine, cucurbitacins -containing plants have been known for their antipyretic, analgesic, anti-

**H**

**H**

**H**

**H CO2H**

Alkaloids are a highly diverse class of secondary metabolites, with more than 5000 compounds being identified ranging from simple to highly complicated structures. These compounds contain a ring structure and a nitrogen atom, in most cases, the nitrogen is part of a heterocyclic ring structure. Alkaloids are known to exhibit significant biological activities. Examples include the relieving action of ephedrine for asthma, the analgesic action of morphine and the anticancer effects of vinblastine. Vinca alkaloids like vinblastine, vincristine, and vinorelbine are widely used cytotoxic drugs that elicit their effects through disruption of microtubules, resulting in metaphase arrest in dividing cells [27]. Thus, these compounds would benefit from a controlled release dosage form that would result in a prolonged duration of exposure over extended period of time. However, in spite of their significant bioactivities, these compounds suffer from side effects. The major adverse effect of vinblastine is hematologic toxicity which occurs much more frequently than with vincristine therapy. Other side effects include nausea, vomiting and constipation, dyspnea, chest or tumor pain, wheezing and fever. Many recent publications dealt with loading vinca alkaloids in liposomal nanocarriers to lessen such side effects [27, 28].

However, they cannot be used to tackle other problems accompanying natural active com‐ pounds such as toxicity and stability since micellar systems are very dynamic ones and suffer from fast clearance rate and stability issues. However, some of these disadvantages were to some extent reduced via the preparation of polymeric micelles [33]. Polymeric micelles are

**Figure 8.** a) Sketch of a lipid or surfactant molecule capable of forming micelles and liposomes with a polar head and non-polar tail, b)

**Figure 8.** a) Sketch of a lipid or surfactant molecule capable of forming micelles and liposomes with a polar head and non-polar tail, b) Schematic presentation of a micelle with an insoluble drug encapsulated in the vicinity made by the

*Insoluble drug*

b

Liposomes are spherical vesicles that are composed of lipid bilayer (Figure 9a). Liposomes were discovered in 1961 by the British haematologist Alec Bangham and its resemblance to the cell membrane attracted immediate attention [34, 35, 36]. The name liposome was derived from the two Greek words *lipo* meaning fat and *soma* meaning body, which perfectly describes these spherical objects that are made mainly from lipids. In some cases other constituents are added to modify their chemical and physical properties (Figure 9b). Liposomes are easily prepared by disturbing the lipid film in aqueous medium. This disturbance may be a result of a large shear force produced via several techniques such as sonication. Liposomes are different from micelles (Figure 9) in that they are composed of

Liposomes are spherical vesicles that are composed of lipid bilayer (Figure 9a). Liposomes were discovered in 1961 by the British haematologist Alec Bangham and its resemblance to the cell membrane attracted immediate attention [34, 35, 36]. The name liposome was derived from the two Greek words *lipo* meaning fat and *soma* meaning body, which perfectly describes these spherical objects that are made mainly from lipids. In some cases other constituents are added to modify their chemical and physical properties (Figure 9b). Liposomes are easily prepared by disturbing the lipid film in aqueous medium. This disturbance may be a result from a large shear force produced via several techniques such as sonication. Liposomes are different from micelles (Figure 9) in that they are composed of bilayer lipid membrane whereas

There are different types of liposomes, including Small Unilamellar Vesicles (SUV, Figure 10b), Multilamellar Vesicles (MLV, Figure 10c), Large Unilamellar Vesicles (LUV, Figure 10d), Multivesicle Vesicles (MVV, Figure 10e) and cochleate vesicles (Figure 11). Each type of liposome is formed depending on experimental conditions. In addition, a dominant liposome type, size can be determined and/or made, after they are prepared via a series of extrusion process accompanied by shear or via several freeze-thaw processes since these structures are

Liposomes are very important as drug carrier systems due to many factors including their suitability to encapsulate polar and non polar drugs, their stability and long shelf life, con‐ trollable properties such as size and charge, ability to functionalize and modify the surface due to the presence of many functional groups, and finally their biocompatibility and degradabil‐ ity. However, liposomes suffer from various disadvantages which include their short half-life

Schematic presentation of a micelle with an insoluble drug encapsulated in the vicinity made by the non-polar tails

bilayer lipid membrane whereas micelles are made from monolayer lipid vesicles.

micelles are made from monolayer lipid vesicles.

Micelles are spontaneous aggregates of amphiphiles (such as surfactants, Figure 8a) with usually spherical structures with a size range of 5-25 nm (Figure 8b). Their core is usually hydrophobic if they aggregate in polar medium, however, they do form inverted micellar system in non polar media with a hydrophilic core. Micelles are perfect carriers for drugs and have been used more than any other system of nanoparticles [30]. Micelles come first in mind when tackling solubility issues in aqueous media [31, 32]. The solubilization power of micelles has been known and used for a long time especially as detergent. Their mechanism of action was discovered in early 1900s. Micelles can be used as drug carriers and as solubilizing agents. However, they cannot be used to tackle other problems accompanying natural active compounds such as toxicity and stability since micellar systems are very dynamic ones and suffer from fast clearance rate and stability issues. However, some of these disadvantages were to some extent reduced- via the preparation of polymeric

Nanoflora — How Nanotechnology Enhanced the Use of Active Phytochemicals

http://dx.doi.org/10.5772/58704

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more stable with longer shelf life and stay longer in the body.

a

micelles [33]**.** Polymeric micelles are more stable with longer shelf life and stay longer in the body.

**6.1 Micelles and Liposomes** 

non-polar tails

dynamic.
