**7. Nanotechnology and nanoparticles**

Several nanoparticle systems have been used to aid in the formulation, encapsulation and release of active compounds extracted or derived from natural resources. The main types of these particles are liposomes, solid lipid nanoparticles, inorganic nanoparticles, microemulsion, polymer nanoparticles, dendrimers and many other types.

#### **7.1. Micelles and Liposomes**

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

Micelles are spontaneous aggregates of amphiphiles (such as surfactants, Figure 8a) with usually spherical structures with a size range of

system of nanoparticles [30]. Micelles come first in mind when tackling solubility issues in aqueous media [31, 32]. The solubilization

**6.1 Micelles and Liposomes** 

publications dealt with loading vinca alkaloids in liposomal nanocarriers to lessen such side

As discussed above, herbal medicines are accompanied with many problems that prevent them from reaching their full potential as pharmaceutical formulations. These problems include – but not limited to: low solubility in water, low bioavailability, high toxicity and instability. Nanotechnology has shown great promise for many medical applications such as cancer diagnosis, chemotherapeutic drug delivery, and diabetes treatments [29]. This technology is beneficial in overcoming some difficulties encountered with using bulk variable drug mole‐

In the last decade, tremendous attentions have been paid on replacing synthetic drugs by natural bioactive phytochemicals to eliminate synthetic drugs side effects. In order to reach this goal, the above mentioned limitations need to be overcome. Nanotechnology can play an important role in reducing or even eliminating such drawbacks. Such possibility will open the door for a wide range of candidate compounds that were overlooked in the past due to these limitations, to be revisited again. In this chapter, a systematic overview of the various methods that can be applied to overcome one or more of these limitations and will lead finally to an acceptable formulation composed mainly of the active phytochemical attached to or encapsu‐ lated in a nanocarrier system forming what will be known throughout this chapter as a nanoflora. Such combination is capable of reaching the final phases of testing these active

Several nanoparticle systems have been used to aid in the formulation, encapsulation and release of active compounds extracted or derived from natural resources. The main types of these particles are liposomes, solid lipid nanoparticles, inorganic nanoparticles, micro-

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 media, 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.

effects [27, 28].

350 Application of Nanotechnology in Drug Delivery

**6. Nanoflora**

cules in their synthetic and natural forms.

compounds and be helpful in improving health care systems.

emulsion, polymer nanoparticles, dendrimers and many other types.

**7. Nanotechnology and nanoparticles**

**7.1. Micelles and Liposomes**

**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 non-polar tails **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 non-polar tails

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

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 dynamic.

10

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 Thymoquinone **[**37]

structures are dynamic.

structures are dynamic.

**Figure 9:** Basic structure of: a) bilayer lipid sheet, b) unilamellar liposome and c) optical micro-image of liposomes loaded with **Figure 9.** Basic structure of: a) bilayer lipid sheet, b) unilamellar liposome and c) optical micro-image of liposomes loaded with Thymoquinone [37] 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

10c), large unilamellar vesicles (LUV, Figure 10d), multivesicle vesicles (MVV, Figure 10e) and cochleate vesicles (Figure 11). Each

**Figure 10.** Schematic representation of the different types of liposomes a) the lipid bilayer, b) Small Unilamellar Vesicle (SUV), c) Large Unilamellar Vesicle (LUV), d) Multi Lamellar Vesicle (MLV) and e) Multi Vesicle Vesicle (MVV). **Figure 10.** Schematic representation of the different types of liposomes a) the lipid bilayer, b) Small Unilamellar Vesi‐ cle (SUV), c) Large Unilamellar Vesicle (LUV), d) Multi Lamellar Vesicle (MLV) and e) Multi Vesicle Vesicle (MVV).

11

**7.2. Solid Lipid Nanoparticles (SLN)**

micrographs of cochleates cylinders [42]

cochleates cylinders [42]

unsuitable for non polar drugs.

be used as drug delivery systems [38, 39, 40].

**6.2 Solid Lipid Nanoparticles (SLN)** 

and much easier for scale up productions.

