**8. Enhancing solubility and bioavailability**

Low solubility of active phytochemicals is considered the main obstacle that hinders their usage in pharmaceutical formulations. This is due to two main reasons; the first is that the medium at which drugs work is mainly aqueous. Low solubility in aqueous media will drastically lower the concentration of the drug causing a poor bioavailability. Nanoparticles can provide an alternative medium for these drugs to be solubilized in and carried out through the body to the targeted tissue or organ. The extensively small sizes of nanoparticles give high surface area to volume ratio and as a result, more and more water molecules can surround the particles and the solubility of hydrophobic compound is enhanced [56].

Several nano-vesicles can be used to enhance the solubility such as micelles, liposomes, solid lipid nanoparticles, polymer nanoparticles and many others [57]. Triptolide, is an example of a bioactive diterpenoid epoxide ingredient isolated form *Tripterygium wilfordii*, a plant used in traditional Chinese medicine. This compound was found to be active *in vivo* and *in vitro* mouse models against polycystic kidney disease and against pancreatic cancer. It can also be used in the treatment of autoimmune diseases especially rheumatoid arthritis, psoriasis, and leukemia. However, it suffers from low solubility and high toxicity. In order to overcome its solubility and toxicity issues, it was prepared as a biocompatible and biodegradable tripolide-loaded poly [DL-lactic acid] nanoparticles [58]. It was also studied as a micro-emulsion system for transdermal delivery.

Ceramics nanoparticles are mostly composed from oxides, nitrides and carbides with silica (Figure 15) (SiO2) being the most used. Mainly they are used as hollow shells or cores that are coated with biodegradable and biocompatible polymers. Such surface modifications improve

the properties of these nanoparticles especially for targeted delivery.

356 Application of Nanotechnology in Drug Delivery

**Figure 15.** SEM images of silica nanoparticles with different sizes

**8. Enhancing solubility and bioavailability**

particles and the solubility of hydrophobic compound is enhanced [56].

Low solubility of active phytochemicals is considered the main obstacle that hinders their usage in pharmaceutical formulations. This is due to two main reasons; the first is that the medium at which drugs work is mainly aqueous. Low solubility in aqueous media will drastically lower the concentration of the drug causing a poor bioavailability. Nanoparticles can provide an alternative medium for these drugs to be solubilized in and carried out through the body to the targeted tissue or organ. The extensively small sizes of nanoparticles give high surface area to volume ratio and as a result, more and more water molecules can surround the

The solubility of quercetin (a flavonoid that is naturally present in a wide range of fruits and vegetables especially in onion, apples and many edible fruits) was enhanced 100 times after encapsulation in polymeric nanoparticles suspensions [59].

Tetrandrine, bis-benzylisoquinoline alkaloid, exhibits antitumor activity and is known to acts as a nonselective calcium channel blocker. This compound has very limited clinical applica‐ tions due to its poor water solubility. However, the solubility of this alkaloid was enhanced as a result of its incorporation into SLN [60].

Cryptotanshinone is an active quinoid diterpene isolated from the roots of the Asian medicinal plant, *Salvia miotiorrhiza* Bunge. This diterpene is known to exhibit variable interesting pharmacological activities including anti-inflammatory, cytotoxic, anti-bacterial, anti-parasit‐ ic, anti-angiogenic and anti-oxidative activities but suffers from very low bioavailability as a result of its extremely low water solubility. Cryptotanshinone oral bioavailability was highly enhanced by introducing solid lipid nano-formulations [61].

Hypericin is a natural photosensitizer with limited ability to be used in diagnostic applications because of its high hydrophobicity and limited solubility. Different nano-formulations like hypericin-loaded solid lipid nanoparticles (Hy-SLN) and suspension of Hypericin-polymeric nanoparticles have been developed in order to obtain better photo-detection and photody‐ namic therapy [57, 62].

