**8. Drug delivery system**

Nanotechnology is the nano-sized materials science, involves materials manipulation at atomic and molecular scale in order to produce materials, systems and devices with unprecedented features. Recently, nanotechnology become the most promising technology in a wide variety of fields, one of these fields is medicine field. In fact, the employment of nanotechnology in medicine field is called

nanomedicine which regarded as a tool enabled doctors to reach the human body at the molecular and cellular levels and treat the damaged tissues [67].

It is believed that this technology will have a great impact on the health care field via its effect on the sickness diagnosing and treating [67, 68]. There are several features of using nanotechnology in medical field, for example, when it is used for drug delivery, this technology will protect drug from degradation within human body before reaching the target also, it is improving drugs absorption into the diseased cells and at the same time it give assurance that there is no any interactions between drugs and the healthy cells [67, 68].

Therefore, nanomedicine is one division of nanotechnology and nanoscience has the ability of treating the diseased and damaged cells or organs within human body at the cellular and molecular levels via nano-devices and nano-structured materials [68]. There are three main sectors within nanomedicine: Nano- diagnosis, which involving detection and analysis of the diseased cell using different devices such as imaging devices. Nano- therapy, this sector involving the direct transfer or delivery of drugs to the diseased cells with the least possible of side effects. And the last one is renovated medicine, which involving fixation and replacement the deteriorated parts within human body using different nano-devices and nanomaterials [67].

In the following we will discuss the role of carbon based- nanomaterials (fullerene and nanodiamond) as a drug delivery systems.

#### **9. Significance of carbon based- nanomaterials in drug delivery**

Generally, the suitable choice of nano- drug delivery systems aids to overcome many health issues usually associated with using traditional treatment strategies. For example, in the case of cancer chemotherapy, the traditional strategies leads to several undesired side effects such as suppression of bone marrow, hair loss, gastric and renal damage and other toxicity effects [67].

On the other side, there are many features and reasons related to the nature and structure of nanomaterials make it as an attractive subject for intense bio-studies from one side and as an attractive materials for drug delivery systems from a other side [69, 70]. The most significant features are: their quantum property, their sizes which determine their in vivo and in vitro behavior, their structure and aggregation ability as well as their surface atoms or molecules. In fact, all these features determine their ability for binding, carrying and adsorbing other compounds or in other words these features determine their pharmacology behavior [70–72].

Furthermore, the main characteristics that nanomaterials should have to be use in drug delivery systems are high- solubility, bio- compatibility, bio- availability, bio- distribution and targeting ability, drug incorporation and release ability, their shelf- time, anti- clotting property and bio- degradability [71].

#### **9.1 Fullerene-drug delivery system**

Some of the most interesting characteristics of fullerene are their size, electronic configuration, hollow and cage structure, their inertness and surface modification ability that offer the utilization of using fullerene in biological and medical chemistry fields and open new horizons in nanomedicine [73]. The main problems facing the previous possibilities are the insoluble nature in aqueous media with high aggregation tendency [73]. But on the other side, there are several attempts have been done to overcome these problems. One of these attempts involving encapsulation in specific carriers such as calixarenes, micelles and liposomes. Other attempts used chemical functionalization methods with carboxylic acid, polyhydroxyl and

**101**

process will takes place [75].

**9.2 Nanodiamond-drug delivery system**

*Fullerenes and Nanodiamonds for Medical Drug Delivery*

killing cancer cells and other undesired cells [75].

amphiphilic polymers to increase the hydrophilicity property of these structures [73]. Furthermore, fullerene shows a nontoxic behavior which tend to decreasing with increasing surface functional groups, while the circulation and biodistribution property depending on the composition of the existing derivative groups. In addition, the presence of functional groups acts as a flexible interfaces for tuning the required drug delivery and its action besides the size of fullerenes even with their

Both exohedral fullerene which have additional atoms, ions, or clusters attached its outer spheres structure and endohedral fullerene which have additional atoms, ions, or clusters enclosed within its inner spheres structure, have been employed in nanomedicine field as drug carriers. Endohedral fullerene and its derivatives can used to deliver atoms or ions in biological systems, for example, metallofullerene can be serve as drug delivery depending on the composition and properties of the trapped metal within its structure [75]. Depending on the type of functional groups, exohedral fullerene can be exist in three main forms. The first one is called surface- derivative fullerene, the biological action of this type is driven from the inherent properties of its structure such as: their size, reactive property and photochemistry property. The candidate application for this type is as antioxidants systems due to its electronegative nature in association with its reaction ability with different radicals. So, this type work as antioxidants radicals' scavenger. Furthermore, surface- derivative fullerene can be used to generate a reactive- oxygen species by light irradiation, so this type is useful as photodynamic therapy for