**Figure 12.** Structure of Solid Lipid Nanoparticle (SLN) stabilized with surfactant molecules

**Figure 13.** Schematic representation of polymer nanoparticles preparation [48]

Another type of particles that draw large attention is polymer nanoparticles [44]. These (Figure 13) are easily made - mostly from biodegradable polymers - and can increase the stability, time of circulation, controlled release and easy methods for scale up and at the same time they are biocompatible and non toxic [45]. The most used two polymers include both poly (lactide-co-glycolic acid) (PLGA) and poly (lactic acid) (PLA) [46]. Other polymers are also good candidates to form nanoparticles and be suitable to act as drug carriers. These include sugars [47], proteins [48] such as albumin [49], gelatin nanoparticles [50] and many other naturally occurring

**Figure 12.** Structure of Solid Lipid Nanoparticle (SLN) stabilized with surfactant molecules 12

Lipid drug loaded core

These are usually spherical structures composing of a lipid core - capable of solubilizing lipophilic drugs - surrounded with surfactants that stabilizes the lipid core and can be used for the hydrophilic drugs and other fictionalizations processes (Figure 12) [43]. SLN share other types of nano-carriers' their common advantages like its suitability to encapsulate non polar insoluble drugs in its polymeric core, shielding the drug from outside - which could be sometimes harsh - environment and as consequence increases the drug stability and reduces its toxicity to the body. Other advantages include not only the ability to functionalize the SLN surface with markers and targeting devices in order to enhance the targeting process, but also their ability to produce a sustained and slow release of the drug in the targeted site. However, SLN have advantages over other types of delivery systems in that they are easier to prepare, cheaper and much

Dendrimers are repetitive branched molecules attached to each in a tree-like manner and typically are symmetric around their core. They can also be categorized as polymeric nanoparticles, and are characterized by their structural perfection, water solubility and

monodispersity. Dendrimers are good encapsulating agents for hydrophobic drugs due to their nonpolar core.

**6.3 Polymer Nanoparticles** 

easier in the scale up productions.

macromolecules.

These are usually spherical structures composed of a lipid core, capable of solubilizing lipophilic drugs, surrounded with surfactants that stabilizes the lipid core and can be used for the hydrophilic drugs and other fictionalizations processes (Figure 12) [43]. SLN share other types of nano-carriers' their common advantages like their suitability to encapsulate non polar insoluble drugs in its polymeric core, shielding the drug the outside environment - which could be sometimes harsh - and as consequence increases the drug stability and reduces its toxicity to the body. Other advantages include not only the ability to functionalize the SLN surface with markers and targeting devices in order to enhance the targeting process, but also their ability to produce a sustained and slow release of the drug in the targeted site. However, SLN have advantages over other types of delivery systems in that they are easier to prepare, cheaper

Another promising type of nanoparticles is the phytosomes. The phospholipid in these types of nanoparticles (considered mainly as liposomes) is covalently attached to the phytochemical. Phytosomes are gaining increased interest and are the focus of more research to

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, controllable 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 degradability. However, liposomes suffer from various disadvantages which include their short half-life in the circulation system, although it can be enhanced by better controlling the size of the liposome vesicle and modifying its composition. Even though liposomes are suitable to encapsulate non polar drugs in the hydrophobic bilayer of the vesicle (Figure 9a and 10a), sometimes, such drugs affect the integrity of these vesicles rendering them

 (a) (b) (c) **Figure 11.** a) Optical micro image of cochleates [41], b) SEM image of cochleates [42], and c) freeze fracture electron micrographs of

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**Figure 11.** a) Optical micro image of cochleates [41], b) SEM image of cochleates [42], and c) freeze fracture electron

13

in the circulation system, although it can be enhanced by better controlling the size of the liposome vesicle and modifying its composition. Even though liposomes are suitable to encapsulate non polar drugs in the hydrophobic bilayer of the vesicle (Figure 9a and 10a), sometimes, such drugs affect the integrity of these vesicles rendering them unsuitable for non polar drugs. **Figure 10.** Schematic representation of the different types of liposomes a) the lipid bilayer, b) Small Unilamellar Vesicle (SUV), c) Large Unilamellar Vesicle (LUV), d) Multi Lamellar Vesicle (MLV) and e) Multi Vesicle Vesicle (MVV). d e

Another promising type of nanoparticles is the phytosomes. The phospholipid in these types of nanoparticles (considered mainly as liposomes) is covalently attached to the phytochemical. Phytosomes are gaining increased interest and are the focus of more research to be used as drug delivery systems [38, 39, 40]. 11