Thymoquinone (Figure 4) is an active ingredient found in Black Seeds (*N. sativa*). It has anticancer activity in addition to other therapeutic effects [13, 18, 63]. However, this compound suffers from poor solubility and high hydrophobicity leading to poor formulations for pharmaceutical applications. This problem was solved by encapsulating thymoquinone in various carriers such as polymer nanoparticles [45], liposomes (Figure 16) [37] and in cyclo‐ dextrin (Figure 17) [64].

Bioavailability can also be enhanced due to encapsulation of drugs or active compounds in nanocarriers. For example, ampelopsin, a flavonoid extracted from *Ampelopsis grossedentata*, is known to possess many pharmacological activities including anti-inflammatory, antimicrobi‐ al, anticarcinogenic activities in addition to its antioxidation, antihypertension, hepatoprotec‐ tive and cough relieving effects. However, not only ampelopsin suffers from poor solubility in water, it also has very low permeability. Ampelopsin was successfully encapsulated in a the intestinal mucosa [65].

nanoparticles [45], liposomes (Figure 16) [37] and in cyclodextrin (Figure 17) [64].

enhanced as a result of its incorporation into SLN [60].

microemulsion that enhanced its bioavailability by both enhancing its solubility and penetra‐ tion through the intestinal mucosa [65]. inflammatory, antimicrobial, anticarcinogenic activities in addition to its antioxidation, antihypertension, hepatoprotective and cough relieving effects. However, not only ampelopsin suffers from poor solubility in water, it also has very low permeability. Ampelopsin was successfully encapsulated in a microemulsion that enhanced its bioavailability by both enhancing its solubility and penetration through

flavonoid that is extracted from *Ampelopsis grossedentata* is known to possess many pharmacological activities including anti-

Tetrandrine, a bisbenzylisoquinoline alkaloid, exhibits antitumor activity and is known to acts as a nonselective calcium channel blocker. This compound has very limited clinical applications due to its poor water solubility. However, the solubility of this alkaloid is

Cryptotanshinone is a quinoid diterpene isolated from the roots of the Asian medicinal plant, *Salvia miotiorrhiza* Bunge. This diterpene is known to exhibit variable interesting pharmacological activities including anti-inflammatory, cytotoxic, anti-bacterial, anti-parasitic, anti-angiogenic, and anti-oxidative activities but suffers from very low bioavailability as a result of its extremely low water solubility.

Hypericin is a natural photosensitizer with limited ability to be used in diagnostic applications because of its high hydrophobicity and limited solubility. Different nano-formulations like hypericin-loaded solid lipid nanoparticles (Hy-SLN) and suspension of Hypericin-

Thymoquinone (figure 4) is an active ingredient found in Black Seeds (*N. sativa*). It has anticancer activity in addition to other therapeutic effects [13, 18, 63]. However, this compound suffers from poor solubility and high hydrophicity leading to poor formulations for pharmaceutical applications. This problem was solved by encapsulating thymoquinone in various carriers such as polymer

polymeric nanoparticles have been developed in order to obtain better photo-detection and photodynamic therapy [57, 62].

Cryptotanshinone oral bioavailability is highly enhanced by introducing solid lipid nano-formulations [61].

**Figure 16.** a) SEM, b) TEM and c) light microscope images of TQ-loaded liposomes [37] **Figure 16.** a) SEM, b) TEM and c) light microscope images of TQ-loaded liposomes [37]

17

and proteins. For example, triptolide, which was mentioned previously to have anti-tumor activity, has a side effect of being irritating to the gastric systems. Such gastric irritation can be reduced by changing the nanoparticle carrier. When triptolide is encapsulated in Solid Lipid Nanoparticles (SLN), such irritations are minimized [32]. Nanoparticles in general shield these toxic drugs and isolate them until reaching their destination via targeted delivery mechanism. Such mechanism of delivery depends on the capability to functionalize the surface of the

Nanoflora — How Nanotechnology Enhanced the Use of Active Phytochemicals

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

359

Targeted drug delivery is deliberately increasing the concentration of the drug in specific part of the body relative to other parts in order to increase the efficacy of drug and decrease the side effects. The complex cellular network of organisms makes targeting a difficult mission. There are variable methods of targeting such as modification of surface charge, inserting ligands, and using biomarkers. The targeting mechanism can be divided into two mechanisms:

Passive targeting refers to the preferable accumulation of chemotherapeutic agent in solid tumor as a result of enhanced vascular permeability of tumor tissue as compared to healthy

Tumors have unique features, which make them distinct from normal tissue. The intact tissue has non leaky microvasculars, while tumor tissue has leaky capillary beds. This situation promotes the delivery and retention of drug loaded nonparticles through tumor tissue. This phenomenon is recognized as the enhanced permeability and retention effect (EPR). The hydrophobic surfaces of nanomaterials are highly susceptible to osponization and clearance [66, 67]. When the surfaces were modified by becoming more hydrophilic, the rapid clearance problems can be solved and longer circulation can be obtained because the hydrophilic coating on the surfaces repels plasma and protein so drug loaded nanoparticles become invisible to

Active targeting refers to the use of drug carriers with ligands (antibody, peptide) that are selectively recognized by a receptor on the cell of interest. Since ligand-receptor interaction can be highly selective, a more precise targeting is achieved with improved target cell recog‐

Particle size and size distribution are the most important characteristics of nanoparticle systems. Many studies have proved that nanometer particles are more effective and beneficial than micrometer particles in drug delivery system. In nano scale, the surface area to volume ratio is high; this situation makes the loaded drug less susceptible to reticular endothelial system clearances. The nano-sized particles have better ability to penetrate through cells and even small capillaries [68]. However, the ultimate small size of particles and large surface area lead sometimes to limited drug loading and burst release pattern [69]. Surface modification can be helpful in increasing residence time in the blood and reducing nonspecific distribu‐ tion.Unsuccessful surface modification ultimately is the main limiting factor for long-circu‐

nanoparticle carriers.

tissue [66].

passive targeting and active targeting.

mononuclear phagocytic system (MPS).

nition and target cell uptake [67].

lating nanoparticle systems [70].

**Figure 17.** TEM image of a nanoparticle of thymoquinone with cyclodextrin β [64]

### **9. Reduced toxicity and side effects**

Most research focuses on reducing the toxicity and side effects of drugs, especially for those used in chemotherapy. Many Nanoparticles systems can be used to encapsulate the toxic drug and deliver it to specific sites in the body. These Nanoparticles are mainly made from biode‐ gradable, biocompatible materials such as natural polymers which include polysaccharides and proteins. For example, triptolide, which was mentioned previously to have anti-tumor activity, has a side effect of being irritating to the gastric systems. Such gastric irritation can be reduced by changing the nanoparticle carrier. When triptolide is encapsulated in Solid Lipid Nanoparticles (SLN), such irritations are minimized [32]. Nanoparticles in general shield these toxic drugs and isolate them until reaching their destination via targeted delivery mechanism. Such mechanism of delivery depends on the capability to functionalize the surface of the nanoparticle carriers.

microemulsion that enhanced its bioavailability by both enhancing its solubility and penetra‐

**(C)**

Bioavailability can also be enhanced due to encapsulation of drugs or active compound in nanocarriers. For example, ampelopsin is a flavonoid that is extracted from *Ampelopsis grossedentata* is known to possess many pharmacological activities including antiinflammatory, antimicrobial, anticarcinogenic activities in addition to its antioxidation, antihypertension, hepatoprotective and cough relieving effects. However, not only ampelopsin suffers from poor solubility in water, it also has very low permeability. Ampelopsin was successfully encapsulated in a microemulsion that enhanced its bioavailability by both enhancing its solubility and penetration through

Tetrandrine, a bisbenzylisoquinoline alkaloid, exhibits antitumor activity and is known to acts as a nonselective calcium channel blocker. This compound has very limited clinical applications due to its poor water solubility. However, the solubility of this alkaloid is

Cryptotanshinone is a quinoid diterpene isolated from the roots of the Asian medicinal plant, *Salvia miotiorrhiza* Bunge. This diterpene is known to exhibit variable interesting pharmacological activities including anti-inflammatory, cytotoxic, anti-bacterial, anti-parasitic, anti-angiogenic, and anti-oxidative activities but suffers from very low bioavailability as a result of its extremely low water solubility.

