**3. Phenolic compounds**

Natural phenolic compounds are secondary metabolites present in all vascular plants and embracing a vast range of aromatic organic compounds with one or more hydroxyl substitu‐ ent(s). The parent compound is phenol but most of these naturally occurring compounds are polyphenolics, which to date, exceeds 8000 structurally identified compounds. Plant polyphe‐ nolics are grouped into different classes depending on their chemical structure. Flavanoids are the largest and most important group of natural polyphenolics with more than 6000 molecules identified so far. Other classes include phenolic quinones, lignans, xanthones, coumarines, polymeric lignins and tanins [5]. Within each class of compounds, the variations around the basic chemical skeleton essentially concern the degrees of oxidation, hydroxylation, methyla‐ tion, glycosylation and the possible connections to other molecules (primary metabolites such as carbohydrates, lipids, proteins, or phenolic secondary metabolites [6].

Polyphenols were the focus of special attention as a result of the so-called Mediterranean diet rich in fruits and vegetables. This diet appears to protect against cardiovascular diseases in addition to potential beneficial health properties, as evidenced by several epidemiological studies showing that diets rich in fruits and vegetables are generally associated with a lower cancer incidence and other diseases, such as inflammatory or cardiovascular pathologies [7].

The bioavailability of the orally administrated polyphenols is very low due to their low water solubility, poor absorption, extensive and rapid metabolism. To overcome these problems, several bioactive polyphenols were formulated into various pharmaceutical formulations that could improve their bioavailability.

Among the types of naturally occurring polyphenols, flavonoids (Figure 1) are a large and a highly diverse group of structurally related secondary metabolites produced by plants. The main flavonoids subclasses include flavones (Figure 1a), flavonols (Figure 1b), flavans (Figure 1c), flavanones (Figure 1d) in addition to dihidroflavanols (Figure 1e), isoflavons (Figure 1f) and biflavones. [8].

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

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

**1**

**7**

**8**

**9**

**6**

**2**

**5**

**3 4**

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

the actual or real activity of the salt form, the need for further studies to insure the presence of the bioactive form of the drug and the extent of its bioavailability. In this aspect, nanotech‐ nology is a very promising tool for enhancing the use of herbal medicines, or in more accurate words, to re-discover their full potential in pharmaceutical formulation. Extensive libraries of nanoparticles-that can be used for the delivery of natural bioactive compounds to a certain target-have been studied. These different nanoparticles can be designed, prepared in different shapes, sizes, compositions, functionalized and modified chemically/physically to suite specific properties depending on the characteristics of both the drug and the targeted organ. These nanoparticles can be anything from emulsion and micro-emulsions, dendrimers, fullerenes, liquid crystals, quantum dots, nano rods, solid lipid nanoparticles (SLN), lipo‐

In this chapter, a brief focus on herbal medicines, nanotechnological approaches to enhance their promised action will be reviewed and discussed. At the end, successful stories of nanoparticle loaded active phytochemicals that reached the market will be presented as case

Natural products chemistry is one of the oldest sciences sought for medicine throughout the history of mankind. Its roots dates back in time, thousands of years ago, through the use of many herbal mixtures as remedies for many diseases. It was clear from the beginning that certain herbs, plants, etc… have certain positive influence when used as remedies for sickness, but it was unclear how the mechanism of remedy was attained. As a consequence of the accumulation of many years of knowledge, traditional medicine has come forth to group, organize and categorize these remedies according to their effects on diseases, whereby, biomedicine and chemistry came to shed more light on the active ingredients of these folk

Currently, natural product chemistry has evolved to be an interdisciplinary area of science, concerned with the isolation, characterization and determination of the biological activity of the pure phytochemicals. These active components, generally referred to as secondary metabolites, include phenolics, terpenoids, alkaloids and steroids. Even though it has been proved that many natural products have a strong therapeutic value, limitations related to their poor solubility and bioavailability in addition to toxicity and stability have severely hindered their use as drugs [3]. According to U.S. Food and Drug Administration (FDA), the definition of bioavailability is "the rate and extent to which the active ingredient or active moiety is

Natural phenolic compounds are secondary metabolites present in all vascular plants and embracing a vast range of aromatic organic compounds with one or more hydroxyl substitu‐

absorbed from a drug product and becomes available at the site of action" [4].

somes, gels and many other different types.

344 Application of Nanotechnology in Drug Delivery

remedies and on the mechanism of their action.

studies in this field.

**2. Herbal medicine**

**3. Phenolic compounds**

Flavonoids received considerable attention due to their wide biological activities. Many of them are known to possess hepatotoxic, anti-Flavonoids received considerable attention due to their wide biological activities. Many of them are known to possess hepatotoxic, anti-inflammatory, antimicrobial, antiviral, anti-

inflammatory, 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

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.

**1**

**7 8 9**

**3 2**

**5 6**

**4**

**a b**

**1'**

**7' 8' 9'**

**2' 3'**

**6' 5'**

**4'**

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

5

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

**O**

**O**

**O**

**O**

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

**O**

**O**

**O**

**a b c**

**OH**

**O**

**d e f**

**OH**

**O**

**O**

**O**

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 (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.

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

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. 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 suffer from poor solubility problems. Thus, etoposide, teniposide, etopophos and GL-331 were synthesized; all are potent chemotherapeutic agents for a variety of tumors. Still, etoposide and its analogues suffer from poor solubility problems.

5

**4. Terpenoids**

properties [15].

other plants

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‐

Nanoflora — How Nanotechnology Enhanced the Use of Active Phytochemicals

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

347

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

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.

7

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

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

**HO**

**H**

**H**

**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

**H CO2H**

**a b**

**H**

**HO**

**H**

**H CO2H**

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.

6

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,

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.

**Figure 3.** Structure of podophyllotoxin **Figure 3.** Structure of podophyllotoxin

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

**4. Terpenoids** 