**Figure 11.** a) Optical micro image of cochleates [41], b) SEM image of cochleates [42], and c) freeze fracture electron micrographs of cochleates cylinders [42] **Figure 11.** a) Optical micro image of cochleates [41], b) SEM image of cochleates [42], and c) freeze fracture electron micrographs of cochleates cylinders [42]

drugs, their stability and long shelf life, controllable properties such as size and charge, ability to functionalize and modify the surface

#### **7.2. Solid Lipid Nanoparticles (SLN)** Liposomes are very important as drug carrier systems due to many factors including their suitability to encapsulate polar and non polar

in the circulation system, although it can be enhanced by better controlling the size of the liposome vesicle and modifying its composition. Even though liposomes are suitable to encapsulate non polar drugs in the hydrophobic bilayer of the vesicle (Figure 9a and 10a), sometimes, such drugs affect the integrity of these vesicles rendering them unsuitable for non

d e

**Figure 10.** Schematic representation of the different types of liposomes a) the lipid bilayer, b) Small Unilamellar Vesi‐ cle (SUV), c) Large Unilamellar Vesicle (LUV), d) Multi Lamellar Vesicle (MLV) and e) Multi Vesicle Vesicle (MVV).

**Figure 10.** Schematic representation of the different types of liposomes a) the lipid bilayer, b) Small Unilamellar Vesicle (SUV), c)

**Figure 9:** Basic structure of: a) bilayer lipid sheet, b) unilamellar liposome and c) optical micro-image of liposomes loaded with

<sup>a</sup> <sup>b</sup> <sup>c</sup>

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

a

<sup>b</sup> <sup>c</sup>

**Figure 9.** Basic structure of: a) bilayer lipid sheet, b) unilamellar liposome and c) optical micro-image of liposomes

**Figure 9:** Basic structure of: a) bilayer lipid sheet, b) unilamellar liposome and c) optical micro-image of liposomes loaded with

<sup>a</sup> <sup>b</sup> <sup>c</sup>

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

Another promising type of nanoparticles is the phytosomes. The phospholipid in these types of nanoparticles (considered mainly as liposomes) is covalently attached to the phytochemical. Phytosomes are gaining increased interest and are the focus of more research to be used as

**Figure 10.** Schematic representation of the different types of liposomes a) the lipid bilayer, b) Small Unilamellar Vesicle (SUV), c)

d e

Large Unilamellar Vesicle (LUV), d) Multi Lamellar Vesicle (MLV) and e) Multi Vesicle Vesicle (MVV).

a

<sup>b</sup> <sup>c</sup>

Large Unilamellar Vesicle (LUV), d) Multi Lamellar Vesicle (MLV) and e) Multi Vesicle Vesicle (MVV).

11

11

polar drugs.

Thymoquinone **[**37]

loaded with Thymoquinone [37]

structures are dynamic.

Thymoquinone **[**37]

352 Application of Nanotechnology in Drug Delivery

structures are dynamic.

drug delivery systems [38, 39, 40].

These are usually spherical structures composed of a lipid core, capable of solubilizing lipophilic drugs, surrounded with surfactants that stabilizes the lipid core and can be used for the hydrophilic drugs and other fictionalizations processes (Figure 12) [43]. SLN share other types of nano-carriers' their common advantages like their suitability to encapsulate non polar insoluble drugs in its polymeric core, shielding the drug the outside environment - which could be sometimes harsh - and as consequence increases the drug stability and reduces its toxicity to the body. Other advantages include not only the ability to functionalize the SLN surface with markers and targeting devices in order to enhance the targeting process, but also their ability to produce a sustained and slow release of the drug in the targeted site. However, SLN have advantages over other types of delivery systems in that they are easier to prepare, cheaper and much easier for scale up productions. due to the presence of many functional groups, and finally their biocompatibility and degradability. However, liposomes suffer from various disadvantages which include their short half-life in the circulation system, although it can be enhanced by better controlling the size of the liposome vesicle and modifying its composition. Even though liposomes are suitable to encapsulate non polar drugs in the hydrophobic bilayer of the vesicle (Figure 9a and 10a), sometimes, such drugs affect the integrity of these vesicles rendering them unsuitable for non polar drugs. Another promising type of nanoparticles is the phytosomes. The phospholipid in these types of nanoparticles (considered mainly as liposomes) is covalently attached to the phytochemical. Phytosomes are gaining increased interest and are the focus of more research to be used as drug delivery systems [38, 39, 40]. **6.2 Solid Lipid Nanoparticles (SLN)** 