The second type of exohedral fullerene is known as covalently fullerene. In this type, the derivative surface of fullerene is directly connected to the pharmaceutical activated compounds via covalent bonds. This fullerene molecule has unique biofunctions with biological body such as drug release with selective targeting at the same time. For example, C60- paclitaxel fullerene used in lung cancer treatment [76], here the paclitaxel has been conjugated to C60 derivative via hydrolysableester- group linker used for slow release of drug to the diseased cells [76]. Furthermore, this type of fullerene has high tendency to attach covalently with different biological relevant like sugar, cholesterol, carbohydrates and others [76]. The third type of exohedral fullerene is called non- covalently fullerene. Here, fullerene and its derivatives tend to form a complex species via a wide variety of interactions. These interactions could be exist as pi-pi interaction, van der Waals interaction, electrostatic interaction, hydrophobic interaction and it could be exist as a hydrogen bonding. An example of using this type of fullerene in nanomedicine is the protease inhabitation of Human Immunodeficiency Virus (HIV) [77] by C60 fullerene of this type. The active catalytic sites of HIV protease enzyme is as a hydrophobic bag with a 1 nm diameter which is very close to the size of C60 molecule. Hence, this fullerene will bind with the active sites and virus inhabitation

Nanodiamonds are one of the most interesting material in nanomedicine have the ability to conjugate with different drug molecules [48]. This fact is born out of their unique structure and properties. High surface flexibility, small size, high surface area and functionalization ability with different molecules besides their biocompatibility which is more than that of other carbon based- nanomaterials like fullerene and carbon nanotubes. All these features make ND as an attractive tool for both in vivo and in vitro applications [38, 50, 78, 79]. Conversely, there are many concerns and challenges related to their structure and nature toward their

derivatives are still smaller than other types of nanoparticles [73, 74].

*DOI: http://dx.doi.org/10.5772/intechopen.97867*

#### *Fullerenes and Nanodiamonds for Medical Drug Delivery DOI: http://dx.doi.org/10.5772/intechopen.97867*

*Materials at the Nanoscale*

nanomedicine which regarded as a tool enabled doctors to reach the human body at

It is believed that this technology will have a great impact on the health care field via its effect on the sickness diagnosing and treating [67, 68]. There are several features of using nanotechnology in medical field, for example, when it is used for drug delivery, this technology will protect drug from degradation within human body before reaching the target also, it is improving drugs absorption into the diseased cells and at the same time it give assurance that there is no any interactions

Therefore, nanomedicine is one division of nanotechnology and nanoscience has the ability of treating the diseased and damaged cells or organs within human body at the cellular and molecular levels via nano-devices and nano-structured materials [68]. There are three main sectors within nanomedicine: Nano- diagnosis, which involving detection and analysis of the diseased cell using different devices such as imaging devices. Nano- therapy, this sector involving the direct transfer or delivery of drugs to the diseased cells with the least possible of side effects. And the last one is renovated medicine, which involving fixation and replacement the deteriorated parts within human body using different nano-devices and nanomaterials [67]. In the following we will discuss the role of carbon based- nanomaterials

the molecular and cellular levels and treat the damaged tissues [67].

between drugs and the healthy cells [67, 68].

(fullerene and nanodiamond) as a drug delivery systems.

and renal damage and other toxicity effects [67].

**9.1 Fullerene-drug delivery system**

**9. Significance of carbon based- nanomaterials in drug delivery**

ability as well as their surface atoms or molecules. In fact, all these features

shelf- time, anti- clotting property and bio- degradability [71].

determine their ability for binding, carrying and adsorbing other compounds or in other words these features determine their pharmacology behavior [70–72].

Furthermore, the main characteristics that nanomaterials should have to be use in drug delivery systems are high- solubility, bio- compatibility, bio- availability, bio- distribution and targeting ability, drug incorporation and release ability, their

Some of the most interesting characteristics of fullerene are their size, electronic

configuration, hollow and cage structure, their inertness and surface modification ability that offer the utilization of using fullerene in biological and medical chemistry fields and open new horizons in nanomedicine [73]. The main problems facing the previous possibilities are the insoluble nature in aqueous media with high aggregation tendency [73]. But on the other side, there are several attempts have been done to overcome these problems. One of these attempts involving encapsulation in specific carriers such as calixarenes, micelles and liposomes. Other attempts used chemical functionalization methods with carboxylic acid, polyhydroxyl and

