**4. Terpenoids**

5

6

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

**HO**

**H**

**H**

allergic and anti-ulcer effects. Also, flavonoids are known to be potent antioxidants with free radical scavenging abilities [9, 10]. Some flavonoids are known to provide protection against cardiovascular mortality. Moreover, they have been shown to inhibit the growth of various cancer cell lines *in vitro*, and reduce tumor development in experimental animals [11]. Flavanoids, as natural compounds have several great advantages over therapeutic agents because many diets are rich in flavonoids and polyphenolic compounds [9]. The therapeutic

Flavonoids received considerable attention due to their wide biological activities. Many of them are known to possess hepatotoxic, antiinflammatory, antimicrobial, antiviral, anti-allergic and anti-ulcer effects. Also, flavonoids are known to be potent antioxidants with free radical scavenging abilities [9, 10]. Some flavonoids are known to provide protection against cardiovascular mortality. Moreover, they have been shown to inhibit the growth of various cancer cell lines *in vitro*, and reduce tumor development in experimental animals [11]. Flavanoids, as natural compounds have several great advantages over therapeutic agents because many diets are rich in polyphenolic

**O**

**O**

**O**

**a b c**

**OH**

**O**

**d e f**

**OH**

**O**

**O**

**O**

**1'**

**7' 8' 9'**

**2' 3'**

**6' 5'**

**4'**

Lignans (Figure 2) are among the important polyphenolic compounds that are recognized with a wide spectrum of biological activities. These compounds generally represent a group of

Lignans (Figure 2) are among the important polyphenolic compounds that are recognized with a wide spectrum of biological activities. These compounds generally represent a group of dimeric phenylpropanoids where two C6-C3 are attached by its central carbon C-8.

Lignans are known for their antiviral, anticancer, cancer prevention, anti-inflammatory, antimicrobial and antioxidant activities. Also, lignans are known for their immunosuppressive, hepatoprotective and osterporosis prevention effects. Podophyllotoxin (Figure 3) has long been known to possess anti-mitotic activity with early clinical trials indicating its high efficacy. Unfortunately, this compound is known to be toxic limiting its direct application as a drug **[**12**]**. To solve the problem of toxicity, several modifications were made to the podophyllotoxin structure in hope of obtaining compounds with low toxicity but retain the desired activities of the parent compound.

Thus, etoposide, teniposide, etopophos and GL-331 were synthesized; all are potent chemotherapeutic agents for a variety of tumors.

**H OH**

**H**

**O**

**O**

**OMe**

Terpenoids, as represented by more than 40 000 identified compounds, are among the most widespread group of natural products, with several new compounds being discovered every year. These terpenes can be generally defined as a group of molecules whose structure is based on various but definite number of isoprene (3-methyl-1,3-butadiene) units. Based on the number of isoprene building blocks, terpenoids can be classified into monoterpenes (such as thymoquinone), sesquiterpenes, diterpenes (such as retinol, *trans*-retonic acid,

**OMe**

**MeO**

**O**

**O**

From a chemical point of view, terpenoids are usually cyclic unsaturated hydrocarbons, with different degrees of oxygen in the constituent groups attached to the basic isoprene skeleton. A wide range of terpenoids have been found to possess preventive and pharmacological activity against many human ailments including cancer and alzheimer **[**13, 14**]**. Several studies also indicated that terpenoids have antimicrobial, antifungal, antiparasitic, antiviral, anti-allergenic, anti-spasmodic, antihyperglycemic, anti-inflammatory

Monoterpenes are among the best known plant secondary metabolites and are one of the main classes of terpenoids detected in essential oils, floral scents and defensive resins (both constitutive and induced) of aromatic plants **[**16**]**. A number of monoterpenes have shown antitumor activity. Examples include thymoquinone (Figure 4), limonene and perilla alcohol. Thymoquinone, which is the main active constituent of the essential oil obtained from the medicinal plant *Nigella sativa* (commonly referred to as Black seeds in Arabic countries), have interesting anticancer, anti-oxidant and anti-inflammatory activities both *in vivo* and *in vitro* **[**14, 17, 18, 19**]** as well as chemo preventive properties. The interesting *in vitro* anticancer activity of this monoterpene against different types of cancer cell lines including human colorectal cancer cells [13**]**, myeloblastic leukemia cells **[**20**]**, prostate cancer **[**17**]** pancreatic adenocarcinoma **[**14**]**, ovarian and breast adenocarcinoma **[**21**]** were faced by several limitations that not only hindered its pharmaceutical applications, but also limited the available suitable approaches that can be used to enhance its bioavailability. Such limitations included the poor solubility,

sclareol), sesterterpenes, triterpenes (such as oleanolic and usrolic acids) and tetraterpenes.

extreme lipophiliciy causing poor formulation characteristics in addition to light and heat instability.

Lignans are known for their antiviral, anticancer, cancer prevention, anti-inflammatory, antimicrobial and antioxidant activities. Also, lignans are known for their immunosuppres‐ sive, hepatoprotective and osterporosis prevention effects. Podophyllotoxin (Figure 3) has long been known to possess anti-mitotic activity with early clinical trials indicating its high efficacy. Unfortunately, the toxicity of this compound limits its direct application as a drug [12]. To solve the problem of toxicity, several modifications were made to the podophyllotoxin structure in hope of obtaining compounds with low toxicity but retain the desired activities of the parent compound. Thus, etoposide, teniposide, etopophos and GL-331 were synthesized; all are potent chemotherapeutic agents for a variety of tumors. Still, etoposide and its analogues

**1**

**7 8 9**

**3 2**

**5 6**

dimeric phenylpropanoids where two C6-C3 are attached by its central carbon C-8.