These are usually spherical structures composing of a lipid core - capable of solubilizing lipophilic drugs - surrounded with surfactants

Another type of particles that draw large attention is polymer nanoparticles [44]. These (Figure 13) are easily made - mostly from biodegradable polymers - and can increase the stability, time of circulation, controlled release and easy methods for scale up and at the same time they are biocompatible and non toxic [45]. The most used two polymers include both poly (lactide-co-glycolic acid) (PLGA) and poly (lactic acid) (PLA) [46]. Other polymers are also good candidates to form nanoparticles and be suitable to act as drug carriers. These include sugars [47], proteins [48] such as albumin [49], gelatin nanoparticles [50] and many other naturally occurring

Dendrimers are repetitive branched molecules attached to each in a tree-like manner and typically are symmetric around their core. They can also be categorized as polymeric nanoparticles, and are characterized by their structural perfection, water solubility and

monodispersity. Dendrimers are good encapsulating agents for hydrophobic drugs due to their nonpolar core.

13

**Figure 12.** Structure of Solid Lipid Nanoparticle (SLN) stabilized with surfactant molecules **Figure 12.** Structure of Solid Lipid Nanoparticle (SLN) stabilized with surfactant molecules 12

**Figure 13.** Schematic representation of polymer nanoparticles preparation [48]

**6.3 Polymer Nanoparticles** 

easier in the scale up productions.

macromolecules.

#### **7.3. Polymer Nanoparticles**

Another type of particles that draw large attention is polymer nanoparticles [44]. These types of nanoparticles (Figure 13) are easily made-mostly from biodegradable polymers and can increase the stability and time of circulation. Moreover, in addition of being non toxic, other advantages of these polymer nanoparticles include controlled drug release, biocompatability and their suitability for scale up methods [45]. The most used two polymers include both poly (lactide-co-glycolic acid) (PLGA) and poly (lactic acid) (PLA) [46]. Other polymers are also good candidates to form polymeric nanoparticles and be suitable to act as drug carriers. These include sugars [47], proteins [48] such as albumin [49], gelatin nanoparticles [50] and many other naturally occurring macromolecules.

the: i) transition metal nanoparticles, ii) ceramics nanoparticles and iii) carbon nanoparticles

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Transition metal nanoparticles (Figure 14) such as Au, Ti, Pt are gaining increasing interest in the medical field [52]. There are many methods were transition metals can be applied in medicine, drug delivery being one of them. For example, many transition metals can act as drugs themselves when excited by light radiation. Depending on the excitation process and the type of metal involved, when the absorbed energy is released, it can damage the DNA and/ or modify the protein, promote lipid peroxidation and destroy the cell microenvironment, hence causing cell death. This method is promising in fighting cancer cells. Also, these nanoparticles can be very powerful in imaging, which is very important in both diagnosis and therapy monitoring [53]. One of the most promising nanoparticles in combating cancer is Au nanoparticle [54]. However, these metals can be used as drug carriers. For example, Au shuttles can be used for site specific delivery of toxic drugs [52]. However, these nanoparticles suffer from loaming safety and clearance concerns. Metals in the nanometer scale range have special properties and penetrations, making them very powerful catalysts that can trigger undesired reaction. Nowadays, there are large concerns regarding safety of specifically metal nanopar‐

in addition to other types.

ticles and nanoparticles in general.

**Figure 14.** TEM images of metal nanoparticles with different geometries [55]

**Figure 13.** Schematic representation of polymer nanoparticles preparation [48]

Dendrimers are repetitive branched molecules attached to each other in a tree-like manner and typically are symmetric around their core. They can also be categorized as polymeric nano‐ particles, and are characterized by their structural perfection, water solubility and monodis‐ persity. Dendrimers are good encapsulating agents for hydrophobic drugs due to their non polar core.