Generally, the suitable choice of nano- drug delivery systems aids to overcome many health issues usually associated with using traditional treatment strategies. For example, in the case of cancer chemotherapy, the traditional strategies leads to several undesired side effects such as suppression of bone marrow, hair loss, gastric

On the other side, there are many features and reasons related to the nature and structure of nanomaterials make it as an attractive subject for intense bio-studies from one side and as an attractive materials for drug delivery systems from a other side [69, 70]. The most significant features are: their quantum property, their sizes which determine their in vivo and in vitro behavior, their structure and aggregation

**100**

amphiphilic polymers to increase the hydrophilicity property of these structures [73]. Furthermore, fullerene shows a nontoxic behavior which tend to decreasing with increasing surface functional groups, while the circulation and biodistribution property depending on the composition of the existing derivative groups. In addition, the presence of functional groups acts as a flexible interfaces for tuning the required drug delivery and its action besides the size of fullerenes even with their derivatives are still smaller than other types of nanoparticles [73, 74].

Both exohedral fullerene which have additional atoms, ions, or clusters attached its outer spheres structure and endohedral fullerene which have additional atoms, ions, or clusters enclosed within its inner spheres structure, have been employed in nanomedicine field as drug carriers. Endohedral fullerene and its derivatives can used to deliver atoms or ions in biological systems, for example, metallofullerene can be serve as drug delivery depending on the composition and properties of the trapped metal within its structure [75]. Depending on the type of functional groups, exohedral fullerene can be exist in three main forms. The first one is called surface- derivative fullerene, the biological action of this type is driven from the inherent properties of its structure such as: their size, reactive property and photochemistry property. The candidate application for this type is as antioxidants systems due to its electronegative nature in association with its reaction ability with different radicals. So, this type work as antioxidants radicals' scavenger. Furthermore, surface- derivative fullerene can be used to generate a reactive- oxygen species by light irradiation, so this type is useful as photodynamic therapy for killing cancer cells and other undesired cells [75].

The second type of exohedral fullerene is known as covalently fullerene. In this type, the derivative surface of fullerene is directly connected to the pharmaceutical activated compounds via covalent bonds. This fullerene molecule has unique biofunctions with biological body such as drug release with selective targeting at the same time. For example, C60- paclitaxel fullerene used in lung cancer treatment [76], here the paclitaxel has been conjugated to C60 derivative via hydrolysableester- group linker used for slow release of drug to the diseased cells [76]. Furthermore, this type of fullerene has high tendency to attach covalently with different biological relevant like sugar, cholesterol, carbohydrates and others [76].

The third type of exohedral fullerene is called non- covalently fullerene. Here, fullerene and its derivatives tend to form a complex species via a wide variety of interactions. These interactions could be exist as pi-pi interaction, van der Waals interaction, electrostatic interaction, hydrophobic interaction and it could be exist as a hydrogen bonding. An example of using this type of fullerene in nanomedicine is the protease inhabitation of Human Immunodeficiency Virus (HIV) [77] by C60 fullerene of this type. The active catalytic sites of HIV protease enzyme is as a hydrophobic bag with a 1 nm diameter which is very close to the size of C60 molecule. Hence, this fullerene will bind with the active sites and virus inhabitation process will takes place [75].

#### **9.2 Nanodiamond-drug delivery system**

Nanodiamonds are one of the most interesting material in nanomedicine have the ability to conjugate with different drug molecules [48]. This fact is born out of their unique structure and properties. High surface flexibility, small size, high surface area and functionalization ability with different molecules besides their biocompatibility which is more than that of other carbon based- nanomaterials like fullerene and carbon nanotubes. All these features make ND as an attractive tool for both in vivo and in vitro applications [38, 50, 78, 79]. Conversely, there are many concerns and challenges related to their structure and nature toward their

interactions with the living cells. Therefore, this situation requires many in- depth studies about the interaction nature between ND particles and the living cells. For example, some types of ND have a strong tendency to aggregate in specific medium which hindering and limiting their applications [48]. In fact, this aggregation tendency is related upon some synthesis techniques leads to produce ND particles with high dangling bonds on their surface such as detonation technique [48]. Hence the free electrons of the surfaces tend to form many functional groups and then these functional groups tend to form covalent bonds with the primary particle forming core- aggregates [48]. On the other side, the existing of sp2C around ND leads to bond these particles together into core aggregate [48].