Hypericin is a natural photosensitizer with limited ability to be used in diagnostic applications because of its high hydrophobicity and limited solubility. Different nano-formulations like hypericin-loaded solid lipid nanoparticles (Hy-SLN) and suspension of Hypericin-

Thymoquinone (figure 4) is an active ingredient found in Black Seeds (*N. sativa*). It has anticancer activity in addition to other therapeutic effects [13, 18, 63]. However, this compound suffers from poor solubility and high hydrophicity leading to poor formulations for pharmaceutical applications. This problem was solved by encapsulating thymoquinone in various carriers such as polymer

polymeric nanoparticles have been developed in order to obtain better photo-detection and photodynamic therapy [57, 62].

Cryptotanshinone oral bioavailability is highly enhanced by introducing solid lipid nano-formulations [61].

17

tion through the intestinal mucosa [65].

358 Application of Nanotechnology in Drug Delivery

the intestinal mucosa [65].

nanoparticles [45], liposomes (Figure 16) [37] and in cyclodextrin (Figure 17) [64].

**Figure 16.** a) SEM, b) TEM and c) light microscope images of TQ-loaded liposomes [37]

**Figure 16.** a) SEM, b) TEM and c) light microscope images of TQ-loaded liposomes [37]

**Figure 17.** TEM image of a nanoparticle of thymoquinone with cyclodextrin β [64]

Most research focuses on reducing the toxicity and side effects of drugs, especially for those used in chemotherapy. Many Nanoparticles systems can be used to encapsulate the toxic drug and deliver it to specific sites in the body. These Nanoparticles are mainly made from biode‐ gradable, biocompatible materials such as natural polymers which include polysaccharides

**9. Reduced toxicity and side effects**

enhanced as a result of its incorporation into SLN [60].

Targeted drug delivery is deliberately increasing the concentration of the drug in specific part of the body relative to other parts in order to increase the efficacy of drug and decrease the side effects. The complex cellular network of organisms makes targeting a difficult mission. There are variable methods of targeting such as modification of surface charge, inserting ligands, and using biomarkers. The targeting mechanism can be divided into two mechanisms: passive targeting and active targeting.

Passive targeting refers to the preferable accumulation of chemotherapeutic agent in solid tumor as a result of enhanced vascular permeability of tumor tissue as compared to healthy tissue [66].

Tumors have unique features, which make them distinct from normal tissue. The intact tissue has non leaky microvasculars, while tumor tissue has leaky capillary beds. This situation promotes the delivery and retention of drug loaded nonparticles through tumor tissue. This phenomenon is recognized as the enhanced permeability and retention effect (EPR). The hydrophobic surfaces of nanomaterials are highly susceptible to osponization and clearance [66, 67]. When the surfaces were modified by becoming more hydrophilic, the rapid clearance problems can be solved and longer circulation can be obtained because the hydrophilic coating on the surfaces repels plasma and protein so drug loaded nanoparticles become invisible to mononuclear phagocytic system (MPS).

Active targeting refers to the use of drug carriers with ligands (antibody, peptide) that are selectively recognized by a receptor on the cell of interest. Since ligand-receptor interaction can be highly selective, a more precise targeting is achieved with improved target cell recog‐ nition and target cell uptake [67].

Particle size and size distribution are the most important characteristics of nanoparticle systems. Many studies have proved that nanometer particles are more effective and beneficial than micrometer particles in drug delivery system. In nano scale, the surface area to volume ratio is high; this situation makes the loaded drug less susceptible to reticular endothelial system clearances. The nano-sized particles have better ability to penetrate through cells and even small capillaries [68]. However, the ultimate small size of particles and large surface area lead sometimes to limited drug loading and burst release pattern [69]. Surface modification can be helpful in increasing residence time in the blood and reducing nonspecific distribu‐ tion.Unsuccessful surface modification ultimately is the main limiting factor for long-circu‐ lating nanoparticle systems [70].