#### **7.4. Microemulsions (ME)**

Microemulsions are usually made from oil, water, surfactant and a co-surfactant. They are thermodynamically stable (in contrast to emulsions), transparent, and form spontaneously. The particle size ranges from 10 to 100 nm, which enhances their penetration through cellular membranes making microemulsions suitable as drug carriers. Due to the presence of polar and non polar components in ME's, they are very good solubilizing agents. Their properties can be adjusted to suit the drug to be carried by optimizing compositions, types of both the surfactant and the co-surfactant in addition of course to the oil used in the composition [51].

#### **7.5. Inorganic nanoparticles**

Inorganic nanoparticles such as gold nanoparticles, silver nanoparticles, ceramics, carbon nanoparticles and nanotubes were the focus of very extensive research and in many fields. Inorganic nanoparticles can be mainly classified into three different main categories including the: i) transition metal nanoparticles, ii) ceramics nanoparticles and iii) carbon nanoparticles in addition to other types.

**7.3. Polymer Nanoparticles**

354 Application of Nanotechnology in Drug Delivery

polar core.

**7.4. Microemulsions (ME)**

**7.5. Inorganic nanoparticles**

other naturally occurring macromolecules.

**Figure 13.** Schematic representation of polymer nanoparticles preparation [48]

Another type of particles that draw large attention is polymer nanoparticles [44]. These types of nanoparticles (Figure 13) are easily made-mostly from biodegradable polymers and can increase the stability and time of circulation. Moreover, in addition of being non toxic, other advantages of these polymer nanoparticles include controlled drug release, biocompatability and their suitability for scale up methods [45]. The most used two polymers include both poly (lactide-co-glycolic acid) (PLGA) and poly (lactic acid) (PLA) [46]. Other polymers are also good candidates to form polymeric nanoparticles and be suitable to act as drug carriers. These include sugars [47], proteins [48] such as albumin [49], gelatin nanoparticles [50] and many

Dendrimers are repetitive branched molecules attached to each other in a tree-like manner and typically are symmetric around their core. They can also be categorized as polymeric nano‐ particles, and are characterized by their structural perfection, water solubility and monodis‐ persity. Dendrimers are good encapsulating agents for hydrophobic drugs due to their non

Microemulsions are usually made from oil, water, surfactant and a co-surfactant. They are thermodynamically stable (in contrast to emulsions), transparent, and form spontaneously. The particle size ranges from 10 to 100 nm, which enhances their penetration through cellular membranes making microemulsions suitable as drug carriers. Due to the presence of polar and non polar components in ME's, they are very good solubilizing agents. Their properties can be adjusted to suit the drug to be carried by optimizing compositions, types of both the surfactant and the co-surfactant in addition of course to the oil used in the composition [51].

Inorganic nanoparticles such as gold nanoparticles, silver nanoparticles, ceramics, carbon nanoparticles and nanotubes were the focus of very extensive research and in many fields. Inorganic nanoparticles can be mainly classified into three different main categories including Transition metal nanoparticles (Figure 14) such as Au, Ti, Pt are gaining increasing interest in the medical field [52]. There are many methods were transition metals can be applied in medicine, drug delivery being one of them. For example, many transition metals can act as drugs themselves when excited by light radiation. Depending on the excitation process and the type of metal involved, when the absorbed energy is released, it can damage the DNA and/ or modify the protein, promote lipid peroxidation and destroy the cell microenvironment, hence causing cell death. This method is promising in fighting cancer cells. Also, these nanoparticles can be very powerful in imaging, which is very important in both diagnosis and therapy monitoring [53]. One of the most promising nanoparticles in combating cancer is Au nanoparticle [54]. However, these metals can be used as drug carriers. For example, Au shuttles can be used for site specific delivery of toxic drugs [52]. However, these nanoparticles suffer from loaming safety and clearance concerns. Metals in the nanometer scale range have special properties and penetrations, making them very powerful catalysts that can trigger undesired reaction. Nowadays, there are large concerns regarding safety of specifically metal nanopar‐ ticles and nanoparticles in general.

**Figure 14.** TEM images of metal nanoparticles with different geometries [55]

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.

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

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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

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

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

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‐

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‐

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

encapsulation in polymeric nanoparticles suspensions [59].

enhanced by introducing solid lipid nano-formulations [61].

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

transdermal delivery.

namic therapy [57, 62].

dextrin (Figure 17) [64].

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