Several methodologies have been carried for disintegration process, the most attractive one is the beads assisted sonication method which involving the double actions of shear force (induced by using zirconia beads) and cavitation effect (induced by ultrasound waves). The results shows colloid stability for one year after sonication for one hour [80]. While surface functionalization process has been recommended as an active way to reduce the aggregation size of ND. In fact there are several surface functionalization techniques, one of them involving generating specific surface radicals which then will act as a substrate used for synthesis of ND with carboxylic acid and dicarboxylic acid functionalization [48].

From a biocompatibility point of view, several studies have been demonstrated that ND toxicity can be varied and it is affected by surface chemistry of ND, cell- line type and the composition of treatment medium. In this field, the mitochondrial activity and the inflammatory activity of the cell have been used as toxicity indicator. So depending on these keys and the results of many clinical experiments, it was found that there is no manifestation of toxicity with ND dose (100 μg/ml concentration) after 24 hour of incubation period [81]. In addition, ND with high loading capacity, payload with high concentrations is allowed via using less delivery agents in association with the ability of releasing the cargo from the carrier in controlled manner, these two important features of ND developing the bio- applications of them either for small molecules delivery or for bio- technology product delivery [48].

In 2007, the suitability of ND particles as a delivery agent of doxorubicin hydrochloride (DOX) was studied by H. Huang et al. [81]. The study was based on the rationale that the surface carboxylic and hydroxylic groups of ND can interacts with the amine groups of DOX via ionic- forces when dispersing them in aqueous medium. The surface loading of DOX on ND particles was increased from 0.5 to 10 wt% via addition of 1% solution of sodium chloride to their aqueous dispersion, and the removal of salt favored the release of DOX. ND particles loaded with DOX were recommended to assemble in the form of loose- clusters, such that a certain amount of DOX adsorbed on the ND particle's surface resides within the cavity of the cluster [81].

This methodology of drug- entrapment in loose aggregates of ND particles could provide a feature by minimizing the systemic adverse effects of the naked- DOX. Thus, ND-based delivery systems could overcome the problem to the use of high concentrations of chemotherapeutic drugs in cancer treatments. In addition, the lower levels of cytotoxicity of the ND-DOX composites in mouse macrophages and human colorectal cancer cells compared with bare DOX in a 48-hour period could be beneficial in sustained drug release [81]. The potential of using ND particles as a targeted protein-delivery- vehicle was investigated in a pH-dependent system. By means of the physical- adsorption, ND particles achieved a considerable high surface loadings of bovine insulin about80% in pH-neutral water with a weight ratio of 1:4 of insulin:ND. Also, the aggregation properties of the insulin improved after interacting with ND particles. This propose that ND particles have the ability to

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**Author details**

Basma H. Al-Tamimi\* and Saad B.H. Farid

provided the original work is properly cited.

Department of Materials Engineering, University of Technology, Baghdad, Iraq

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: 130074@uotechnology.edu.iq

*Fullerenes and Nanodiamonds for Medical Drug Delivery*

facilitate the formation of a uniform-sized complex. Further, the release of insulin from the ND particle's surface was about 20- times higher when at a pH of about 10.5 than when in a neutral pH medium. Another advantage of using ND particles is the viability of cells, this effect had been observed with sodium hydroxide treated ND-insulin higher than what observed in neutral pH treated ND-insulin. Hence, the inherent and enhanced characteristics of ND particles make them as an active

In summary, fullerene and nanodiamonds have been studied for drug delivery applications. Fullerenes and nanodiamonds are attractive allotropes in the carbon nanomaterials family. They can be synthesized with attractive properties in higher purity, higher surface homogeneity, and different surface functionalization and in controlled sizes that make them essential in nanomedicine fields. Utilization of fullerenes and nanodiamonds in drug delivery systems show higher advantages with enhanced targeted delivery and controlled drug release ability than other traditional strategies. But on the other side, further in-depth research about toxicity concerns are necessary in order to achieve the full advantages of utilization these

*DOI: http://dx.doi.org/10.5772/intechopen.97867*

tool in drug delivery systems [48].

nanomaterials in human body.

**10. Conclusion**

*Fullerenes and Nanodiamonds for Medical Drug Delivery DOI: http://dx.doi.org/10.5772/intechopen.97867*

facilitate the formation of a uniform-sized complex. Further, the release of insulin from the ND particle's surface was about 20- times higher when at a pH of about 10.5 than when in a neutral pH medium. Another advantage of using ND particles is the viability of cells, this effect had been observed with sodium hydroxide treated ND-insulin higher than what observed in neutral pH treated ND-insulin. Hence, the inherent and enhanced characteristics of ND particles make them as an active tool in drug delivery systems [48].