**a b**

**4**

potential of flavonoids makes them valuable targets for drug design [8].

compounds [9]. The therapeutic potential of flavonoids makes them valuable targets for drug design [8].

**O**

**O**

**O**

**O**

**Figure 2.** Basic structure of lignans: a) Phenylpropanoid unit; b) Lignan structure

**Figure 2.** Basic structure of lignans: a) Phenylpropanoid unit; b) Lignan structure

**1**

**7**

**8**

**9**

**6**

**2**

**5**

suffer from poor solubility problems.

**Figure 3.** Structure of podophyllotoxin

**Figure 3.** Structure of podophyllotoxin

and immunomodulatory properties **[**15**]**.

**4. Terpenoids** 

Still, etoposide and its analogues suffer from poor solubility problems.

**3 4**

**Figure 1.** Basic structures of some flavonoids' backbone

346 Application of Nanotechnology in Drug Delivery

Terpenoids, as represented by more than 40000 identified compounds, are among the most widespread group of natural products, with several new compounds being discovered every year. Terpenes can be generally defined as a group of molecules whose structure is based on various but definite number of isoprene (3-methyl-1,3-butadiene) units. Based on the number of isoprene building blocks, terpenoids can be classified into monoterpenes (such as thymo‐ quinone), sesquiterpenes, diterpenes (such as retinol, *trans*-retonic acid, sclareol), sesterter‐ penes, triterpenes (such as oleanolic and usrolic acids) and tetraterpenes.

From a chemical point of view, terpenoids are usually cyclic unsaturated hydrocarbons, with different degrees of oxygen in the constituent groups attached to the basic isoprene skeleton. A wide range of terpenoids have been found to possess preventive and pharmacological activity against many human ailments including cancer and alzheimer [13, 14]. Several studies also indicated that terpenoids have antimicrobial, antifungal, antiparasitic, antiviral, antiallergenic, anti-spasmodic, antihyperglycemic, anti-inflammatory and immunomodulatory properties [15].

Monoterpenes are among the best known plant secondary metabolites and are one of the main classes of terpenoids detected in essential oils, floral scents and defensive resins (both constitu‐ tive and induced) of aromatic plants [16]. A number of monoterpenes have shown antitumor activity. Examples include thymoquinone (Figure 4), limonene and perilla alcohol. Thymoqui‐ none, which is the main active constituent of the essential oil obtained from the medicinal plant *Nigella sativa* (commonly referred to as Black seeds in Arabic countries), has interesting anticancer, anti-oxidant and anti-inflammatory activities both *in vivo* and *in vitro* [14, 17, 18, 19] as well as chemo-preventive properties. The interesting *in vitro* anticancer activity of this monoterpene against differenttypes of cancer cell lines including human colorectal cancer cells [13], myeloblastic leukemia cells [20], prostate cancer [17] pancreatic adenocarcinoma [14], ovarianandbreastadenocarcinoma[21]werefacedbyseverallimitations thatnotonlyhindered its pharmaceutical applications, but also limited the available suitable approaches that can be used to enhance its bioavailability. Such limitations included the poor solubility, extreme lipophiliciy causing poor formulation characteristics in addition to light and heat instability.

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

**H CO2H**

**a b**

**H**

**HO**

**H**

**H CO2H**

7

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

**Figure 5.** Structures of a) oleanolic acid and b) ursolic acid 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 its usage as a drug. 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 its usage as a drug.

7

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 *Cucurbita‐ ceae,* 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 *Thymelaea‐ ceae*. 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,

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**

There are 17 main molecules from cucurbitacin A to cucurbitacin T, and hundreds of com‐ pounds derived from them. Among them, cucurbitacins B, D, F, I and compounds derived

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

**H**

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**

Nanoflora — How Nanotechnology Enhanced the Use of Active Phytochemicals

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

349

8

analgesic, anti-inflammatory, antimicrobial, and antitumor activities [26].

**H**

from them have been extenively investigated for their anticancer activities.

**H**

**H**

**OH**

**H**

**HO**

**HO**

hence hinders its usage as a drug.

**Figure 6**. Structure of Asiatic acid

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

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

**5. Alkaloids**

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

8

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**

**Figure 6**. Structure of Asiatic acid **Figure 6.** Structure of Asiatic acid

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

**H**

**H**

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

8

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 *Cucurbita‐ ceae,* 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 *Thymelaea‐ ceae*. 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-inflammatory, antimicrobial, and antitumor activities [26]. **Figure 6**. Structure of Asiatic acid 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-**OH**

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**

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

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

**HO**

**H**

**HO**

hence hinders its usage as a drug.

There are 17 main molecules from cucurbitacin A to cucurbitacin T, and hundreds of com‐ pounds derived from them. Among them, cucurbitacins B, D, F, I and compounds derived from them have been extenively investigated for their anticancer activities.
